0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Article |

Functional Magnetic Resonance Imaging Investigation of the Amphetamine Sensitization Model of Schizophrenia in Healthy Male Volunteers FREE

Owen Gareth O’Daly, MSc, PhD; Daniel Joyce, PhD; Klaas Enno Stephan, MD, Dr med, PhD; Robin McGregor Murray, FRS, MD, DSc, FRCP, FRCPsych, FMedSci; Sukhwinder S. Shergill, BSc, MBBS, FRCPsych, PhD
[+] Author Affiliations

Author Affiliations: Cognition, Schizophrenia and Imaging Lab, Department of Psychosis Studies (Drs O’Daly, Joyce, and Shergill and Prof Murray), and Centre for Neuroimaging Sciences, Department of Clinical Neuroscience (Dr O’Daly), Institute of Psychiatry, King's College London, and Wellcome Trust Centre for Neuroimaging, Institute of Neurology, University College London (Prof Stephan), London, England; and Laboratory for Social and Neural Systems Research, Institute of Empirical Research in Economics, University of Zurich, Zurich, Switzerland (Prof Stephan).


Arch Gen Psychiatry. 2011;68(6):545-554. doi:10.1001/archgenpsychiatry.2011.3.
Text Size: A A A
Published online

Patients with schizophrenia, and those with stimulant-induced psychosis, commonly display stress hypersensitivity and a profoundly reduced threshold for the psychotogenic action of stimulant drugs.17 These effects have been linked to enhanced drug-induced striatal dopamine release.810 Rodents receiving repeated intermittent amphetamine exposure display a similar “sensitization” to stress,11,12 the psychomotor stimulatory effects of the drug,1319 and the elevation of striatal dopamine levels.20 Thus, amphetamine sensitization in rodents is used to model some aspects of schizophrenia.

It is well established that patients with schizophrenia have significant cognitive deficits in various domains, including working memory (WM), executive control, attention, affective processing, and learning.2123 This is a challenge for the amphetamine sensitization model in rodents because while sensitization does alter some aspects of rodent function, including prepulse and latent inhibition24,25 and attentional set-shifting,26,27 there is little evidence that sensitized rodents display deficits in, for example, WM where patients are severely impaired.26,28,29 In contrast, sensitized primates do display profound deficits in spatial delayed response (a test of spatial WM) linked to reduced dopamine turnover in the cortex30 in addition to a complex set of aberrant behaviors more akin to schizophrenia,3032 including hypervigilance and hallucinatory-like activity. In general, the literature shows that the amphetamine model of sensitization replicates a proportion of the cognitive deficits associated with schizophrenia.

In the cortex, dopamine signaling within a narrow “optimal” range enhances cortical efficiency,3335 acting to reduce physiological noise and enhancing the signal to noise ratio for salient or sustained prefrontal cortical inputs.36,37 Notably, both overstimulation and understimulation of cortical D1 receptors are equally detrimental to cognitive performance. It has been suggested that a reduction, rather than an excess, in prefrontal cortical dopamine signaling gives rise to the cognitive dysfunction seen in patients.38,39 However, the compensatory upregulation of cortical D1 receptors seen in patients38 would also render patients hypersensitive to drug- or stress-related elevation of cortical dopamine.40 Following amphetamine administration, healthy controls homozygous for the Val158Met polymorphism of the catechol-O-methyl transferase gene (COMT) display a similar pattern of relatively inefficient prefrontal recruitment (ie, hyperactivity to maintain the same performance level) during a high-load WM task.41 This effect is reminiscent of frontal and striatal hyperactivity seen in patients with schizophrenia during a similar task.42,43

Beyond cognitive performance, dorsolateral prefrontal cortex (DLPFC) hyperactivity is also seen in patients with acute psychosis44,45 and in healthy volunteers following the administration of hallucinogenic agents,4649 suggesting that this cortical region plays an important role in the genesis of psychosis.50 Indeed, while prefrontal lesions block behavioral (locomotor) sensitization in rodents, such ablation in primates impedes only the sensitization of hallucinatory-type behavior and in fact enhances psychomotor sensitization.51 Such findings suggest important between-species differences in prefrontal function and, implicitly, frontostriatal connectivity, with particular respect to the expression of psychosis-like behaviors.52

Contemporary cognitive models of schizophrenia emphasize the importance of disrupted cortico-cortical integration (eg, frontotemporal dysconnectivity)5357 over dopamine dysregulation in the development of psychotic symptoms.58 A central challenge for the field is to marry pharmacological and cognitive perspectives of the disorder. For example, dopaminergic medication can partially normalize abnormal frontal activity,59,60 and recent pathophysiological theories of schizophrenia emphasize the importance of dopamine-dependent regulation of synaptic plasticity.6163 Thus, dopamine-sensitive cortical circuits represent attractive targets for translational modeling using amphetamine sensitization. Recently, both behavioral (eye-blink) and neurochemical sensitization of striatal dopamine have been robustly demonstrated in healthy volunteers.64 However, in contrast to the extensive animal literature, a neurophysiological examination of the effects of amphetamine sensitization on brain function in humans is still lacking. Herein, we explore the effects of a sensitizing regimen of amphetamine on brain activity during a WM task using language stimuli (letters). Given the extensive literature on schizophrenic abnormalities in frontotemporal areas during language processing5357 and in frontostriatal circuitry during executive control processes like WM,42,65 we put a particular emphasis on the prefrontal cortex, striatum, and temporal cortex, which were used as regions of interest in our functional magnetic resonance imaging (fMRI) analyses. Explicitly, we tested the hypotheses that (1) repeated placebo administration will not be associated with any significant changes in cortical functioning, (2) a sensitizing regimen of amphetamine will lead to reduced efficiency in cortical function, evident as increased prefrontal activity in the high-load condition,41 and (3) this prefrontal dysfunction will be associated with dysregulation of the temporal ipsilateral lobe

Twenty-two right-handed male volunteers (mean [SD] age, 30.8 [8.5] years) were recruited and assigned to receive either 4 oral doses of dexamphetamine (20 mg) or 4 doses of a placebo, using the same pattern of amphetamine administration, albeit with a fixed dose across all participants, as that used by Boileau et al.64 Subjects received the first 3 doses with a 48-hour interdose interval (sessions 1-3) and again (fourth dose) after a 2-week washout period (session 4) using a double-blind procedure. Participants were excluded if they had personal history of psychiatric or neurological disorders, were taking any medications, or had a family history of mental illness or substance abuse problems. Furthermore, on each visit, a drug-urine analysis was carried out to exclude the use of recreational drugs. Subjects were scanned approximately 120 minutes postadministration during sessions 1 (short-term exposure) and 4 (repeated/sensitized exposure) in an effort to model the effects of sensitization-related dopaminergic dysregulation on the neural substrates of WM. Participants additionally performed a rewarded decision-making task and an explicit motor sequence learning task. The data from these paradigms are not included herein and will be the subjects of separate articles. The project was approved by the Institute of Psychiatry research ethics committee (REC ref 022/03).

DATA ACQUISITION

Imaging was performed with a 1.5-T GE scanner (GE Healthcare, Milwaukee, Wisconsin). One hundred eighty volumes (matrix size 64 × 64) with whole-brain coverage were acquired during each functional run. Each volume comprised 36 slices, collected in an interleaved manner, with a slice thickness of 3 mm, with an additional 0.3-mm gap between slices. The repetition time was 3 seconds, echo time = 40 milliseconds, and flip angle = 90°. Total acquisition time was 9 minutes (540 seconds). High-resolution structural scans were also acquired (spoiled gradient recalled and high-resolution gradient echo).

N-BACK WM TASK

While lying in the scanner, subjects performed a standard blocked N-back WM task using visually presented letters.66 This task involved 9 alternating 30-second blocks of WM, with 4 levels of difficulty (N = 0, 1, 2, or 3). In the control condition (N = 0), subjects were asked to press the button whenever they saw the letter X. Subjects were informed at the start of each 30-second block as to the nature of the response required (N = 0, 1, 2, or 3). Stimuli were presented with an International Sensitivity Index of 2000 milliseconds.

ANALYSIS
Assessment of Sensitization

During each visit, self-reported subjective drug effects were assessed using the Addiction Research Center Inventory (ARCI) Amphetamine Scale,6769 the Profile of Mood States,70 and Visual Analog Mood Scales71 at baseline and every 60 minutes for 240 minutes. When completing these ratings, subjects were asked to score each item for “how they feel at the present moment” and the questionnaires were administered hourly. Physiological data including eye-blink rate, pulse, and blood pressure were also collected by the same researcher in the same environmental context. Pulse and blood pressure were collected seated following a resting period of 5 minutes using an electronic sphygmomanometer. Eye-blink rate was taken as the average number of blinks counted over a 3-minute period while subjects were at rest; participants were not explicitly informed when this measure was being collected.

We expected the expression of behavioral (subjective) sensitization would mirror previous findings.64,7274 While there is some divergence between the findings of Boileau et al64 and Strakowski et al,7274 we expected to see enhanced amphetamine-like experience, amphetamine-induced euphoria (ARCI–Morphine Benzedrine Group Scale), and Profile of Mood States activity-vigor, alertness and attentiveness, and positive affect (happy-sad subscale). Physiologically, we expected that the resting eye-blink rate would show sensitization.

For statistical analyses of each dependent variable, a group × administration/day analysis of variance (ANOVA) with repeated measures on the second factor was used. The group factor had 2 levels (amphetamine vs placebo), and administrations had 4 levels (day 1, 3, 5, and 19). The chosen level of significance was P < .05 with Greenhouse-Geisser correction. All calculations were performed using SPSS version 12.1 for Windows (SPSS Inc, Chicago, Illinois).

Behavioral Analyses

A repeated-measures ANOVA (group × time × load) was used to test for any significant between-group differences in both performance accuracy (false-positives and misses) and reaction time. Additional post hoc paired t tests were used to test specific hypotheses in the amphetamine group. To confirm a relationship between behavioral and subjective sensitization, we tested for correlations between both sensitized measures after correcting for individual differences in intersession plasma amphetamine concentration. All calculations were performed using SPSS version 13 for Windows (SPSS Inc).

fMRI Analysis

After preprocessing, including realignment, image distortion correction,75,76 and normalization, statistical analysis was carried out using the general linear model77,78 as implemented in Statistical Parametric Mapping 2 (Wellcome Trust Centre for Neuroimaging, London, England). Each subject's echoplanar imaging data were normalized to a Montreal Neurological Institute (MNI) T1 template. Our model coded separate regressors for each of the 4 conditions (control, 1-back, 2-back, and 3-back). The blood oxygen level–dependent (BOLD) response was convolved with a canonical hemodynamic response function.79 The data were high-pass filtered (cutoff 128 seconds) and corrected for serial correlations using a first-order autoregressive model.

At the group level, we performed a random-effect analysis. Images of parameter estimates for each of the 4 conditions of interest (N = 0, 1, 2, and 3) from the first-level analysis were entered into the second level of analysis using 2-sample t tests to compare groups (placebo vs amphetamine). Separate 4 × 2 ANOVAs (F tests) were used to test for a main effect of time (session) and a time × condition interaction in each group. Finally, because we expected the hypothesized cortical inefficiency to be most apparent during a high-load WM challenge, a paired t test (within-group session 1 vs session 2 comparison) was used to probe the effects of sensitization during this primary condition of interest (N = 3). In the case of ANOVAs, contrasts were calculated according to the Henson and Penny technical note “ANOVAs and SPM” (http://www.fil.ion.ucl.ac.uk/~wpenny/publications/rik_anova.pdf).

Statistical parametric maps of the t statistic were constructed using a generalized Greenhouse-Geisser correction. For both F tests and t tests, statistical parametric maps were thresholded at P < .05 following familywise error correction for multiple testing in predefined volumes of interest. To test our primary hypothesis regarding the reduction in frontal cortical efficiency, a priori regions of interest were defined on the basis of the results of Mattay et al,41 wherein amphetamine-induced cortical hyperactivity was seen during a high-load cognitive challenge in methionine homozygotes for the Val158Met polymorphism of the COMT gene (Met/Met). However, because we had no explicit hypothesis regarding laterality of any sensitization effect, the image used for small-volume correction included 15-mm spheres covering the left middle frontal gyrus41 and a second sphere in the opposite hemisphere. Additionally, the striatum was defined according to Mawlawi et al.80 Given the paucity of literature on amphetamine-induced dysregulation of temporal lobe activity in healthy controls, a conservatively defined (ie, large) region of interest including the superior temporal gyrus (STG) bilaterally, drawn from the Automated Anatomical Labeling Toolbox,81 was used.

To establish that changes in BOLD responses were related to sensitization-related processes, rather than simply a consequence of drug tolerance, we tested for correlation between subjective measures of sensitization and the mean signal in the right prefrontal region of interest and the anatomically defined striatal regions of interest. At the group level, there were no significant differences in mean plasma amphetamine levels across the 2 sessions, suggesting that our group effects did not reflect dosage differences. Because we had used a standard dose for all subjects, we controlled for individual differences in intersession plasma amphetamine concentration in these correlational analyses (using partial correlation).

Group × session interactions identified sensitization-related changes (enhancement confirmed with post hoc t tests) in both amphetamine-like experiences (ARCI Amphetamine Scale: F2.5,49.8 = 4.15; P < .02) (Figure 1). Unlike Boileau et al,64 but in keeping with findings of Strakowski et al,7274 drug-induced euphoria was also sensitized (ARCI–Morphine Benzedrine Group Scale [euphoria]: F2.3,46.3 = 5.13; P < .009). Furthermore, subjective vigor (Profile of Mood States activity-vigor subscale: F2.8,55.8 = 3.73; P < .02), alertness (Visual Analog Mood Scales alert-drowsy subscale: F = 4.15; P < .02), and attentiveness (Visual Analog Mood Scales attentive-dreamy subscale: F3,32.4 = 3.99; P < .02) were also significantly enhanced following sensitization. These effects were relatively robust and were evident in at least 7 of 11 participants in each case. Neither eye-blink rate (F2.5,50.9 = 1.49; P < .63), a commonly used index of psychomotor activity, nor cardiovascular parameters (pulse: F3,50 = 1.49; P < .23; blood pressure: F2.2,44.4 = 0.18; P < .85) were sensitized following repeated amphetamine exposure.

Place holder to copy figure label and caption
Figure 1.

Subjective effects of amphetamine sensitization. A, Group × session interaction for the subjective reports of amphetamine-like experience. ARCI indicates Addiction Research Center Inventory. B, Session × hour measures of amphetamine-like effects in the amphetamine group. C, The significant correlation between the sensitization of amphetamine-like experiences (difference between peak amphetamine-like experiences scores at sessions 1 and 4) against the sensitization of reaction time. PC indicates plasma concentration.

Graphic Jump Location

We tested whether task performance was sensitive to group (treatment), session (first and last dosing), or WM load using a repeated-measures 4 × 2 × 2 ANOVA for correct responses and reaction time and found evidence for a main effect of WM load on task accuracy (F2,41 = 1932.9; P < .001) and response time (F2,38 = 32.7; P < .001). No significant interactions were found. However, because we expected sensitization to be linked with psychomotor stimulation only, we tested the corresponding simple main effect and found that the amphetamine group was faster on session 4 (postsensitization) than on session 1 (short-term exposure) (t10 = 2.398; P < .02 [1-tailed]). Interestingly, the sensitization of reaction time was most pronounced in the medium-load condition (2-back) (t10 = 3.79; P < .002 [1-tailed]) (eFigure 1). Importantly, this sensitization of reaction time during the medium-load condition was significantly correlated with the sensitization of the subjective “amphetamine-like” experience after correcting for individual differences in plasma amphetamine concentration at the 2 sessions (as measured by the ARCI score for amphetamine; partial correlation coefficient of 0.727; P < .009) (Figure 1). Together, these data suggest that there may be a common neural substrate for the behavioral and subjectively perceived aspects of sensitization.

The fMRI data showed a similar load-dependent network during memory performance in both the placebo and amphetamine groups (eFigure 2, eTable 1, and eTable 2). No significant differences were seen between the placebo and amphetamine groups on day 1 (presensitization). Similarly, no main effect of session, or session × WM load interaction, was seen in the placebo group. However, in the amphetamine group, activity in the right STG showed a significant main effect of time (MNI coordinates 60, −9, and 6; P < .05 corrected), with activity in this region elevated following sensitization, compared with the first session (short-term exposure) (Table 1 and Table 2). A significant interaction between session and WM load was also evident in the STG in this group, although the cluster extended into the operculum and putamen (MNI coordinates 60, −9, and 6; P < .007) (Figure 2 and Table 1). In particular, in the STG BOLD signal decreased with greater WM load following short-term exposure (day 1), whereas it increased at the highest load following sensitization (Figure 2A).

Place holder to copy figure label and caption
Figure 2.

Effects of sensitization on N-back–related blood oxygen level–dependent responses. A, The red brain regions' activity shows a main effect of session (time) in the amphetamine group whereas the yellow regions show a significant load × session interaction (for display purposes, results are shown at P < .001 uncorrected, with a cluster threshold of 30 contiguous voxels). B, For visualization of the nature of the interaction, the parameter estimates extracted from the peak voxel in the right superior temporal gyrus (rSTG) are plotted (Montreal Neurological Institute coordinates 60, −9, and 6). This demonstrates a load-dependent failure of the normal suppression of the STG, with increasing demands on the working memory system.

Graphic Jump Location
Table Graphic Jump LocationTable 1. Amphetamine Effect of Time and Load × Time Interactiona
Table Graphic Jump LocationTable 2. Amphetamine Paired t Test Session 4 Greater Than Session 1 (High-Load Working Memory Task Greater Than Control)a

We scrutinized this interaction further by testing for a simple main effect of time under a high-load WM task, contrasting the effects of amphetamine exposure following sensitization with those after short-term exposure. This contrast confirmed a significant increase of BOLD activity within the right STG (MNI coordinates 57, −12, and 12; P < .04). The same increase was found in the right DLPFC (MNI coordinates 33, 48, and 30; P < .02), and there was a trend toward significance within the striatum (MNI coordinates 15, 15, and 9; P < .06). As explained in the “Methods” section, these results were based on height-level correction for multiple comparisons within predefined volumes of interest. Notably, however, all 3 regions (and an additional 2 regions within the right hemisphere, thalamus, and precuneus) survived a whole-brain correction for multiple comparisons at the cluster level (Figure 3 and Table 2). This amphetamine-induced hyperactivity in the prefrontal cortex, striatum, and thalamus during a high-load WM challenge shows striking parallels to previous findings of abnormally high activity in these regions in schizophrenic patients performing a similar WM task.42

Place holder to copy figure label and caption
Figure 3.

Effect of sensitization on blood oxygen level–dependent response to a high-load cognitive challenge. A, The red brain regions' activity is elevated during the high-load condition following amphetamine sensitization (P < .05 whole-brain corrected at the cluster level, with a voxel-level threshold of P < .001). B, The negative correlation between sensitization of positive affect (Visual Analogue Mood Scales [VAMS] happy-sad subscale) and the change in striatal activation during the high-load working memory challenge. C, The positive correlation between sensitized alertness and the change in prefrontal activity during the high-load working memory challenge.82 PC indicates plasma concentration.

Graphic Jump Location

Finally, the increase in prefrontal activity following sensitization was evident in 10 of 11 individual participants. Furthermore, the change in prefrontal BOLD signal was positively correlated with the sensitization of subjective alertness (after controlling for between-session differences in amphetamine plasma concentration; partial correlation coefficient of 0.657; P < .02 [1-tailed]) (Figure 3B and C). The right striatum showed correlation with the sensitization of subjective happiness (Visual Analog Mood Scales happy-sad subscale), although surprisingly it reflected a negative relationship (r = −6.08; P < .04 [2-tailed]), but was at trend significance following correction for individual differences in drug concentration (partial correlation coefficient of −6.08; P < .06 [2-tailed]).

The sensitization of subjective measures seen herein is in keeping with earlier observations of enhanced amphetamine-like experiences, euphoria, happiness, activity-vigor, and attentiveness.64,7274 We suggest that the dosage pattern used herein produces a robust sensitization. This is supported by the first demonstration, to our knowledge, of a functional consequence of experimentally induced sensitization in humans, ie, faster cognitive performance. Within the context of the study design, it is not possible to determine whether this reaction time effect reflects simple psychomotor sensitization, enhanced motor readiness, attentional processing, or increased motivation to perform. However, the lack of faster responding during control and low-load conditions would argue against a simple psychomotor speeding. Furthermore, the lack of significant enhancement during the high-load condition suggests that this performance benefit is dependent on efficient prefrontal cortical recruitment.

When exploring the fMRI data in the amphetamine group, a simple main effect of time contrast, across all loads, was associated with increased BOLD signal in the right STG, precuneus, rolandic operculum and insula, putamen, cerebellum, and a number of areas on the ventral visual pathway. We will discuss the STG and precuneus in greater detail later. However, because these other regions were not predicted a priori, it is hard to be definitive about these effects. Nonetheless, the evidence for changes in motor networks (ie, putamen and cerebellum) is consistent with the speeding of reaction times following sensitization and the role of dopamine in motor function. Furthermore, the enhancement of the ventral visual pathway (ie, fusiform and inferior temporal gyri) could be indicative of enhanced attentional processing following sensitization.

We also observed a significant load × time interaction in the right STG and precuneus activity during our verbal WM paradigm (N-back). The left-lateralized homologues of these 2 regions, in addition to the middle frontal gyrus (DLPFC) and anterior cingulate cortex,83 subserve verbal fluency performance.84 Numerous neuroimaging studies of schizophrenia have demonstrated disruption of this network across a number of different paradigms,55,8588 often in a load- or state-dependent manner.54,87,89 Importantly, some evidence suggests that disruption of this network, and associated failure to suppress temporal lobe activity in the face of frontal hyperactivity, may be linked to elevated cortical dopamine transmission, rather than hypodopaminergia.59,60 Further examination has demonstrated a dynamic pattern of effective connectivity within this network during task performance, with the prefrontal cortex modulating cingulate function and frontotemporal connectivity, possibly via the precuneus.84 Our findings could reflect a similar process in the right hemisphere, where increased cognitive demand might lead to failure in recruiting the cingulate and thus an inability to maintain prefrontal cortical suppression of the STG.

We failed to identify a significant load × session interaction in the DLPFC. This may be because of the complex nonlinear relationship known to exist between prefrontal neuronal recruitment, baseline cortical dopamine levels, task difficulty, and performance.22,41,90 When the high-load condition was examined in isolation, we found that sensitization was associated with prefrontal hyperactivity, in the absence of any performance deficits. Ten of the 11 participants in each group in this study were heterozygous for the Val/Met polymorphism of COMT, and thus, variation in baseline dopamine level due to this polymorphism was theoretically minimized. In accordance with this intermittent (Val/Met) phenotype, we found that amphetamine and placebo groups showed very little difference in prefrontal activation during session 1 (short-term amphetamine exposure), with both groups demonstrating a linear recruitment of the prefrontal cortex up to the high-load condition, but importantly, neuronal recruitment diminished as WM capacity was exceeded (consistent with the inverted-U load-activity curve). The shifting of this curve to the left in patients with schizophrenia is thought to lead to the same hyperrecruitment, followed by hypoactivity, at far lower-load cognitive challenges (ie, hypofrontality). Our findings are suggestive of a similar frontal “inefficiency” as that seen in patients, albeit with a far smaller magnitude more akin to the effects of short-term amphetamine use in Met-Met homozygotes. Thus, the cortical effects of sensitization in humans are to some degree equivalent to those associated with gaining a COMT methionine allele (Val/Met to Met/Met).

Comparisons of amphetamine sensitization effects across species are complicated by several confounding factors, including differences in the source of prefrontal dopaminergic innervation91,92 or cortical dopamine kinetics.93 Primates display reduced cortical dopamine turnover following chronic exposure to amphetamine,30 although it has been suggested that a transient period of hyperresponsivity of the ascending dopamine system precedes the decline seen with chronic use.52 The cortical hyperactivity evident in our volunteers following brief exposure to amphetamine aligns with these suggestions.

Unlike the cortical inefficiency observed by Mattay et al,41 in addition to disrupting frontal and temporal activity, the hyperactivity seen during the high-load condition following sensitization was evident throughout the associative frontostriatal loop,94,95 similar to that seen in schizophrenia.42 Given the role of striatal dopamine signaling in modulating cortico-striato-thalamic activity, the hyperactivity of the caudate nucleus may be relevant for clarifying the origin of the concomitant observed frontal hyperactivity. In transgenic mice, Kellendonk et al96 have shown that selective upregulation of striatal D2 dopamine receptors produced a prolonged prefrontal dysfunction in rodents that was maintained even after the transgene had been switched off and striatal D2 receptors had normalized. This suggests that dysregulation of striatal D2 signaling can have a long-lasting deleterious effect on prefrontal development and functioning and that the prefrontal dysfunction evident in patients with schizophrenia, as well as sensitized animals, could arise from the dysregulation of striatal dopamine signaling. Such striatal dependency is also seen for the recruitment of the frontal lobes in patients with Parkinson disease. In this case, frontal hypoactivity, linked to reduced striatal dopamine, is only evident when task performance necessitates the recruitment of the caudate nucleus.83,97,98 In our study, the higher-load cognitive task demands greater manipulation of information and consequent caudate activation.99 Thus, the striatal recruitment, combined presumably with elevated striatal dopamine, would be expected to elicit the observed hyperactivation of the prefrontal cortex. This would accord with the recent observations in patients with schizophrenia that dopamine depletion unmasks significantly more D2 receptors, indicating higher basal dopamine function, in the associative rather than limbic portion of the striatum.100

Concerning the relation between neurophysiological consequences of amphetamine sensitization and subjectively perceived state, we found that subjective measures of sensitization-induced happiness were negatively correlated with striatal activity, while the DLPFC showed a positive correlation with subjective measures of alertness. The finding that subjective experience of sensitization does not correlate with DLPFC activity, but sensitized alertness does, accords with the role of the prefrontal cortex in mediating sensitization-induced hypervigilance in primates and suggests negative striatal correlation and two separate neural substrates of sensitized behavior.

Our present findings on the effects of amphetamine sensitization are of interest with regard to current pathophysiological theories of schizophrenia. Amphetamine has previously been shown to blunt striatal BOLD activity during the performance of a monetarily rewarded task,101 which sits well with the absence of striatal activity change in the current study. A mechanism underlying this could be an enhancement of well-established regulatory glutamatergic projections from the prefrontal cortex to the ventral tegmental area,102,103 a critical pathway for sensitization in rodents.104 This enhanced prefrontal influence on the ventral tegmental area would result in an augmentation of activity in GABAergic interneurons in the ventral tegmental area, suppressing dopaminergic mesostriatal transmission. N -methyl-D-aspartic acid–dependent synaptic plasticity plays a central role in regulating the strength of the glutamatergic projections from the DLPFC to the ventral tegmental area.105,106 Critically, this N -methyl-D-aspartic acid–dependent plasticity is modulated by dopamine itself, and this modulation has been proposed as a critical pathophysiological component in schizophrenia.63 Furthermore, the interaction between D1 dopamine and N -methyl-D-aspartic acid receptor signaling may play a vital role in determining the synaptic consequences of repeated stimulant exposure.52,107

Finally, the observed change in prefrontal activity during a high-load WM challenge after only 4 intermittent low-dose exposures to amphetamine suggests that the recent rapid growth in the use of psychostimulants to boost alertness108 or to enhance cognitive performance109 may necessitate caution, especially given that sensitization is still evident 1 year after cessation of amphetamine use64 and preliminary evidence demonstrates cross-sensitization with stress following this dosage regimen.110 While our data might be expected to speak to the long-term use of stimulants to treat attention-deficit/hyperactivity disorder, the evidence for elevated risk of psychosis in these patients is scant,111 especially considering the number of individuals using these drugs. It is likely that brain maturational processes in adolescents and the pattern of administration are not conducive to this form of neuroadaptation. In clinical practice, sensitization could offer one explanation for the relapsing nature of schizophrenia: while symptoms can be controlled by dopamine-blocking antipsychotic medication, they are still sensitive to any stress-induced perturbations. This may be because sensitized responses remain in place over a much longer period than the short-term effects of the stimulant drugs.

The primary limitation of this study is the relatively small sample size. Despite the small group size, we found that sensitization was associated with a significant change in frontostriatal and temporal BOLD signal in accord with our hypotheses and consistent with the observed role of dopamine modulation of cognitive function. The addition of placebo scans either presensitization or postsensitization would have permitted a more powerful within-subjects test for the main effect of amphetamine use (short-term) and could permit us to assess whether sensitization-related changes were evident without drug administration, indicating altered cortical sensitivity at baseline. However, the primary aim of this study was to assess whether the effects of amphetamine in a “sensitized brain” were different from short-term exposure, and the repeated-measures design ensured that we could test this directly. The degree to which sensitization alters baseline (ie, drug-free) brain function remains to be explored, although data suggest that sensitized volunteers also display an elevated placebo-induced dopamine release, consistent with a role for conditioning in the effects of sensitization.112 Finally, because of the small sample size, we limited ourselves to testing our primary (core) hypotheses. With a larger sample size, we could have carried out additional secondary examination of other interesting correlations with appropriate multiple-comparisons correction.

To conclude, we present herein the first demonstration, to our knowledge, of amphetamine sensitization-related changes in task performance and cortical functioning in healthy humans. As in nonhuman primates, striatal and cortical systems displayed separate, opposed, sensitization profiles. We found similarities between the neural substrates of sensitization-related changes in cognition in humans (eg, hyperactivity of DLPFC, striatum, and thalamus during a high-load WM challenge) and previous neuroimaging findings in patients with schizophrenia performing similar tasks. This implies that amphetamine sensitization may be a useful model for investigating pathophysiological processes in schizophrenia and may help to bridge theories that emphasize pharmacological (dopaminergic) and cognitive mechanisms, respectively.

Correspondence: Owen Gareth O’Daly, MSc, PhD, Centre for Neuroimaging Sciences, Institute of Psychiatry, King's College London, Denmark Hill, London SE5 8AF, England (o.o'daly@iop.kcl.ac.uk).

Submitted for Publication: June 25, 2010; final revision received September 30, 2010; accepted November 26, 2010.

Published Online: February 7, 2011. doi:10.1001/archgenpsychiatry.2011.3

Financial Disclosure: None reported.

Funding/Support: This study was supported by a generous grant from the Psychiatry Research Trust, a charitable foundation based at the Institute of Psychiatry, King's College London.

Additional Contributions: Jeff Dalton, MSc, David Gasston, and Christopher Andrew provided technical support. Gabi Samson, BSc, DClinPsy, and Panayiota Michalopoulou, MD, assisted with data collection. We thank the Psychiatry Research Trust for their generous financial support of Dr O’Daly and this study.

Angrist  BMGershon  S The phenomenology of experimentally induced amphetamine psychosis: preliminary observations. Biol Psychiatry 1970;2 (2) 95- 107
PubMed
Connell  PH Amphetamine Psychosis.  Glasgow, Scotland Chapman Hall for the Institute of Psychiatry1958;
Curran  CByrappa  NMcBride  A Stimulant psychosis: systematic review. Br J Psychiatry 2004;185196- 204
PubMed Link to Article
Lieberman  JAKane  JMAlvir  J Provocative tests with psychostimulant drugs in schizophrenia. Psychopharmacology (Berl) 1987;91 (4) 415- 433
PubMed Link to Article
Lieberman  JAKane  JMGadaletta  DRamos-Lorenzi  JBergmann  KWegner  JNovacenko  H Methylphenidate challenge tests and course of schizophrenia. Psychopharmacol Bull 1985;21 (1) 123- 129
PubMed
Lieberman  JASheitman  BBKinon  BJ Neurochemical sensitization in the pathophysiology of schizophrenia: deficits and dysfunction in neuronal regulation and plasticity. Neuropsychopharmacology 1997;17 (4) 205- 229
PubMed Link to Article
Segal  DSKuczenski  R Repeated binge exposures to amphetamine and methamphetamine: behavioral and neurochemical characterization. J Pharmacol Exp Ther 1997;282 (2) 561- 573
PubMed
Breier  ASu  TPSaunders  RCarson  REKolachana  BSde Bartolomeis  AWeinberger  DRWeisenfeld  NMalhotra  AKEckelman  WCPickar  D Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method. Proc Natl Acad Sci U S A 1997;94 (6) 2569- 2574
PubMed Link to Article
Laruelle  MAbi-Dargham  AGil  RKegeles  LInnis  R Increased dopamine transmission in schizophrenia: relationship to illness phases. Biol Psychiatry 1999;46 (1) 56- 72
PubMed Link to Article
Laruelle  MAbi-Dargham  Avan Dyck  CHGil  RD’Souza  CDErdos  JMcCance  ERosenblatt  WFingado  CZoghbi  SSBaldwin  RMSeibyl  JPKrystal  JHCharney  DSInnis  RB Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. Proc Natl Acad Sci U S A 1996;93 (17) 9235- 9240
PubMed Link to Article
Kalivas  PWRichardson-Carlson  RVan Orden  G Cross-sensitization between foot shock stress and enkephalin-induced motor activity. Biol Psychiatry 1986;21 (10) 939- 950
PubMed Link to Article
Piazza  PVDeminiere  JMle Moal  MSimon  H Stress- and pharmacologically-induced behavioral sensitization increases vulnerability to acquisition of amphetamine self-administration. Brain Res 1990;514 (1) 22- 26
PubMed Link to Article
Kalivas  PWDuffy  P Effect of acute and daily cocaine treatment on extracellular dopamine in the nucleus accumbens. Synapse 1990;5 (1) 48- 58
PubMed Link to Article
Kalivas  PWDuffy  P Time course of extracellular dopamine and behavioral sensitization to cocaine, I: dopamine axon terminals. J Neurosci 1993;13 (1) 266- 275
PubMed
Kalivas  PWDuffy  P Time course of extracellular dopamine and behavioral sensitization to cocaine, II: dopamine perikarya. J Neurosci 1993;13 (1) 276- 284
PubMed
Kalivas  PWSorg  BAHooks  MS The pharmacology and neural circuitry of sensitization to psychostimulants. Behav Pharmacol 1993;4 (4) 315- 334
PubMed Link to Article
Mueller  K Locomotor stereotypy is produced by methylphenidate and amfonelic acid and reduced by haloperidol but not clozapine or thioridazine. Pharmacol Biochem Behav 1993;45 (1) 71- 76
PubMed Link to Article
Paulson  PERobinson  TE Amphetamine-induced time-dependent sensitization of dopamine neurotransmission in the dorsal and ventral striatum: a microdialysis study in behaving rats. Synapse 1995;19 (1) 56- 65
PubMed Link to Article
Robinson  TEBecker  JB Enduring changes in brain and behavior produced by chronic amphetamine administration: a review and evaluation of animal models of amphetamine psychosis. Brain Res 1986;396 (2) 157- 198
PubMed Link to Article
Kalivas  PWStewart  J Dopamine transmission in the initiation and expression of drug- and stress-induced sensitization of motor activity. Brain Res Brain Res Rev 1991;16 (3) 223- 244
PubMed Link to Article
Gur  RCGur  RE Hypofrontality in schizophrenia: RIP. Lancet 1995;345 (8962) 1383- 1384
PubMed Link to Article
Manoach  DS Prefrontal cortex dysfunction during working memory performance in schizophrenia: reconciling discrepant findings. Schizophr Res 2003;60 (2-3) 285- 298
PubMed Link to Article
Weinberger  DRBerman  KF Prefrontal function in schizophrenia: confounds and controversies. Philos Trans R Soc Lond B Biol Sci 1996;351 (1346) 1495- 1503
PubMed Link to Article
Tenn  CCFletcher  PJKapur  S Amphetamine-sensitized animals show a sensorimotor gating and neurochemical abnormality similar to that of schizophrenia. Schizophr Res 2003;64 (2-3) 103- 114
PubMed Link to Article
Tenn  CCKapur  SFletcher  PJ Sensitization to amphetamine, but not phencyclidine, disrupts prepulse inhibition and latent inhibition. Psychopharmacology (Berl) 2005;180 (2) 366- 376
PubMed Link to Article
Featherstone  RERizos  ZKapur  SFletcher  PJ A sensitizing regimen of amphetamine that disrupts attentional set-shifting does not disrupt working or long-term memory. Behav Brain Res 2008;189 (1) 170- 179
PubMed Link to Article
Fletcher  PJTenn  CCRizos  ZLovic  VKapur  S Sensitization to amphetamine, but not PCP, impairs attentional set shifting: reversal by a D1 receptor agonist injected into the medial prefrontal cortex. Psychopharmacology (Berl) 2005;183 (2) 190- 200
PubMed Link to Article
Shoblock  JRMaisonneuve  IMGlick  SD Differences between d-methamphetamine and d-amphetamine in rats: working memory, tolerance, and extinction. Psychopharmacology (Berl) 2003;170 (2) 150- 156
PubMed Link to Article
Stefani  MRMoghaddam  B Effects of repeated treatment with amphetamine or phencyclidine on working memory in the rat. Behav Brain Res 2002;134 (1-2) 267- 274
PubMed Link to Article
Castner  SAVosler  PSGoldman-Rakic  PS Amphetamine sensitization impairs cognition and reduces dopamine turnover in primate prefrontal cortex. Biol Psychiatry 2005;57 (7) 743- 751
PubMed Link to Article
Castner  SAal-Tikriti  MSBaldwin  RMSeibyl  JPInnis  RBGoldman-Rakic  PS Behavioral changes and [123I]IBZM equilibrium SPECT measurement of amphetamine-induced dopamine release in rhesus monkeys exposed to subchronic amphetamine. Neuropsychopharmacology 2000;22 (1) 4- 13
PubMed Link to Article
Castner  SAGoldman-Rakic  PS Long-lasting psychotomimetic consequences of repeated low-dose amphetamine exposure in rhesus monkeys. Neuropsychopharmacology 1999;20 (1) 10- 28
PubMed Link to Article
Arnsten  AFCai  JXMurphy  BLGoldman-Rakic  PS Dopamine D1 receptor mechanisms in the cognitive performance of young adult and aged monkeys. Psychopharmacology (Berl) 1994;116 (2) 143- 151
PubMed Link to Article
Sawaguchi  TGoldman-Rakic  PS D1 dopamine receptors in prefrontal cortex: involvement in working memory. Science 1991;251 (4996) 947- 950
PubMed Link to Article
Williams  GVGoldman-Rakic  PS Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature 1995;376 (6541) 572- 575
PubMed Link to Article
Durstewitz  DSeamans  JKSejnowski  TJ Dopamine-mediated stabilization of delay-period activity in a network model of prefrontal cortex. J Neurophysiol 2000;83 (3) 1733- 1750
PubMed
Seamans  JKDurstewitz  DChristie  BRStevens  CFSejnowski  TJ Dopamine D1/D5 receptor modulation of excitatory synaptic inputs to layer V prefrontal cortex neurons. Proc Natl Acad Sci U S A 2001;98 (1) 301- 306
PubMed Link to Article
Abi-Dargham  AMawlawi  OLombardo  IGil  RMartinez  DHuang  YHwang  DRKeilp  JKochan  LVan Heertum  RGorman  JMLaruelle  M Prefrontal dopamine D1 receptors and working memory in schizophrenia. J Neurosci 2002;22 (9) 3708- 3719
PubMed
Davis  KLKahn  RSKo  GDavidson  M Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry 1991;148 (11) 1474- 1486
PubMed
Finlay  JMZigmond  MJAbercrombie  ED Increased dopamine and norepinephrine release in medial prefrontal cortex induced by acute and chronic stress: effects of diazepam. Neuroscience 1995;64 (3) 619- 628
PubMed Link to Article
Mattay  VSGoldberg  TEFera  FHariri  ARTessitore  AEgan  MFKolachana  BCallicott  JHWeinberger  DR Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine. Proc Natl Acad Sci U S A 2003;100 (10) 6186- 6191
PubMed Link to Article
Manoach  DSGollub  RLBenson  ESSearl  MMGoff  DCHalpern  ESaper  CBRauch  SL Schizophrenic subjects show aberrant fMRI activation of dorsolateral prefrontal cortex and basal ganglia during working memory performance. Biol Psychiatry 2000;48 (2) 99- 109
PubMed Link to Article
Manoach  DSPress  DZThangaraj  VSearl  MMGoff  DCHalpern  ESaper  CBWarach  S Schizophrenic subjects activate dorsolateral prefrontal cortex during a working memory task, as measured by fMRI. Biol Psychiatry 1999;45 (9) 1128- 1137
PubMed Link to Article
Copolov  DLSeal  MLMaruff  PUlusoy  RWong  MTTochon-Danguy  HJEgan  GF Cortical activation associated with the experience of auditory hallucinations and perception of human speech in schizophrenia: a PET correlation study. Psychiatry Res 2003;122 (3) 139- 152
PubMed Link to Article
Shergill  SSBrammer  MJWilliams  SCMurray  RMMcGuire  PK Mapping auditory hallucinations in schizophrenia using functional magnetic resonance imaging. Arch Gen Psychiatry 2000;57 (11) 1033- 1038
PubMed Link to Article
Krystal  JHAnand  AMoghaddam  B Effects of NMDA receptor antagonists: implications for the pathophysiology of schizophrenia. Arch Gen Psychiatry 2002;59 (7) 663- 664
PubMed Link to Article
Krystal  JHKarper  LPSeibyl  JPFreeman  GKDelaney  RBremner  JDHeninger  GRBowers  MB  JrCharney  DS Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans: psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 1994;51 (3) 199- 214
PubMed Link to Article
Vollenweider  FXLeenders  KLScharfetter  CMaguire  PStadelmann  OAngst  J Positron emission tomography and fluorodeoxyglucose studies of metabolic hyperfrontality and psychopathology in the psilocybin model of psychosis. Neuropsychopharmacology 1997;16 (5) 357- 372
PubMed Link to Article
Vollenweider  FXMaguire  RPLeenders  KLMathys  KAngst  J Effects of high amphetamine dose on mood and cerebral glucose metabolism in normal volunteers using positron emission tomography (PET). Psychiatry Res 1998;83 (3) 149- 162
PubMed Link to Article
Corlett  PRMurray  GKHoney  GDAitken  MRShanks  DRRobbins  TWBullmore  ETDickinson  AFletcher  PC Disrupted prediction-error signal in psychosis: evidence for an associative account of delusions. Brain 2007;130 (pt 9) 2387- 2400
PubMed Link to Article
Castner  SAGoldman-Rakic  PS Amphetamine sensitization of hallucinatory-like behaviors is dependent on prefrontal cortex in nonhuman primates. Biol Psychiatry 2003;54 (2) 105- 110
PubMed Link to Article
Castner  SAWilliams  GV From vice to virtue: insights from sensitization in the nonhuman primate. Prog Neuropsychopharmacol Biol Psychiatry 2007;31 (8) 1572- 1592
PubMed Link to Article
Friston  KJFrith  CD Schizophrenia: a disconnection syndrome? Clin Neurosci 1995;3 (2) 89- 97
PubMed
Frith  CDFriston  KJHerold  SSilbersweig  DFletcher  PCahill  CDolan  RJFrackowiak  RSLiddle  PF Regional brain activity in chronic schizophrenic patients during the performance of a verbal fluency task. Br J Psychiatry 1995;167 (3) 343- 349
PubMed Link to Article
Lawrie  SMBuechel  CWhalley  HCFrith  CDFriston  KJJohnstone  EC Reduced frontotemporal functional connectivity in schizophrenia associated with auditory hallucinations. Biol Psychiatry 2002;51 (12) 1008- 1011
PubMed Link to Article
Shergill  SSBrammer  MJFukuda  RWilliams  SCMurray  RMMcGuire  PK Engagement of brain areas implicated in processing inner speech in people with auditory hallucinations. Br J Psychiatry 2003;182525- 531
PubMed Link to Article
Shergill  SSKanaan  RAChitnis  XAO’Daly  OJones  DKFrangou  SWilliams  SCHoward  RJBarker  GJMurray  RMMcGuire  P A diffusion tensor imaging study of fasciculi in schizophrenia. Am J Psychiatry 2007;164 (3) 467- 473
PubMed Link to Article
Kapur  S Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia. Am J Psychiatry 2003;160 (1) 13- 23
PubMed Link to Article
Dolan  RJFletcher  PFrith  CDFriston  KJFrackowiak  RSGrasby  PM Dopaminergic modulation of impaired cognitive activation in the anterior cingulate cortex in schizophrenia. Nature 1995;378 (6553) 180- 182
PubMed Link to Article
Fletcher  PCFrith  CDGrasby  PMFriston  KJDolan  RJ Local and distributed effects of apomorphine on fronto-temporal function in acute unmedicated schizophrenia. J Neurosci 1996;16 (21) 7055- 7062
PubMed
Friston  KJ The disconnection hypothesis. Schizophr Res 1998;30 (2) 115- 125
PubMed Link to Article
Stephan  KEBaldeweg  TFriston  KJ Synaptic plasticity and dysconnection in schizophrenia. Biol Psychiatry 2006;59 (10) 929- 939
PubMed Link to Article
Stephan  KEFriston  KJFrith  CD Dysconnection in schizophrenia: from abnormal synaptic plasticity to failures of self-monitoring. Schizophr Bull 2009;35 (3) 509- 527
PubMed Link to Article
Boileau  IDagher  ALeyton  MGunn  RNBaker  GBDiksic  MBenkelfat  C Modeling sensitization to stimulants in humans: an [11C]raclopride/positron emission tomography study in healthy men. Arch Gen Psychiatry 2006;63 (12) 1386- 1395
PubMed Link to Article
Morey  RAInan  SMitchell  TVPerkins  DOLieberman  JABelger  A Imaging frontostriatal function in ultra-high-risk, early, and chronic schizophrenia during executive processing. Arch Gen Psychiatry 2005;62 (3) 254- 262
PubMed Link to Article
Gevins  ACutillo  B Spatiotemporal dynamics of component processes in human working memory. Electroencephalogr Clin Neurophysiol 1993;87 (3) 128- 143
PubMed Link to Article
Haertzen  CAHill  HE Assessing subjective effects of drugs: an index of carelessness and confusion for use with the Addiction Research Center Inventory (ARCI). J Clin Psychol 1963;19407- 412
PubMed Link to Article
Haertzen  CAHill  HEBelleville  RE Development of the Addiction Research Center Inventory (ARCI): selection of items that are sensitive to the effects of various drugs. Psychopharmacologia 1963;4155- 166
PubMed Link to Article
Haertzen  CAHickey  JE Addiction Research Center Inventory (ARCI): measurement of euphoria and other drug effects. MA  BozarthIn: ed.Methods of Assessing the Reinforcing Properties of Abused Drugs. New York, NY Springer-Verlag1987;489- 524
McNair  DMLorr  MDroppleman  LF EdITS Manual for the Profile of Mood States.  San Diego, CA Educational and Industrial Testing Service1992;
Kumari  VMulligan  OFCotter  PAPoon  LToone  BKCheckley  SAGray  JA Effects of single oral administrations of haloperidol and d-amphetamine on prepulse inhibition of the acoustic startle reflex in healthy male volunteers. Behav Pharmacol 1998;9 (7) 567- 576
PubMed Link to Article
Strakowski  SMSax  KW Progressive behavioral response to repeated d-amphetamine challenge: further evidence for sensitization in humans. Biol Psychiatry 1998;44 (11) 1171- 1177
PubMed Link to Article
Strakowski  SMSax  KWRosenberg  HLDelBello  MPAdler  CM Human response to repeated low-dose d-amphetamine: evidence for behavioral enhancement and tolerance. Neuropsychopharmacology 2001;25 (4) 548- 554
PubMed Link to Article
Strakowski  SMSax  KWSetters  MJKeck  PE  Jr Enhanced response to repeated d-amphetamine challenge: evidence for behavioral sensitization in humans. Biol Psychiatry 1996;40 (9) 872- 880
PubMed Link to Article
Andersson  JLHutton  CAshburner  JTurner  RFriston  K Modeling geometric deformations in EPI time series. Neuroimage 2001;13 (5) 903- 919
PubMed Link to Article
Hutton  CBork  AJosephs  ODeichmann  RAshburner  JTurner  R Image distortion correction in fMRI: a quantitative evaluation. Neuroimage 2002;16 (1) 217- 240
PubMed Link to Article
Friston  KJFrith  CDTurner  RFrackowiak  RS Characterizing evoked hemodynamics with fMRI. Neuroimage 1995;2 (2) 157- 165
PubMed Link to Article
Friston  KJHolmes  APPoline  JBGrasby  PJWilliams  SCFrackowiak  RSTurner  R Analysis of fMRI time-series revisited. Neuroimage 1995;2 (1) 45- 53
PubMed Link to Article
Friston  KJFletcher  PJosephs  OHolmes  ARugg  MDTurner  R Event-related fMRI: characterizing differential responses. Neuroimage 1998;7 (1) 30- 40
PubMed Link to Article
Mawlawi  OMartinez  DSlifstein  MBroft  AChatterjee  RHwang  DRHuang  YSimpson  NNgo  KVan Heertum  RLaruelle  M Imaging human mesolimbic dopamine transmission with positron emission tomography, I: accuracy and precision of D(2) receptor parameter measurements in ventral striatum. J Cereb Blood Flow Metab 2001;21 (9) 1034- 1057
PubMed Link to Article
Tzourio-Mazoyer  NLandeau  BPapathanassiou  DCrivello  FEtard  ODelcroix  NMazoyer  BJoliot  M Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. Neuroimage 2002;15 (1) 273- 289
PubMed Link to Article
Wright  ICMcGuire  PKPoline  JBTravere  JMMurray  RMFrith  CDFrackowiak  RSFriston  KJ A voxel-based method for the statistical analysis of gray and white matter density applied to schizophrenia. Neuroimage 1995;2 (4) 244- 252
PubMed Link to Article
Strafella  APKo  JHGrant  JFraraccio  MMonchi  O Corticostriatal functional interactions in Parkinson's disease: a rTMS/[11C]raclopride PET study. Eur J Neurosci 2005;22 (11) 2946- 2952
PubMed Link to Article
Fu  CHMcIntosh  ARKim  JChau  WBullmore  ETWilliams  SCHoney  GDMcGuire  PK Modulation of effective connectivity by cognitive demand in phonological verbal fluency. Neuroimage 2006;30 (1) 266- 271
PubMed Link to Article
Breakspear  MTerry  JRFriston  KJ Modulation of excitatory synaptic coupling facilitates synchronization and complex dynamics in a biophysical model of neuronal dynamics. Network 2003;14 (4) 703- 732
PubMed Link to Article
Fletcher  PCMcKenna  PJFrith  CDGrasby  PMFriston  KJDolan  RJ Brain activations in schizophrenia during a graded memory task studied with functional neuroimaging. Arch Gen Psychiatry 1998;55 (11) 1001- 1008
PubMed Link to Article
Spence  SALiddle  PFStefan  MDHellewell  JSSharma  TFriston  KJHirsch  SRFrith  CDMurray  RMDeakin  JFGrasby  PM Functional anatomy of verbal fluency in people with schizophrenia and those at genetic risk: focal dysfunction and distributed disconnectivity reappraised. Br J Psychiatry 2000;17652- 60
PubMed Link to Article
Crossley  NAMechelli  AFusar-Poli  PBroome  MRMatthiasson  PJohns  LCBramon  EValmaggia  LWilliams  SCMcGuire  PK Superior temporal lobe dysfunction and frontotemporal dysconnectivity in subjects at risk of psychosis and in first-episode psychosis. Hum Brain Mapp 2009;30 (12) 4129- 4137
PubMed Link to Article
Fu  CHSuckling  JWilliams  SCAndrew  CMVythelingum  GNMcGuire  PK Effects of psychotic state and task demand on prefrontal function in schizophrenia: an fMRI study of overt verbal fluency. Am J Psychiatry 2005;162 (3) 485- 494
PubMed Link to Article
Williams  GVCastner  SA Under the curve: critical issues for elucidating D1 receptor function in working memory. Neuroscience 2006;139 (1) 263- 276
PubMed Link to Article
Williams  SMGoldman-Rakic  PS Characterization of the dopaminergic innervation of the primate frontal cortex using a dopamine-specific antibody. Cereb Cortex 1993;3 (3) 199- 222
PubMed Link to Article
Williams  SMGoldman-Rakic  PS Widespread origin of the primate mesofrontal dopamine system. Cereb Cortex 1998;8 (4) 321- 345
PubMed Link to Article
Garris  PACollins  LBJones  SRWightman  RM Evoked extracellular dopamine in vivo in the medial prefrontal cortex. J Neurochem 1993;61 (2) 637- 647
PubMed Link to Article
Alexander  GECrutcher  MD Functional architecture of basal ganglia circuits: neural substrates of parallel processing. Trends Neurosci 1990;13 (7) 266- 271
PubMed Link to Article
Alexander  GEDeLong  MRStrick  PL Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci 1986;9357- 381
PubMed Link to Article
Kellendonk  CSimpson  EHPolan  HJMalleret  GVronskaya  SWiniger  VMoore  HKandel  ER Transient and selective overexpression of dopamine D2 receptors in the striatum causes persistent abnormalities in prefrontal cortex functioning. Neuron 2006;49 (4) 603- 615
PubMed Link to Article
Monchi  OPetrides  MMejia-Constain  BStrafella  AP Cortical activity in Parkinson's disease during executive processing depends on striatal involvement. Brain 2007;130 (pt 1) 233- 244
PubMed Link to Article
Monchi  OTaylor  JGDagher  A A neural model of working memory processes in normal subjects, Parkinson's disease and schizophrenia for fMRI design and predictions. Neural Netw 2000;13 (8-9) 953- 973
PubMed Link to Article
Lewis  SJDove  ARobbins  TWBarker  RAOwen  AM Striatal contributions to working memory: a functional magnetic resonance imaging study in humans. Eur J Neurosci 2004;19 (3) 755- 760
PubMed Link to Article
Kegeles  LSAbi-Dargham  AFrankle  WGGil  RCooper  TBSlifstein  MHwang  DRHuang  YHaber  SNLaruelle  M Increased synaptic dopamine function in associative regions of the striatum in schizophrenia. Arch Gen Psychiatry 2010;67 (3) 231- 239
PubMed Link to Article
Knutson  BBjork  JMFong  GWHommer  DMattay  VSWeinberger  DR Amphetamine modulates human incentive processing. Neuron 2004;43 (2) 261- 269
PubMed Link to Article
Jackson  MEFrost  ASMoghaddam  B Stimulation of prefrontal cortex at physiologically relevant frequencies inhibits dopamine release in the nucleus accumbens. J Neurochem 2001;78 (4) 920- 923
PubMed Link to Article
Sesack  SRCarr  DB Selective prefrontal cortex inputs to dopamine cells: implications for schizophrenia. Physiol Behav 2002;77 (4-5) 513- 517
PubMed Link to Article
Cador  MBjijou  YCailhol  SStinus  L D-amphetamine-induced behavioral sensitization: implication of a glutamatergic medial prefrontal cortex-ventral tegmental area innervation. Neuroscience 1999;94 (3) 705- 721
PubMed Link to Article
Bonci  AMalenka  RC Properties and plasticity of excitatory synapses on dopaminergic and GABAergic cells in the ventral tegmental area. J Neurosci 1999;19 (10) 3723- 3730
PubMed
Mansvelder  HDMcGehee  DS Long-term potentiation of excitatory inputs to brain reward areas by nicotine. Neuron 2000;27 (2) 349- 357
PubMed Link to Article
Cepeda  CLevine  MS Where do you think you are going? the NMDA-D1 receptor trap. Sci STKE 2006;2006 (333) pe20
PubMed
Bower  EAPhelan  JR Use of amphetamines in the military environment. Lancet 2003;362(suppl)s18- s19
PubMed Link to Article
Greely  HSahakian  BHarris  JKessler  RCGazzaniga  MCampbell  PFarah  MJ Towards responsible use of cognitive-enhancing drugs by the healthy. Nature 2008;456 (7223) 702- 705
PubMed Link to Article
Booij  LWelfeld  KLeyton  M  et al.  Cross-sensitization between stimulants and stress in humans: behavioral and neurochemical correlates. 50th Annual Conference of Scandinavian College of Neuropsychopharmacology (SCNP). 2 Copenhagen, Denmark Scandinavian College of Neuropsychopharmacology (SCNP)2009;
Volkow  NDSwanson  JM Does childhood treatment of ADHD with stimulant medication affect substance abuse in adulthood? Am J Psychiatry 2008;165 (5) 553- 555
PubMed Link to Article
Boileau  IDagher  ALeyton  MWelfeld  KBooij  LDiksic  MBenkelfat  C Conditioned dopamine release in humans: a positron emission tomography [11C]raclopride study with amphetamine. J Neurosci 2007;27 (15) 3998- 4003
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Subjective effects of amphetamine sensitization. A, Group × session interaction for the subjective reports of amphetamine-like experience. ARCI indicates Addiction Research Center Inventory. B, Session × hour measures of amphetamine-like effects in the amphetamine group. C, The significant correlation between the sensitization of amphetamine-like experiences (difference between peak amphetamine-like experiences scores at sessions 1 and 4) against the sensitization of reaction time. PC indicates plasma concentration.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Effects of sensitization on N-back–related blood oxygen level–dependent responses. A, The red brain regions' activity shows a main effect of session (time) in the amphetamine group whereas the yellow regions show a significant load × session interaction (for display purposes, results are shown at P < .001 uncorrected, with a cluster threshold of 30 contiguous voxels). B, For visualization of the nature of the interaction, the parameter estimates extracted from the peak voxel in the right superior temporal gyrus (rSTG) are plotted (Montreal Neurological Institute coordinates 60, −9, and 6). This demonstrates a load-dependent failure of the normal suppression of the STG, with increasing demands on the working memory system.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Effect of sensitization on blood oxygen level–dependent response to a high-load cognitive challenge. A, The red brain regions' activity is elevated during the high-load condition following amphetamine sensitization (P < .05 whole-brain corrected at the cluster level, with a voxel-level threshold of P < .001). B, The negative correlation between sensitization of positive affect (Visual Analogue Mood Scales [VAMS] happy-sad subscale) and the change in striatal activation during the high-load working memory challenge. C, The positive correlation between sensitized alertness and the change in prefrontal activity during the high-load working memory challenge.82 PC indicates plasma concentration.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Amphetamine Effect of Time and Load × Time Interactiona
Table Graphic Jump LocationTable 2. Amphetamine Paired t Test Session 4 Greater Than Session 1 (High-Load Working Memory Task Greater Than Control)a

References

Angrist  BMGershon  S The phenomenology of experimentally induced amphetamine psychosis: preliminary observations. Biol Psychiatry 1970;2 (2) 95- 107
PubMed
Connell  PH Amphetamine Psychosis.  Glasgow, Scotland Chapman Hall for the Institute of Psychiatry1958;
Curran  CByrappa  NMcBride  A Stimulant psychosis: systematic review. Br J Psychiatry 2004;185196- 204
PubMed Link to Article
Lieberman  JAKane  JMAlvir  J Provocative tests with psychostimulant drugs in schizophrenia. Psychopharmacology (Berl) 1987;91 (4) 415- 433
PubMed Link to Article
Lieberman  JAKane  JMGadaletta  DRamos-Lorenzi  JBergmann  KWegner  JNovacenko  H Methylphenidate challenge tests and course of schizophrenia. Psychopharmacol Bull 1985;21 (1) 123- 129
PubMed
Lieberman  JASheitman  BBKinon  BJ Neurochemical sensitization in the pathophysiology of schizophrenia: deficits and dysfunction in neuronal regulation and plasticity. Neuropsychopharmacology 1997;17 (4) 205- 229
PubMed Link to Article
Segal  DSKuczenski  R Repeated binge exposures to amphetamine and methamphetamine: behavioral and neurochemical characterization. J Pharmacol Exp Ther 1997;282 (2) 561- 573
PubMed
Breier  ASu  TPSaunders  RCarson  REKolachana  BSde Bartolomeis  AWeinberger  DRWeisenfeld  NMalhotra  AKEckelman  WCPickar  D Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method. Proc Natl Acad Sci U S A 1997;94 (6) 2569- 2574
PubMed Link to Article
Laruelle  MAbi-Dargham  AGil  RKegeles  LInnis  R Increased dopamine transmission in schizophrenia: relationship to illness phases. Biol Psychiatry 1999;46 (1) 56- 72
PubMed Link to Article
Laruelle  MAbi-Dargham  Avan Dyck  CHGil  RD’Souza  CDErdos  JMcCance  ERosenblatt  WFingado  CZoghbi  SSBaldwin  RMSeibyl  JPKrystal  JHCharney  DSInnis  RB Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. Proc Natl Acad Sci U S A 1996;93 (17) 9235- 9240
PubMed Link to Article
Kalivas  PWRichardson-Carlson  RVan Orden  G Cross-sensitization between foot shock stress and enkephalin-induced motor activity. Biol Psychiatry 1986;21 (10) 939- 950
PubMed Link to Article
Piazza  PVDeminiere  JMle Moal  MSimon  H Stress- and pharmacologically-induced behavioral sensitization increases vulnerability to acquisition of amphetamine self-administration. Brain Res 1990;514 (1) 22- 26
PubMed Link to Article
Kalivas  PWDuffy  P Effect of acute and daily cocaine treatment on extracellular dopamine in the nucleus accumbens. Synapse 1990;5 (1) 48- 58
PubMed Link to Article
Kalivas  PWDuffy  P Time course of extracellular dopamine and behavioral sensitization to cocaine, I: dopamine axon terminals. J Neurosci 1993;13 (1) 266- 275
PubMed
Kalivas  PWDuffy  P Time course of extracellular dopamine and behavioral sensitization to cocaine, II: dopamine perikarya. J Neurosci 1993;13 (1) 276- 284
PubMed
Kalivas  PWSorg  BAHooks  MS The pharmacology and neural circuitry of sensitization to psychostimulants. Behav Pharmacol 1993;4 (4) 315- 334
PubMed Link to Article
Mueller  K Locomotor stereotypy is produced by methylphenidate and amfonelic acid and reduced by haloperidol but not clozapine or thioridazine. Pharmacol Biochem Behav 1993;45 (1) 71- 76
PubMed Link to Article
Paulson  PERobinson  TE Amphetamine-induced time-dependent sensitization of dopamine neurotransmission in the dorsal and ventral striatum: a microdialysis study in behaving rats. Synapse 1995;19 (1) 56- 65
PubMed Link to Article
Robinson  TEBecker  JB Enduring changes in brain and behavior produced by chronic amphetamine administration: a review and evaluation of animal models of amphetamine psychosis. Brain Res 1986;396 (2) 157- 198
PubMed Link to Article
Kalivas  PWStewart  J Dopamine transmission in the initiation and expression of drug- and stress-induced sensitization of motor activity. Brain Res Brain Res Rev 1991;16 (3) 223- 244
PubMed Link to Article
Gur  RCGur  RE Hypofrontality in schizophrenia: RIP. Lancet 1995;345 (8962) 1383- 1384
PubMed Link to Article
Manoach  DS Prefrontal cortex dysfunction during working memory performance in schizophrenia: reconciling discrepant findings. Schizophr Res 2003;60 (2-3) 285- 298
PubMed Link to Article
Weinberger  DRBerman  KF Prefrontal function in schizophrenia: confounds and controversies. Philos Trans R Soc Lond B Biol Sci 1996;351 (1346) 1495- 1503
PubMed Link to Article
Tenn  CCFletcher  PJKapur  S Amphetamine-sensitized animals show a sensorimotor gating and neurochemical abnormality similar to that of schizophrenia. Schizophr Res 2003;64 (2-3) 103- 114
PubMed Link to Article
Tenn  CCKapur  SFletcher  PJ Sensitization to amphetamine, but not phencyclidine, disrupts prepulse inhibition and latent inhibition. Psychopharmacology (Berl) 2005;180 (2) 366- 376
PubMed Link to Article
Featherstone  RERizos  ZKapur  SFletcher  PJ A sensitizing regimen of amphetamine that disrupts attentional set-shifting does not disrupt working or long-term memory. Behav Brain Res 2008;189 (1) 170- 179
PubMed Link to Article
Fletcher  PJTenn  CCRizos  ZLovic  VKapur  S Sensitization to amphetamine, but not PCP, impairs attentional set shifting: reversal by a D1 receptor agonist injected into the medial prefrontal cortex. Psychopharmacology (Berl) 2005;183 (2) 190- 200
PubMed Link to Article
Shoblock  JRMaisonneuve  IMGlick  SD Differences between d-methamphetamine and d-amphetamine in rats: working memory, tolerance, and extinction. Psychopharmacology (Berl) 2003;170 (2) 150- 156
PubMed Link to Article
Stefani  MRMoghaddam  B Effects of repeated treatment with amphetamine or phencyclidine on working memory in the rat. Behav Brain Res 2002;134 (1-2) 267- 274
PubMed Link to Article
Castner  SAVosler  PSGoldman-Rakic  PS Amphetamine sensitization impairs cognition and reduces dopamine turnover in primate prefrontal cortex. Biol Psychiatry 2005;57 (7) 743- 751
PubMed Link to Article
Castner  SAal-Tikriti  MSBaldwin  RMSeibyl  JPInnis  RBGoldman-Rakic  PS Behavioral changes and [123I]IBZM equilibrium SPECT measurement of amphetamine-induced dopamine release in rhesus monkeys exposed to subchronic amphetamine. Neuropsychopharmacology 2000;22 (1) 4- 13
PubMed Link to Article
Castner  SAGoldman-Rakic  PS Long-lasting psychotomimetic consequences of repeated low-dose amphetamine exposure in rhesus monkeys. Neuropsychopharmacology 1999;20 (1) 10- 28
PubMed Link to Article
Arnsten  AFCai  JXMurphy  BLGoldman-Rakic  PS Dopamine D1 receptor mechanisms in the cognitive performance of young adult and aged monkeys. Psychopharmacology (Berl) 1994;116 (2) 143- 151
PubMed Link to Article
Sawaguchi  TGoldman-Rakic  PS D1 dopamine receptors in prefrontal cortex: involvement in working memory. Science 1991;251 (4996) 947- 950
PubMed Link to Article
Williams  GVGoldman-Rakic  PS Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature 1995;376 (6541) 572- 575
PubMed Link to Article
Durstewitz  DSeamans  JKSejnowski  TJ Dopamine-mediated stabilization of delay-period activity in a network model of prefrontal cortex. J Neurophysiol 2000;83 (3) 1733- 1750
PubMed
Seamans  JKDurstewitz  DChristie  BRStevens  CFSejnowski  TJ Dopamine D1/D5 receptor modulation of excitatory synaptic inputs to layer V prefrontal cortex neurons. Proc Natl Acad Sci U S A 2001;98 (1) 301- 306
PubMed Link to Article
Abi-Dargham  AMawlawi  OLombardo  IGil  RMartinez  DHuang  YHwang  DRKeilp  JKochan  LVan Heertum  RGorman  JMLaruelle  M Prefrontal dopamine D1 receptors and working memory in schizophrenia. J Neurosci 2002;22 (9) 3708- 3719
PubMed
Davis  KLKahn  RSKo  GDavidson  M Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry 1991;148 (11) 1474- 1486
PubMed
Finlay  JMZigmond  MJAbercrombie  ED Increased dopamine and norepinephrine release in medial prefrontal cortex induced by acute and chronic stress: effects of diazepam. Neuroscience 1995;64 (3) 619- 628
PubMed Link to Article
Mattay  VSGoldberg  TEFera  FHariri  ARTessitore  AEgan  MFKolachana  BCallicott  JHWeinberger  DR Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine. Proc Natl Acad Sci U S A 2003;100 (10) 6186- 6191
PubMed Link to Article
Manoach  DSGollub  RLBenson  ESSearl  MMGoff  DCHalpern  ESaper  CBRauch  SL Schizophrenic subjects show aberrant fMRI activation of dorsolateral prefrontal cortex and basal ganglia during working memory performance. Biol Psychiatry 2000;48 (2) 99- 109
PubMed Link to Article
Manoach  DSPress  DZThangaraj  VSearl  MMGoff  DCHalpern  ESaper  CBWarach  S Schizophrenic subjects activate dorsolateral prefrontal cortex during a working memory task, as measured by fMRI. Biol Psychiatry 1999;45 (9) 1128- 1137
PubMed Link to Article
Copolov  DLSeal  MLMaruff  PUlusoy  RWong  MTTochon-Danguy  HJEgan  GF Cortical activation associated with the experience of auditory hallucinations and perception of human speech in schizophrenia: a PET correlation study. Psychiatry Res 2003;122 (3) 139- 152
PubMed Link to Article
Shergill  SSBrammer  MJWilliams  SCMurray  RMMcGuire  PK Mapping auditory hallucinations in schizophrenia using functional magnetic resonance imaging. Arch Gen Psychiatry 2000;57 (11) 1033- 1038
PubMed Link to Article
Krystal  JHAnand  AMoghaddam  B Effects of NMDA receptor antagonists: implications for the pathophysiology of schizophrenia. Arch Gen Psychiatry 2002;59 (7) 663- 664
PubMed Link to Article
Krystal  JHKarper  LPSeibyl  JPFreeman  GKDelaney  RBremner  JDHeninger  GRBowers  MB  JrCharney  DS Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans: psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 1994;51 (3) 199- 214
PubMed Link to Article
Vollenweider  FXLeenders  KLScharfetter  CMaguire  PStadelmann  OAngst  J Positron emission tomography and fluorodeoxyglucose studies of metabolic hyperfrontality and psychopathology in the psilocybin model of psychosis. Neuropsychopharmacology 1997;16 (5) 357- 372
PubMed Link to Article
Vollenweider  FXMaguire  RPLeenders  KLMathys  KAngst  J Effects of high amphetamine dose on mood and cerebral glucose metabolism in normal volunteers using positron emission tomography (PET). Psychiatry Res 1998;83 (3) 149- 162
PubMed Link to Article
Corlett  PRMurray  GKHoney  GDAitken  MRShanks  DRRobbins  TWBullmore  ETDickinson  AFletcher  PC Disrupted prediction-error signal in psychosis: evidence for an associative account of delusions. Brain 2007;130 (pt 9) 2387- 2400
PubMed Link to Article
Castner  SAGoldman-Rakic  PS Amphetamine sensitization of hallucinatory-like behaviors is dependent on prefrontal cortex in nonhuman primates. Biol Psychiatry 2003;54 (2) 105- 110
PubMed Link to Article
Castner  SAWilliams  GV From vice to virtue: insights from sensitization in the nonhuman primate. Prog Neuropsychopharmacol Biol Psychiatry 2007;31 (8) 1572- 1592
PubMed Link to Article
Friston  KJFrith  CD Schizophrenia: a disconnection syndrome? Clin Neurosci 1995;3 (2) 89- 97
PubMed
Frith  CDFriston  KJHerold  SSilbersweig  DFletcher  PCahill  CDolan  RJFrackowiak  RSLiddle  PF Regional brain activity in chronic schizophrenic patients during the performance of a verbal fluency task. Br J Psychiatry 1995;167 (3) 343- 349
PubMed Link to Article
Lawrie  SMBuechel  CWhalley  HCFrith  CDFriston  KJJohnstone  EC Reduced frontotemporal functional connectivity in schizophrenia associated with auditory hallucinations. Biol Psychiatry 2002;51 (12) 1008- 1011
PubMed Link to Article
Shergill  SSBrammer  MJFukuda  RWilliams  SCMurray  RMMcGuire  PK Engagement of brain areas implicated in processing inner speech in people with auditory hallucinations. Br J Psychiatry 2003;182525- 531
PubMed Link to Article
Shergill  SSKanaan  RAChitnis  XAO’Daly  OJones  DKFrangou  SWilliams  SCHoward  RJBarker  GJMurray  RMMcGuire  P A diffusion tensor imaging study of fasciculi in schizophrenia. Am J Psychiatry 2007;164 (3) 467- 473
PubMed Link to Article
Kapur  S Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia. Am J Psychiatry 2003;160 (1) 13- 23
PubMed Link to Article
Dolan  RJFletcher  PFrith  CDFriston  KJFrackowiak  RSGrasby  PM Dopaminergic modulation of impaired cognitive activation in the anterior cingulate cortex in schizophrenia. Nature 1995;378 (6553) 180- 182
PubMed Link to Article
Fletcher  PCFrith  CDGrasby  PMFriston  KJDolan  RJ Local and distributed effects of apomorphine on fronto-temporal function in acute unmedicated schizophrenia. J Neurosci 1996;16 (21) 7055- 7062
PubMed
Friston  KJ The disconnection hypothesis. Schizophr Res 1998;30 (2) 115- 125
PubMed Link to Article
Stephan  KEBaldeweg  TFriston  KJ Synaptic plasticity and dysconnection in schizophrenia. Biol Psychiatry 2006;59 (10) 929- 939
PubMed Link to Article
Stephan  KEFriston  KJFrith  CD Dysconnection in schizophrenia: from abnormal synaptic plasticity to failures of self-monitoring. Schizophr Bull 2009;35 (3) 509- 527
PubMed Link to Article
Boileau  IDagher  ALeyton  MGunn  RNBaker  GBDiksic  MBenkelfat  C Modeling sensitization to stimulants in humans: an [11C]raclopride/positron emission tomography study in healthy men. Arch Gen Psychiatry 2006;63 (12) 1386- 1395
PubMed Link to Article
Morey  RAInan  SMitchell  TVPerkins  DOLieberman  JABelger  A Imaging frontostriatal function in ultra-high-risk, early, and chronic schizophrenia during executive processing. Arch Gen Psychiatry 2005;62 (3) 254- 262
PubMed Link to Article
Gevins  ACutillo  B Spatiotemporal dynamics of component processes in human working memory. Electroencephalogr Clin Neurophysiol 1993;87 (3) 128- 143
PubMed Link to Article
Haertzen  CAHill  HE Assessing subjective effects of drugs: an index of carelessness and confusion for use with the Addiction Research Center Inventory (ARCI). J Clin Psychol 1963;19407- 412
PubMed Link to Article
Haertzen  CAHill  HEBelleville  RE Development of the Addiction Research Center Inventory (ARCI): selection of items that are sensitive to the effects of various drugs. Psychopharmacologia 1963;4155- 166
PubMed Link to Article
Haertzen  CAHickey  JE Addiction Research Center Inventory (ARCI): measurement of euphoria and other drug effects. MA  BozarthIn: ed.Methods of Assessing the Reinforcing Properties of Abused Drugs. New York, NY Springer-Verlag1987;489- 524
McNair  DMLorr  MDroppleman  LF EdITS Manual for the Profile of Mood States.  San Diego, CA Educational and Industrial Testing Service1992;
Kumari  VMulligan  OFCotter  PAPoon  LToone  BKCheckley  SAGray  JA Effects of single oral administrations of haloperidol and d-amphetamine on prepulse inhibition of the acoustic startle reflex in healthy male volunteers. Behav Pharmacol 1998;9 (7) 567- 576
PubMed Link to Article
Strakowski  SMSax  KW Progressive behavioral response to repeated d-amphetamine challenge: further evidence for sensitization in humans. Biol Psychiatry 1998;44 (11) 1171- 1177
PubMed Link to Article
Strakowski  SMSax  KWRosenberg  HLDelBello  MPAdler  CM Human response to repeated low-dose d-amphetamine: evidence for behavioral enhancement and tolerance. Neuropsychopharmacology 2001;25 (4) 548- 554
PubMed Link to Article
Strakowski  SMSax  KWSetters  MJKeck  PE  Jr Enhanced response to repeated d-amphetamine challenge: evidence for behavioral sensitization in humans. Biol Psychiatry 1996;40 (9) 872- 880
PubMed Link to Article
Andersson  JLHutton  CAshburner  JTurner  RFriston  K Modeling geometric deformations in EPI time series. Neuroimage 2001;13 (5) 903- 919
PubMed Link to Article
Hutton  CBork  AJosephs  ODeichmann  RAshburner  JTurner  R Image distortion correction in fMRI: a quantitative evaluation. Neuroimage 2002;16 (1) 217- 240
PubMed Link to Article
Friston  KJFrith  CDTurner  RFrackowiak  RS Characterizing evoked hemodynamics with fMRI. Neuroimage 1995;2 (2) 157- 165
PubMed Link to Article
Friston  KJHolmes  APPoline  JBGrasby  PJWilliams  SCFrackowiak  RSTurner  R Analysis of fMRI time-series revisited. Neuroimage 1995;2 (1) 45- 53
PubMed Link to Article
Friston  KJFletcher  PJosephs  OHolmes  ARugg  MDTurner  R Event-related fMRI: characterizing differential responses. Neuroimage 1998;7 (1) 30- 40
PubMed Link to Article
Mawlawi  OMartinez  DSlifstein  MBroft  AChatterjee  RHwang  DRHuang  YSimpson  NNgo  KVan Heertum  RLaruelle  M Imaging human mesolimbic dopamine transmission with positron emission tomography, I: accuracy and precision of D(2) receptor parameter measurements in ventral striatum. J Cereb Blood Flow Metab 2001;21 (9) 1034- 1057
PubMed Link to Article
Tzourio-Mazoyer  NLandeau  BPapathanassiou  DCrivello  FEtard  ODelcroix  NMazoyer  BJoliot  M Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. Neuroimage 2002;15 (1) 273- 289
PubMed Link to Article
Wright  ICMcGuire  PKPoline  JBTravere  JMMurray  RMFrith  CDFrackowiak  RSFriston  KJ A voxel-based method for the statistical analysis of gray and white matter density applied to schizophrenia. Neuroimage 1995;2 (4) 244- 252
PubMed Link to Article
Strafella  APKo  JHGrant  JFraraccio  MMonchi  O Corticostriatal functional interactions in Parkinson's disease: a rTMS/[11C]raclopride PET study. Eur J Neurosci 2005;22 (11) 2946- 2952
PubMed Link to Article
Fu  CHMcIntosh  ARKim  JChau  WBullmore  ETWilliams  SCHoney  GDMcGuire  PK Modulation of effective connectivity by cognitive demand in phonological verbal fluency. Neuroimage 2006;30 (1) 266- 271
PubMed Link to Article
Breakspear  MTerry  JRFriston  KJ Modulation of excitatory synaptic coupling facilitates synchronization and complex dynamics in a biophysical model of neuronal dynamics. Network 2003;14 (4) 703- 732
PubMed Link to Article
Fletcher  PCMcKenna  PJFrith  CDGrasby  PMFriston  KJDolan  RJ Brain activations in schizophrenia during a graded memory task studied with functional neuroimaging. Arch Gen Psychiatry 1998;55 (11) 1001- 1008
PubMed Link to Article
Spence  SALiddle  PFStefan  MDHellewell  JSSharma  TFriston  KJHirsch  SRFrith  CDMurray  RMDeakin  JFGrasby  PM Functional anatomy of verbal fluency in people with schizophrenia and those at genetic risk: focal dysfunction and distributed disconnectivity reappraised. Br J Psychiatry 2000;17652- 60
PubMed Link to Article
Crossley  NAMechelli  AFusar-Poli  PBroome  MRMatthiasson  PJohns  LCBramon  EValmaggia  LWilliams  SCMcGuire  PK Superior temporal lobe dysfunction and frontotemporal dysconnectivity in subjects at risk of psychosis and in first-episode psychosis. Hum Brain Mapp 2009;30 (12) 4129- 4137
PubMed Link to Article
Fu  CHSuckling  JWilliams  SCAndrew  CMVythelingum  GNMcGuire  PK Effects of psychotic state and task demand on prefrontal function in schizophrenia: an fMRI study of overt verbal fluency. Am J Psychiatry 2005;162 (3) 485- 494
PubMed Link to Article
Williams  GVCastner  SA Under the curve: critical issues for elucidating D1 receptor function in working memory. Neuroscience 2006;139 (1) 263- 276
PubMed Link to Article
Williams  SMGoldman-Rakic  PS Characterization of the dopaminergic innervation of the primate frontal cortex using a dopamine-specific antibody. Cereb Cortex 1993;3 (3) 199- 222
PubMed Link to Article
Williams  SMGoldman-Rakic  PS Widespread origin of the primate mesofrontal dopamine system. Cereb Cortex 1998;8 (4) 321- 345
PubMed Link to Article
Garris  PACollins  LBJones  SRWightman  RM Evoked extracellular dopamine in vivo in the medial prefrontal cortex. J Neurochem 1993;61 (2) 637- 647
PubMed Link to Article
Alexander  GECrutcher  MD Functional architecture of basal ganglia circuits: neural substrates of parallel processing. Trends Neurosci 1990;13 (7) 266- 271
PubMed Link to Article
Alexander  GEDeLong  MRStrick  PL Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci 1986;9357- 381
PubMed Link to Article
Kellendonk  CSimpson  EHPolan  HJMalleret  GVronskaya  SWiniger  VMoore  HKandel  ER Transient and selective overexpression of dopamine D2 receptors in the striatum causes persistent abnormalities in prefrontal cortex functioning. Neuron 2006;49 (4) 603- 615
PubMed Link to Article
Monchi  OPetrides  MMejia-Constain  BStrafella  AP Cortical activity in Parkinson's disease during executive processing depends on striatal involvement. Brain 2007;130 (pt 1) 233- 244
PubMed Link to Article
Monchi  OTaylor  JGDagher  A A neural model of working memory processes in normal subjects, Parkinson's disease and schizophrenia for fMRI design and predictions. Neural Netw 2000;13 (8-9) 953- 973
PubMed Link to Article
Lewis  SJDove  ARobbins  TWBarker  RAOwen  AM Striatal contributions to working memory: a functional magnetic resonance imaging study in humans. Eur J Neurosci 2004;19 (3) 755- 760
PubMed Link to Article
Kegeles  LSAbi-Dargham  AFrankle  WGGil  RCooper  TBSlifstein  MHwang  DRHuang  YHaber  SNLaruelle  M Increased synaptic dopamine function in associative regions of the striatum in schizophrenia. Arch Gen Psychiatry 2010;67 (3) 231- 239
PubMed Link to Article
Knutson  BBjork  JMFong  GWHommer  DMattay  VSWeinberger  DR Amphetamine modulates human incentive processing. Neuron 2004;43 (2) 261- 269
PubMed Link to Article
Jackson  MEFrost  ASMoghaddam  B Stimulation of prefrontal cortex at physiologically relevant frequencies inhibits dopamine release in the nucleus accumbens. J Neurochem 2001;78 (4) 920- 923
PubMed Link to Article
Sesack  SRCarr  DB Selective prefrontal cortex inputs to dopamine cells: implications for schizophrenia. Physiol Behav 2002;77 (4-5) 513- 517
PubMed Link to Article
Cador  MBjijou  YCailhol  SStinus  L D-amphetamine-induced behavioral sensitization: implication of a glutamatergic medial prefrontal cortex-ventral tegmental area innervation. Neuroscience 1999;94 (3) 705- 721
PubMed Link to Article
Bonci  AMalenka  RC Properties and plasticity of excitatory synapses on dopaminergic and GABAergic cells in the ventral tegmental area. J Neurosci 1999;19 (10) 3723- 3730
PubMed
Mansvelder  HDMcGehee  DS Long-term potentiation of excitatory inputs to brain reward areas by nicotine. Neuron 2000;27 (2) 349- 357
PubMed Link to Article
Cepeda  CLevine  MS Where do you think you are going? the NMDA-D1 receptor trap. Sci STKE 2006;2006 (333) pe20
PubMed
Bower  EAPhelan  JR Use of amphetamines in the military environment. Lancet 2003;362(suppl)s18- s19
PubMed Link to Article
Greely  HSahakian  BHarris  JKessler  RCGazzaniga  MCampbell  PFarah  MJ Towards responsible use of cognitive-enhancing drugs by the healthy. Nature 2008;456 (7223) 702- 705
PubMed Link to Article
Booij  LWelfeld  KLeyton  M  et al.  Cross-sensitization between stimulants and stress in humans: behavioral and neurochemical correlates. 50th Annual Conference of Scandinavian College of Neuropsychopharmacology (SCNP). 2 Copenhagen, Denmark Scandinavian College of Neuropsychopharmacology (SCNP)2009;
Volkow  NDSwanson  JM Does childhood treatment of ADHD with stimulant medication affect substance abuse in adulthood? Am J Psychiatry 2008;165 (5) 553- 555
PubMed Link to Article
Boileau  IDagher  ALeyton  MWelfeld  KBooij  LDiksic  MBenkelfat  C Conditioned dopamine release in humans: a positron emission tomography [11C]raclopride study with amphetamine. J Neurosci 2007;27 (15) 3998- 4003
PubMed Link to Article

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Functional Magnetic Resonance Imaging Investigation of the Amphetamine Sensitization Model of Schizophrenia in Healthy Male Volunteers
Arch Gen Psychiatry.2011;68(6):545-554.eFigures and eTables

eFigures and eTables -Download PDF (74 KB). This file requires Adobe Reader®.

eTable 1. Placebo main effect of load.

eTable 2. Amphetamine main effect of load.

eFigure 1. Reaction times data for subjects receiving amphetamine.

eFigure 2. Brain maps showing load-dependent BOLD response in the groups receivingplacebo (left) and amphetamine (right) on Day
Supplemental Content

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 12

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles