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Original Article |

Increased Synaptic Dopamine Function in Associative Regions of the Striatum in Schizophrenia FREE

Lawrence S. Kegeles, MD, PhD; Anissa Abi-Dargham, MD; W. Gordon Frankle, MD; Roberto Gil, MD; Thomas B. Cooper, MA; Mark Slifstein, PhD; Dah-Ren Hwang, PhD; Yiyun Huang, PhD; Suzanne N. Haber, PhD; Marc Laruelle, MD
[+] Author Affiliations

Author Affiliations: Departments of Psychiatry (Drs Kegeles, Abi-Dargham, Frankle, Gil, Slifstein, Hwang, Huang, and Laruelle and Mr Cooper) and Radiology (Drs Kegeles, Abi-Dargham, Hwang, and Huang), Columbia University College of Physicians and Surgeons, New York, New York; Division of Translational Imaging, New York State Psychiatric Institute, New York (Drs Kegeles, Abi-Dargham, Frankle, Gil, Slifstein, Hwang, Huang, and Laruelle and Mr Cooper); Departments of Neurobiology and Anatomy, University of Rochester School of Medicine, Rochester, New York (Dr Haber); Schizophrenia and Cognitive Disorder Discovery Performance Unit, Neurosciences Center of Excellence in Drug Discovery, GlaxoSmithKline, Harlow, England (Dr Laruelle); and Department of Neurosciences, Imperial College, London, England (Dr Laruelle).


Arch Gen Psychiatry. 2010;67(3):231-239. doi:10.1001/archgenpsychiatry.2010.10.
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Context  A long-standing version of the dopamine hypothesis of schizophrenia postulates that hyperactivity of dopaminergic transmission at D2 receptors in the limbic striatum is associated with the illness and that blockade of mesolimbic D2 receptors is responsible for the antipsychotic action of D2 receptor antagonists.

Objective  To localize dopaminergic hyperactivity within the striatum in schizophrenia.

Design  Case-control study.

Setting  Inpatient research unit.

Participants  Eighteen untreated patients with schizophrenia and 18 healthy control subjects matched for age, sex, ethnicity, parental socioeconomic status, cigarette smoking, and weight.

Main Outcome Measures  Percentage change in dopamine D2 receptor availability in striatal subregions within each subject measured by positron emission tomography with carbon 11–labeled raclopride before and during pharmacologically induced dopamine depletion.

Results  In the associative striatum, acute dopamine depletion resulted in a larger increase in D2 receptor availability in patients with schizophrenia (mean [SD], 15% [7%]) than in control subjects (10% [7%], P = .045), suggesting higher synaptic dopamine concentration. Within the associative striatum, this effect was most pronounced in the precommissural dorsal caudate (15% [8%] in patients vs 9% [8%] in controls, P = .03). No between-group differences were observed in the limbic and sensorimotor striatum.

Conclusions  These findings suggest that schizophrenia is associated with elevated dopamine function in associative regions of the striatum. Because the precommissural dorsal caudate processes information from the dorsolateral prefrontal cortex, this observation also suggests that elevated subcortical dopamine function might adversely affect performance of the dorsolateral prefrontal cortex in schizophrenia. On the other hand, the absence of a group difference in the limbic striatum brings into question the therapeutic relevance of the mesolimbic selectivity of second-generation antipsychotic drugs.

Figures in this Article

Schizophrenia is a chronic mental illness characterized by disturbances of thought, perception, volition, and cognition. Schizophrenia typically emerges during late adolescence, and the course of the illness is usually characterized by alternating episodes of illness exacerbation and partial remission.1 Manifestations of the illness are commonly divided into positive (delusions, hallucinations, and thought disorganization), negative (lack of drive and motivation, alogia, passivity, and social withdrawal), and cognitive (poor performance on cognitive tasks involving attention, memory, and executive function) symptoms.2,3

The prognosis of schizophrenia has dramatically improved since the introduction of antipsychotic medications in the late 1950s.4 Because all antipsychotic drugs are antagonists at the D2 receptor,5,6 an alteration of dopamine (DA) transmission at this receptor has long been suspected of playing a role in the pathophysiologic mechanism of schizophrenia. Specifically, excess D2 transmission has been proposed to underlie positive symptoms because these symptoms respond better than negative or cognitive symptoms to D2 receptor blockade (for references and review, see Davis et al7).

With advances in brain imaging techniques, direct evidence suggestive of dysregulation of striatal DA transmission in schizophrenia has emerged. Studies have documented an increase in the striatal accumulation of fluorine 18–labeled fluorodopa in schizophrenia,814 consistent with increased activity of dopa-decarboxylase, an enzyme involved in DA synthesis. Investigation of DA synaptic levels was made possible by imaging the competition between DA and radiotracers for binding to D2 receptors. Three of 3 studies using this approach have reported an increase in amphetamine-induced striatal DA release in patients with schizophrenia.1517 Synaptic DA function in the unchallenged state was also evaluated using an acute DA depletion paradigm. In rodents, acute DA depletion is associated with an acute increase in the in vivo binding of radioligands to D2/3 (hereinafter termed D2) receptors.18 The acute DA depletion technique was developed in humans with the use of α-methylparatyrosine (α-MPT) to assess the degree of occupancy of D2 receptors by DA.1923 The method is illustrated in Figure 1.

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Figure 1.

Schematic representation of the experiment. The blue rectangles represent the total population of D2 receptors. At baseline, an unknown proportion of these receptors is occupied by dopamine (shaded area), and only a fraction of receptors are unoccupied and available to binding by carbon 11–labeled raclopride ([11C]RAC). After depletion of endogenous dopamine induced by α-methylparatyrosine (α-MPT), all receptors are available to [11C]RAC binding. Thus, comparing the [11C]RAC binding potential at baseline and after dopamine depletion allows derivation of the proportion of D2 receptors that were masked by dopamine at baseline.

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With this technique, higher occupancy of striatal D2 receptors by DA was found in patients with schizophrenia experiencing an episode of illness exacerbation than in healthy controls.24 The dysregulation of DA transmission demonstrated by the imaging study predicted better response of positive symptoms to antipsychotic treatment. The study provided the first direct evidence of increased occupancy of D2 receptors by DA in the striatum of patients with schizophrenia.

A limitation of the study was that the resolution of the camera used did not allow differentiation of the signal from various regions of the striatum, a limitation now overcome by newer positron emission tomography (PET) cameras. An imaging analytical approach that captures the functional subdivisions of the striatum with the use of the D2 receptor antagonist carbon 11–labeled raclopride ([11C]raclopride) was developed.25,26 The test-retest reliability of [11C]raclopride binding potential (BPND; see the “Methods” section) measurements and the effects of stimulants on [11C]raclopride BPND measurements in healthy volunteers were documented.2530 The agreement between the studies, as well as the consistency between the PET data and microdialysis data in nonhuman primates,31 further documented the robustness of these striatal subdivision measurements.

In this study, we examined baseline occupancy of D2 receptors by DA in functional subdivisions of the striatum in untreated patients with schizophrenia and healthy control subjects. The D2 receptor availability was measured with PET and [11C]raclopride at baseline and during acute DA depletion achieved by administration of high doses of α-MPT for 2 days.32,33

SUBJECTS

The protocol was approved by the institutional review boards of the New York State Psychiatric Institute and Columbia University Medical Center. All subjects provided written informed consent. Patients were recruited after voluntary admission to a research ward (Schizophrenia Research Unit, New York State Psychiatric Institute) and were inpatients throughout the study. Capacity to provide informed consent was evaluated by a psychiatrist not associated with the study. Assent from involved family members was also obtained.

Inclusion and exclusion criteria for patients and controls were as in the study by Abi-Dargham et al,24 except that weight was required to be between 50 and 115 kg. Groups were matched for age, sex, ethnicity, parental socioeconomic level,34 nicotine smoking, and weight. Severity of clinical symptoms was measured with the Positive and Negative Syndrome Scale (PANSS).35

PET PROTOCOL

Subjects underwent 2 measurements of D2 receptor BPND with PET, [11C]raclopride, and the sustained equilibrium–constant infusion technique.36 The first scan was obtained in control conditions (baseline scan) on day 1 of the study. The second scan was obtained on day 3, during DA depletion induced by oral administration of α-MPT, dosed on a sliding scale by subject weight 4 times daily for 2 days. Thus, 2 measures of BPND were obtained in each subject: at baseline (BPNDBASE) and in the depleted state (BPNDDEPL).

On both days, [11C]raclopride was administered as a priming bolus followed by constant infusion for 80 minutes. The bolus to infusion ratio was 105 minutes (ie, 53% of the dose was given in the bolus). [11C]Raclopride was delivered in a 60-mL normal saline solution. A bolus dose of 30 mL was administered over 2 minutes via a pump (Gemini PC-1; IMED, San Diego, California). After the bolus, the pump was reset to deliver 25 mL at 0.3 mL/min for the remaining 80 minutes. This infusion protocol induces a state of sustained binding equilibrium, starting at about 45 minutes.25

Imaging was performed with a PET camera (ECAT EXACT HR+; Siemens/CTI, Knoxville, Tennessee) that acquires 63 sections covering an axial field of view of 15.5 cm (axial sampling of 2.46 mm). The 3-dimensional mode in plane and axial resolutions are 4.4 and 4.1 mm full-width half-maximum at the center of the field of view, respectively. Emission data were collected in the 3-dimensional mode as 8 successive frames of 5 minutes' duration collected from 40 to 80 minutes after the start of the [11C]raclopride infusion.

α-MPT ADMINISTRATION

The regimen of α-MPT administration was selected to provide and maintain significant inhibition of tyrosine hydroxylase activity.37 The α-MPT was given for 2 days because this duration of treatment is adequate to produce marked DA depletion but too short to induce significant D2 receptor upregulation (see discussion in Laruelle et al19). The first α-MPT dose was given on the evening of day 1 (8 PM). On day 2, α-MPT was administered at 7 AM, noon, 6 PM, and 11 PM. On day 3, α-MPT was given at 7 AM, noon, and 1 hour before the beginning of the second scanning session (5 PM).

The dose of α-MPT was adjusted to subjects' weight, according to a sliding scale (50 kg and 115 kg are the weight limits defined by inclusion criteria): 50 to 58 kg, 750 mg; 59 to 75 kg, 1000 mg; 76 to 92 kg, 1250 mg; and 93 to 115 kg, 1500 mg. With the use of this scale, each dose was between 12.9 mg/kg and 16.9 mg/kg for all subjects. To prevent the formation of α-MPT crystals in the urine, subjects were instructed to drink at least 4 L of fluids per day, starting the day before the study, and fluid intake was carefully monitored.37,38 Urinalysis was performed daily. Clinical evaluation, including orthostatic blood pressure monitoring, was performed 4 times a day. Trough plasma α-MPT levels were measured 4 hours after the seventh dose by means of gas chromatography–mass spectrometry.

IMAGE ANALYSIS

Image analysis was performed with image processing and analysis software (MEDx; Sensor Systems Inc, Sterling, Virginia) as described previously.25 For each subject, PET data were coregistered to a T1-weighted high-resolution magnetic resonance image acquired on a 1.5-T imaging system (Signa Advantage; General Electric, Milwaukee, Wisconsin). Regions of interest (ROIs) were drawn on each individual's magnetic resonance image and applied to the coregistered PET images. The striatum was divided into 5 anatomic ROIs comprising 3 functional subdivisions, as described previously.26 The ROIs included the ventral striatum (VST), the precommissural dorsal caudate (preDCA), the precommissural dorsal putamen, the postcommissural caudate, and the postcommissural putamen. Activities from left and right regions were averaged.

On the basis of their cortical and subcortical connections, the preDCA, precommissural dorsal putamen, and postcommissural caudate were classified functionally as belonging to the associative striatum (AST), the VST captured the limbic striatum (LST), and the postcommissural putamen captured the sensorimotor striatum. The cerebellum was used as the region of reference to estimate nonspecific binding.

Specific binding was defined as the difference between activity in the ROI (AROI) and activity in the cerebellum (ACER). The binding potential relative to nonspecific binding (BPND) was defined as follows:

where fND is the fraction of free plus nonspecifically bound ligand in brain, BMAX is the maximal number of binding sites, 1/KD is the affinity of [11C]raclopride for D2 receptors, FDA is the temporal and spatial average concentration of free synaptic DA in the vicinity of D2 receptors, and Ki is the inhibition constant of DA for [11C]raclopride at the D2 receptor.

The α-MPT–induced increase in BPND was calculated as the difference between BPNDBASE and BPNDDEPL, expressed as a percentage of BPNDBASE. Because FDA during the depleted condition is negligible compared with Ki,24 the increase in BPND induced by α-MPT is linearly related to baseline FDA by FDA = Ki(a − 1), where a is the ratio of BPND DEPL to BPND BASE (see derivation in Laruelle et al19). Therefore, the relative increase in BPND from baseline to the depleted state provides an index of the DA synaptic concentration during the baseline state.

STATISTICAL ANALYSIS

Between-group comparisons were performed by factorial analysis of variance or repeated-measures analysis of variance with group × effect interaction, as appropriate. Relationships between continuous variables were analyzed with the Pearson product moment correlation coefficient. A probability value of .05 was selected as the significance level.

GROUP COMPOSITION

Twenty-two patients and 22 controls were recruited for this study. Eighteen patients and 18 controls completed the protocol. Reasons for noncompletion (n = 8) included cyclotron failure on the day of the second scan (n = 1) and intolerance of the adverse effects of α-MPT (n = 7), resulting in withdrawal from the study. Common adverse effects included sedation, orthostatism, tremor, irritability, and bradykinesia. These effects spontaneously resolved within 12 hours of the last α-MPT administration. Uncommon adverse effects included acute dystonia (observed in 1 subject) that resolved within minutes after diphenhydramine hydrochloride administration. Crystalluria was not observed in this study.

Completers were matched for age, sex, ethnicity, parental socioeconomic status,34 cigarette smoking, and weight (Table 1). Among the 18 patients, 6 were antipsychotic-naive and experiencing a first episode of illness. Twelve patients were chronically ill and had been previously treated with antipsychotic drugs. In the previously treated group, 4 patients had not received antipsychotic drugs for more than 1 year. In the remaining 8 patients, the mean (SD) interval between the last antipsychotic administration and the first scan was 110 (96) days (minimum, 20 days; maximum, 300 days). These previously treated patients were experiencing an episode of illness exacerbation at the time of recruitment and were admitted to the hospital for clinical reasons. Total PANSS35 scores at baseline were 78.6 (20.6) (with these and subsequent values given as mean [SD]) in the patient group.

Table Graphic Jump LocationTable 1. Demographic and Clinical Variables
EXPERIMENTAL PARAMETERS

No between-group differences were observed in [11C]raclopride radiation and mass dose or in α-MPT dose or plasma levels (Table 2).

α-MPT EFFECTS ON [11C]RACLOPRIDE BPND

No significant differences were observed between control subjects and patients with schizophrenia in baseline [11C]raclopride BPND in any region (Table 3). The D2 receptor availability was significantly higher after α-MPT exposure than at baseline in all regions (repeated-measures analysis of variance, P < .001; Table 3).

Table Graphic Jump LocationTable 3. Effect of DA Depletion on D2 Receptor Availability in Control Subjects and Patients With Schizophrenia

Table 3 and Figure 2 report the effect of α-MPT on [11C]raclopride BPND (ΔBPND) by group in striatal subregions and in the striatum as a whole. No between-group differences were observed in ΔBPND in the VST and the sensorimotor striatum (P = .56 and .32, respectively). In the AST, ΔBPND was significantly larger in patients than controls (P = .045). Among the AST subregions, a significant between-group difference was observed in the preDCA (P = .03), but not in the other regions. In the striatum as a whole, a trend-level difference was observed between the groups (P = .07). The α-MPT plasma levels were not correlated with ΔBPND, either in the regions or in the striatum as a whole (r2 < 0.03).

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Figure 2.

α-Methylparatyrosine–induced increase in binding potential (BPND) of carbon 11–labeled raclopride ([11C]RAC) at D2 receptors after acute dopamine depletion. Mean percentage increase (SEM) in [11C]RAC BPND is shown for control subjects and patients with schizophrenia in the 3 functional subregions of the striatum: ventral striatum (VST), associative striatum (AST), and sensorimotor striatum (SMST). *P < .05.

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α-MPT EFFECT ON SYMPTOMS

Exposure to α-MPT induced a significant reduction (−15% [15%]) in the severity of positive symptoms, a significant increase in the severity of negative symptoms (+16% [31%]), and no changes in the general pathology subscale or in the total PANSS rating (Table 4).

Table Graphic Jump LocationTable 4. Effect of α-MPT on Symptoms
DOPAMINE LEVELS AND BASELINE SYMPTOMS

The relationship between ΔBPND and baseline positive and negative symptoms was investigated in the patient group. No significant relationship was observed between severity of positive symptoms at baseline and ΔBPND in any of the 5 subregions. No significant relationship was observed between severity of negative symptoms at baseline and ΔBPND in preDCA, precommissural dorsal putamen, postcommissural caudate, or postcommissural putamen. A significant inverse relationship was observed between severity of negative symptoms at baseline and ΔBPND (r2 = 0.31, P = .01). Among the PANSS negative subscale components, the item capturing passivity, apathy, and social withdrawal was the best correlated with low DA tone in the VST (r2 = 0.47, P = .001).

EFFECT OF PREVIOUS ANTIPSYCHOTIC TREATMENT

The ΔBPND was not significantly different between drug-naive patients (n = 6; age, 26 [8] years) and previously treated patients (n = 12; age, 31 [8] years) (Table 5).

Table Graphic Jump LocationTable 5. Effect of DA Depletion on D2 Receptor Availability in Antipsychotic-Naive and Antipsychotic-Free Previously Treated Patients

The results of this study suggest that DA occupies a greater proportion of D2 receptors in untreated patients with schizophrenia than in matched control subjects in the AST during the first episode of illness and subsequent episodes of illness exacerbation. In contrast, no difference was observed between patients and controls in D2 receptor occupancy by DA in the LST or in the sensorimotor striatum. In preDCA, acute DA depletion resulted in 9% (8%) and 15% (8%) increases in D2 receptor availability in control subjects and patients with schizophrenia, respectively, suggesting that the temporal and spatial average synaptic DA concentration in this region is almost double that of healthy controls.

METHODOLOGIC CONSIDERATIONS

The increased magnitude of ΔBPND in the AST is best explained by a higher occupancy of D2 receptors by DA in patients with schizophrenia than in controls during the baseline scan. If α-MPT–induced DA depletion were complete, this increase in D2 receptor availability would indicate that DA occupies 8% (SD, 7%) of AST D2 receptors in controls vs 13% (6%) in patients with schizophrenia. The α-MPT regimen used in this study is estimated to result in about 70% to 80% depletion of striatal DA. At 4 g/d, α-MPT induces 70% depletion in cerebrospinal fluid homovanillic acid, and the magnitude of DA depletion is expected to be larger than that of homovanillic acid depletion.39 Furthermore, at least 80% DA depletion or 80% D2 receptor blockade is needed to produce extrapyramidal symptoms,40,41 which were present at a moderate level in most of the subjects.

The conclusion that occupancy of AST D2 receptors by DA is increased in patients with schizophrenia compared with controls is valid even if the depletion is incomplete (see discussion in Abi-Dargham et al24), provided that the relative magnitude of DA depletion is comparable between groups. This assumption is supported by the observation of similar plasma α-MPT levels in both groups, by the fact that the range of α-MPT plasma concentration observed in this study provides a high degree of tyrosine hydroxylase inhibition, and by the fact that the between-group difference was regionally selective. This conclusion also requires that no significant upregulation of D2 receptors occurred during the acute DA depletion, an assumption confirmed in rodent studies.19,42 Finally, it is important to note that changes in [11C]raclopride BPND following changes in synaptic DA levels might be more complex than accounted for by a simple binding competition model (for review and discussion, see Laruelle18).

COMPARISON WITH THE PREVIOUS STUDY

No between-group difference in baseline D2 receptor availability was seen in this or the previous α-MPT study carried out with single-photon emission computed tomography (SPECT) and iodobenzamide labeled with iodine 123,24 an observation in agreement with most imaging reports in untreated patients with schizophrenia (for review and references, see Laruelle43). This study, in line with the previous α-MPT study,24 confirms that acute DA depletion led to a higher increase in D2 receptor availability in patients with schizophrenia than in controls. In contrast to the previous α-MPT study,24 D2 receptor availability measured during DA depletion was not significantly higher in patients than controls because of large between-subject variability in both groups. These data lend further support to the conclusion that, in schizophrenia, elevated D2 receptor transmission is due to increased stimulation of D2 receptors by DA rather than abnormally high expression of D2 receptors.

At the level of the striatum as a whole, the results of the present study performed with PET and [11C]raclopride were comparable to the results of the previous study. In that study, the α-MPT regimen resulted in an increase of 9% (7%) of [123I]iodobenzamide BPND in control subjects compared with 19% (11%) in patients with schizophrenia (P = .003). In the SPECT study, the difference between patients and controls was significant in the striatal region, whereas in this study it was present only at trend level. This difference is not likely to be due to differences in the patient samples: both groups were recruited from the same hospital ward and exhibited similar levels of symptom severity. Also, the mean doses and α-MPT plasma levels were similar in the 2 studies. Thus, the difference between the 2 studies might simply be related to sampling variability. Also, the striatal ROIs drawn on SPECT images are more rostral and dorsal than the striatal ROIs drawn on magnetic resonance images in the PET study. As a result, the striatal SPECT region might be more weighted toward the AST, the striatal subregion found to have a significant group difference in the PET study.

REGIONAL LOCALIZATION

The LST ΔBPND was similar in patients and controls, an observation that did not support the longstanding hypothesis of a DA elevation in the LST in schizophrenia. The only finding in the LST was that of a correlation between low ΔBPND and severity of negative symptoms, suggesting that low DA activity in this region might contribute to negative symptoms. In contrast, a group difference in ΔBPND was observed in the AST and was more pronounced in the rostral and dorsal part of the caudate nuclei (preDCA). Because our a priori hypothesis was that DA levels would be more elevated in LST than in other regions, this result was unexpected, and replication will be needed before asserting that the increase in DA levels in schizophrenia in AST is a robust finding.

The higher occupancy of AST D2 receptors by DA in patients with schizophrenia was not a long-term consequence of previous exposure to D2 receptor antagonists because the effect was similar in previously treated patients and antipsychotic-naive patients. Thus, this factor appears to be associated with the illness rather than its treatment. No relationship was found between levels of synaptic DA in AST and severity of positive symptoms rated cross-sectionally by the PANSS. In a previous study of striatal DA transmission dysfunction in schizophrenia that used the amphetamine challenge, the magnitude of DA dysregulation was found to be better predicted by the acuity of the positive symptoms rather than their severity.44 This temporal dimension of the positive symptoms is not captured by the PANSS.

The LST is a smaller region than the AST, raising the concern that the lack of detection of a between-group difference in the LST might be related to technical limitations of the imaging method, such as greater measurement noise in the LST. Nevertheless, under the methods used in this study, the test-retest variability of [11C]raclopride BPND measurement did not differ between LST and dorsal caudate,25 nor was between-subject variability in ΔBPND greater in LST than AST in this study. Therefore, there are no indications that the lack of between-group difference in the LST ΔBPND is due to technical limitations.

IMPLICATIONS

The findings of the present study challenge the idea that alterations of DA transmission in schizophrenia affect the mesolimbic rather than the nigrostriatal DA pathways. This hypothesis was formulated in the early 1970s,4549 notably in an influential article by Stevens.50 As pointed out by Lidsky,51 the striatum was conceptualized at that time as being mostly involved in motor control. The mesolimbic theory provided “conceptual relief” to the DA hypothesis of schizophrenia because the territories innervated by the mesolimbic DA system were known to be involved in modulation of drive, affect, and memory, dimensions more related to psychiatric symptoms than the motor functions ascribed to the striatum.

This widely held hypothesis also implied that blockade of D2 receptors in the VST was responsible for the antipsychotic effect, whereas blockade of these receptors in nigrostriatal pathways was associated only with undesirable motor side effects. This hypothesis led to the view that a “mesolimbic selectivity” was a desirable property in the development of new antipsychotic drugs. Indeed, at low doses, most “atypical” or “second-generation” antipsychotic drugs show a dose-related selectivity for affecting the firing of A10 vs A9 neurons and for inducing gene expression in the nucleus accumbens vs the corpus striatum.5258

Nevertheless, it is not yet established whether the mesolimbic-selective effects of these drugs observed at low doses in animals are relevant at the doses used in clinical settings.5962 Furthermore, the therapeutic superiority of “second-generation” antipsychotic drugs has recently been questioned by a number of clinical trials.6365 An important consequence of this study is the proposition that the “mesolimbic” selectivity of second-generation antipsychotic drugs might not be relevant to their therapeutic effectiveness because the primary site of antipsychotic action related to D2 receptor blockade might be the AST. Regarding the LST, the study suggests that, if anything, low DA tone in the VST might be associated with severity of negative symptoms (passivity and social withdrawal). This observation is consistent with the role of limbic DA in reward66 and with the general lack of effectiveness of antipsychotic drugs on these symptoms.

It is now well established that the dorsal striatum, particularly the caudate nucleus, is involved in learning, habituation, memory, attention, motivation, emotion, and volitional behavior.6770 Furthermore, the preDCA is the area of the striatum that receives the largest corticostriatal projections from the dorsolateral prefrontal cortex (DLPFC)7175 (Figure 3), the neocortical area most implicated in the pathophysiologic mechanism of schizophrenia. The D2 receptors in the striatum modulate corticostriatal synapses onto medium spiny neurons and, therefore, the flow of information within corticostriatal loops.7779 The human AST also receives convergent inputs from limbic-related cortical regions and therefore supports some integrative functions ascribed to the nucleus accumbens in rodents.80,81 Thus, the AST, particularly the preDCA, is in a unique position to integrate information from multiple regions and to regulate circuitry affecting DLPFC function. In schizophrenia, increased DA activity at D2 receptors in the AST might reduce the ability of the DLPFC to engage striatal processing functions because D2 receptor stimulation reduces glutamatergic transmission into striatal γ-aminobutyric acid–releasing medium spiny neurons.82

Place holder to copy figure label and caption
Figure 3.

Schematic representation of the tripartite organization of the striatum and its connections, with functional systems color coded: red, limbic striatum; yellow, associative striatum; blue, sensorimotor striatum. The circle captures the schematic localization of the precommissural dorsal caudate, where an increased dopamine transmission at D2 receptors in patients with schizophrenia compared with control subjects was measured in this study. The white line represents the projections from the dorsolateral prefrontal cortex to the precommissural dorsal caudate. Increased D2 receptor transmission in precommissural dorsal caudate might thus affect information processing from the dorsolateral prefrontal cortex (adapted from Haber and McFarland76). C indicates caudate; P, putamen; VA, ventral anterior nucleus of the thalamus; and VL, ventral lateral nucleus of the thalamus.

Graphic Jump Location

Subcortical DA dysregulation in schizophrenia has historically been conceptualized as a consequence of a primary DLPFC dysfunction.83,84 The results of this study suggest that alterations of subcortical DA transmission, if located in the preDCA, might in turn negatively affect DLPFC function. This proposition is directly supported by the recent observation that transgenic mice overexpressing D2 receptors selectively in the striatum exhibit selective cognitive impairments in working memory tasks and behavioral flexibility, behavioral competencies associated with prefrontal cortex.85

In conclusion, this study confirmed that DA occupies a higher proportion of striatal D2 receptors in patients with schizophrenia undergoing an episode of illness exacerbation than in matched controls. This increased DA transmission was localized to the associative regions of the striatum and, most specifically, the rostral and dorsal parts of the caudate, the regions of the striatum most involved in DLPFC information processing. These results, if replicated and extended, have important consequences for the understanding of the role of DA in schizophrenia and for the development of novel medications.

Correspondence: Lawrence S. Kegeles, MD, PhD, Division of Translational Imaging, New York State Psychiatric Institute, 1051 Riverside Dr, Unit 31, New York, NY 10032 (lsk5@columbia.edu).

Submitted for Publication: December 4, 2008; final revision received May 28, 2009; accepted June 21, 2009.

Author Contributions: Drs Kegeles and Laruelle had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Financial Disclosure: Dr Kegeles has received research support from Amgen Inc and Pfizer Inc. Dr Abi-Dargham has received research support from Eli Lilly and Company, Bristol-Myers Squibb, and GlaxoSmithKline; is a consultant or advisory board member for Sanofi-Aventis LLC, Otsuka America Pharmaceutical Inc, Vanda Pharmaceuticals Inc, Eli Lilly and Company, and Intra-Cellular Therapies Inc; and is a member of the Speakers Bureau for Bristol-Myers Squibb. Dr Frankle has received research support from GlaxoSmithKline and Sepracor Inc; is a consultant or advisory board member for Sepracor Inc, Bristol-Myers Squibb, Transcept Pharmaceutical Inc, and Eli Lilly and Company; and is a member of the Speakers Bureau for Bristol-Myers Squibb and Otsuka America Pharmaceutical Inc. Dr Slifstein has received research support from Intra-Cellular Therapies Inc and is a consultant for GlaxoSmithKline and Amgen Inc.

Funding/Support: This study was supported by Public Health Service grants RO1-MH54192 and K02-MH01603-01 from the National Institute of Mental Health.

Additional Contributions: We thank the subjects who participated in this study, Holly Moore for discussions on neuroanatomy, the staff of the Schizophrenia Research Unit, and the Division of Translational Imaging at New York State Psychiatric Institute.

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PubMed
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PubMed
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PubMed
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PubMed
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PubMed
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PubMed
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PubMed
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PubMed
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PubMed
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PubMed
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PubMed
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PubMed
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PubMed
Drevets  WCGautier  CPrice  JCKupfer  DJKinahan  PEGrace  AAPrice  JLMathis  CA Amphetamine-induced dopamine release in human ventral striatum correlates with euphoria. Biol Psychiatry20014928196
PubMed
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PubMed
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Figures

Place holder to copy figure label and caption
Figure 1.

Schematic representation of the experiment. The blue rectangles represent the total population of D2 receptors. At baseline, an unknown proportion of these receptors is occupied by dopamine (shaded area), and only a fraction of receptors are unoccupied and available to binding by carbon 11–labeled raclopride ([11C]RAC). After depletion of endogenous dopamine induced by α-methylparatyrosine (α-MPT), all receptors are available to [11C]RAC binding. Thus, comparing the [11C]RAC binding potential at baseline and after dopamine depletion allows derivation of the proportion of D2 receptors that were masked by dopamine at baseline.

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

α-Methylparatyrosine–induced increase in binding potential (BPND) of carbon 11–labeled raclopride ([11C]RAC) at D2 receptors after acute dopamine depletion. Mean percentage increase (SEM) in [11C]RAC BPND is shown for control subjects and patients with schizophrenia in the 3 functional subregions of the striatum: ventral striatum (VST), associative striatum (AST), and sensorimotor striatum (SMST). *P < .05.

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

Schematic representation of the tripartite organization of the striatum and its connections, with functional systems color coded: red, limbic striatum; yellow, associative striatum; blue, sensorimotor striatum. The circle captures the schematic localization of the precommissural dorsal caudate, where an increased dopamine transmission at D2 receptors in patients with schizophrenia compared with control subjects was measured in this study. The white line represents the projections from the dorsolateral prefrontal cortex to the precommissural dorsal caudate. Increased D2 receptor transmission in precommissural dorsal caudate might thus affect information processing from the dorsolateral prefrontal cortex (adapted from Haber and McFarland76). C indicates caudate; P, putamen; VA, ventral anterior nucleus of the thalamus; and VL, ventral lateral nucleus of the thalamus.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Demographic and Clinical Variables
Table Graphic Jump LocationTable 3. Effect of DA Depletion on D2 Receptor Availability in Control Subjects and Patients With Schizophrenia
Table Graphic Jump LocationTable 4. Effect of α-MPT on Symptoms
Table Graphic Jump LocationTable 5. Effect of DA Depletion on D2 Receptor Availability in Antipsychotic-Naive and Antipsychotic-Free Previously Treated Patients

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