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Original Article |

Decreased Brain GABAA-Benzodiazepine Receptor Binding in Panic Disorder:  Preliminary Results From a Quantitative PET Study FREE

Andrea L. Malizia, MBBS, MRCPsych; Vincent J. Cunningham, PhD; Caroline J. Bell, MBBChir, MRCPsych; Peter F. Liddle, PhD, MBBS, FRCPsych; Terry Jones, PhD, DSc(Hon); David J. Nutt, MBBS, DM, MRCP, FRCPsych
[+] Author Affiliations

From the Cyclotron Unit, Medical Research Council, Clinical Research Centre, Hammersmith Hospital, London, England (Drs Malizia, Cunningham, Liddle, and Jones); Psychopharmacology Unit, School of Medical Sciences, University of Bristol, Bristol, England (Drs Malizia, Bell, and Nutt); and Department of Psychiatry, University of British Columbia, Vancouver (Dr Liddle). Dr Malizia is now with the Clinical Pharmacology Unit, SmithKline Beecham Pharmaceuticals, Harlow, England.


Arch Gen Psychiatry. 1998;55(8):715-720. doi:10.1001/archpsyc.55.8.715.
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Background  Positron emission tomography (PET) allows the measurement of benzodiazepine–γ-aminobutyric acidA (GABAA) receptor kinetics. We employed flumazenil radiolabeled with carbon 11, a radioligand that labels the benzodiazepine site on the GABAA receptor, and fully quantitative, high-sensitivity PET to test the hypothesis that central benzodiazepine site binding is decreased in medication-free patients with panic disorder.

Methods  We compared 7 patients with panic disorder who had been off medication for at least 6 months and who had never abused alcohol with 8 healthy controls. The resulting parametric voxel-by-voxel maps were analyzed by voxel-based and region of interest–based methods using both parametric and nonparametric statistics.

Results  The major finding was that there is a global reduction in benzodiazepine site binding throughout the brain in patients with panic disorder compared with controls. There were sex differences in the 2 samples, but a separate analysis excluding women led to the same conclusions. In addition, the loci with the largest regional decrease in binding (right orbitofrontal cortex and right insula) were areas thought to be essential in the central mediation of anxiety.

Conclusion  These results must be considered preliminary but are congruous with previous clinical psychopharmacologic evidence of involvement of the benzodiazepine-GABAA receptor and demonstrate that decreased flumazenil binding at this site may underlie panic disorder.

Figures in this Article

PANIC DISORDER is an anxiety disorder characterized by spontaneous paroxysms of severe fear1; it has a prevalence of 1% to 2%2,3 and results in considerable morbidity4 and increased mortality.5

Pharmacologic and metabolic probes have revealed that in panic disorder there are alterations of serotonergic,68 noradrenergic,912 GABAergic,13,14 and brain cholecystokinin15,16 function and that there is corticosteroid dysregulation17 as well as increased sensitivity to the anxiety provoking effects of carbon dioxide18,19 and lactate.20,21 Thus, panic disorder may be due to the excessive and inappropriate activation of evolutionary valuable alarm systems, which could be the result of a failure of inhibition secondary to benzodiazepine–γ-aminobutyric acid (GABA) dysfunction. We postulate that this is central to panic disorder.

The evidence for GABAergic involvement in panic disorder is that blocking GABAA receptors with antagonists leads to severe anxiety in man and in animals,22,23 whereas increasing GABA function with agonists reduces anxiety.24,25 Additionally, modulating GABA effects with benzodiazepine site ligands results in anxiety modulation, so that agonists (eg, alprazolam) are panicolytic, while inverse agonists are panicogenic.26,27 Moreover, ontogenetic or phylogenetic alterations in receptor numbers or subtypes are associated with increased anxiety-like behaviors in animals.2830 Finally, patients with panic disorder are less sensitive to benzodiazepines on a number of psychophysiologic measures, such as saccadic eye movements to target and suppression of the norepinephrine appearance rate.13,31

These findings and the discovery of putative endogenous inverse agonists in man (diazepam-binding inhibitor32 and tribulin33) led to theories of panic being precipitated by the pathologic production of a putative endogenous inverse agonist. However, Nutt and colleagues14 discovered that flumazenil, a benzodiazepine site antagonist that has neutral anxiety effects in control subjects, provokes panic attacks in patients with panic disorder, disproving the putative benzodiazepine receptor inverse agonist theory. Two possible explanations may account for this finding: The first is that changed binding/function at the benzodiazepine-GABAA receptor alters the effects of flumazenil so that it behaves like an inverse agonist. The second is that flumazenil blocks a putative endogenous agonist that is present in a compensatory function but is insufficient to prevent the emergence of panic attacks.

The purpose of this study is to investigate whether patients with panic disorder have reduced brain benzodiazepine-GABAA binding in vivo that would explain the existing pharmacologic challenge and clinical data. To this end, we employed fully quantitative positron emission tomography (PET) using flumazenil radiolabeled with carbon 11 to compare the brain volume of distribution of this ligand between patients and controls. The volume of distribution is the ratio of plasma to brain ligand distribution at equilibrium. In accordance with previous work, we hypothesized that decreased binding would be found in limbic and paralimbic structures as well as in some parts of the complex brain network subserving the generation of voluntary saccades to target.13

PATIENTS

Inclusion criteria for patients and volunteers were age 21 to 65 years, no medication for more than 6 months, never having had a prescription for benzodiazepines for anxiety, and no or moderate alcohol use. Patients and volunteers with excessive use of alcohol (>28 U/wk for men and >21 U/wk for women [1 U=8 g]) and current (or previous) regular use of benzodiazepines were excluded, as they might have produced a downregulation of the BZ site that would have contaminated the data.28,34 Patients had to fulfill the criteria for a DSM-IV diagnosis of panic disorder and had to have no concurrent axis I or III diagnoses. Controls had to be men or postmenopausal women (regulatory requirement) with no current or past axis I diagnosis and no current axis III diagnosis. Patients and volunteers had an extensive clinical interview by an experienced psychiatrist (A.L.M.); semistructured interviews done by specialist physicians have previously been shown to have a reasonable concordance with structured interviews, such as the Structured Clinical Interview for DSM-III-R.35 Clinical information, including past prescriptions, was also obtained from primary care physicians, who hold personal medical history records throughout life. Patients were recruited from the Bristol Psychopharmacology Clinic and from a voluntary organization providing support for patients with anxiety disorders. Volunteers were recruited by advertisement. This study was approved by the Administration of Radioactive Substances Advisory Committee of the Department of Health and by the ethics committees of the Hammersmith Hospitals and Royal Postgraduate Medical School. Written informed consent was obtained from each patient and healthy volunteer.

The study sample comprised 8 healthy male volunteers and 7 patients (4 men, 3 women). The mean (SD) ages were 38.9 (9.0) years for the controls and 38.1 (18.4) years for the patients (Mann-Whitney z=0.64, not significant). Mean alcohol consumption was 14.5 (9.3) U/wk for controls and 8.7 (6.2) U/wk for patients (Mann-Whitney z=1.16, not significant). The state anxiety score at the time of scanning, as measured by the Spielberger State Anxiety Inventory,36 was 28.6 (5.3) for controls and 39.9 (12.9) for patients (Mann-Whitney z=1.96, P=.05). Clinical evaluation determined the presence of a previous comorbid psychiatric disorder in 1 patient (major depressive disorder). One patient had taken temazepam for 1 week for insomnia, and 3 controls had occasionally used benzodiazepines for jet lag or insomnia. Three patients had experimented with illicit drugs when younger; in all cases they had not used any illicit drugs for at least 6 months. All participants had negative findings on urine screens for benzodiazepines, alcohol, and drugs of abuse at the time of the scan. Patients were further clinically characterized using the Agoraphobic Cognitions Questionnaire,37 the Spielberger Trait Anxiety Inventory and Spielberger State Anxiety Inventory,36 and the Marks and Sheehan Phobia Scale.38 Further clinical details are summarized in Table 1. Details from volunteers are summarized in Table 2.

Table Graphic Jump LocationTable 1. Clinical Indices for Patients*
Table Graphic Jump LocationTable 2. Characteristics of Healthy Volunteers*
PET FACILITIES AND PROCEDURES

We measured brain GABAA-benzodiazepine receptors in panic disorder using the labeled antagonist [11C]flumazenil and fully quantitative PET. Scans were obtained using a model 953B PET scanner (CTI Inc, Knoxville, Tenn) with the collimating septa retracted (full-width half maximum, 8 mm transaxial and 4 mm axial). This "3-dimensional" technique increases the sensitivity of the scanner up to fivefold.39 However, careful calibration is needed with each scan, as the sensitivity of the crystals to photons in different energy windows40 needed for measured scatter correction varies with temperature changes. Therefore, for all these studies, we performed a scan with a germanium 68 phantom to calibrate scanner counts, and we also obtained a measured attenuation scan using rotating germanium 68 rods with the patient in situ. Patients were positioned in the scanner parallel to the canthomeatal line using laser lines whose positions were known with respect to the camera. The field of view of the scanner is 11 cm in the z direction; hence, our data set consists mainly of data from the middle and lower parts of the brain; for the whole group, this resulted in available data from 4 cm below to 5 cm above the anterior commissure–posterior commissure plane. For each session, 340 MBq (9.2×10−9 Ci) of [11C]flumazenil was injected intravenously in the left antecubital vein, and data were collected for 90 minutes. Each subject had a radial artery cannula to allow continuous counting of blood radioactivity concentrations with a bismuth germanate41 counter (an arterial input function is needed to quantitate brain concentrations of the ligand with respect to blood). Discrete samples were taken at 2.5, 10.5, 20.5, 35.5, 50.5, and 65.5 minutes for calibration of the count data over a well counter and to determine the plasma counts fraction, and samples were taken at 3, 4, 5, 6, 10, 20, 35, and 60 minutes to measure concentrations of [11C]flumazenil and its metabolites. The metabolite concentration was subtracted from the total, resulting in a metabolite-corrected plasma input function. Twenty-four time-dynamic frames were acquired (3 of 1 minute, 19 of 3 minutes, and 2 of 15 minutes). The brain volume of distribution of this tracer was assessed using voxel-by-voxel spectral analysis42 of PET images. This method allows measures of receptor binding to be clearly separated from possible confounding factors, such as blood flow (delivery).

[11C]Flumazenil is a radiolabeled benzodiazepine site PET ligand with very favorable characteristics for studying benzodiazepine-GABAA (BZ) receptor kinetics in man in vivo, as it crosses the blood-brain barrier easily, does not bind to other receptors, has high affinity, and is not metabolized in the brain, while its plasma metabolites are highly polar and therefore do not access brain tissue.43 Brain volume of distribution is a receptor kinetics measure that is proportional to the maximum number of available binding sites divided by the dissociation constant (binding potential); it is the sum of the signal from all 3 tissue compartments (free plus nonspecific binding plus specific binding). This measure is independent of blood flow and can be obtained using only 1 PET scan,42 an important consideration when studying patients with panic disorder, who may find it difficult to endure more than 1 scanning session. Prior to spectral analysis, the various dynamic frames were all realigned using rigid body transformations, as in the realignment procedure in statistical parametric mapping.44 This was necessary to control for possible patient movement, although subjects were regularly checked for movement within the scanner by visualizing external markers drawn over the skull's bony landmarks and aligned with laser beams within the scanner inlet. [11C]Flumazenil is an ideal ligand for realignment, as it has a wide and approximately uniform cortical distribution.

STATISTICAL ANALYSIS

Two separate methods were used to analyze the data (between-subjects test), as there is no agreed optimal method. Voxel-by-voxel analysis avoids the sampling bias associated with region of interest (ROI) selection but has only been validated for use with parametric analyses. Therefore, we also employed ROI analysis and nonparametric methods, as volume of distribution values may not be normally distributed.

Hence, for parametric voxel-by-voxel analysis, the parametric images were put in stereotactic space, smoothed with a 15-mm gaussian filter, and compared using statistical parametric mapping (SPM95)4547 without global normalization, as the scans were fully quantitative.

For nonparametric analysis, ROIs were drawn using an automated stereotactic atlas of regions positioned on the spatially normalized volume of distribution images, as in previous studies.48 Comparisons were then carried out using the Wilcoxon–Mann-Whitney test.

A significant, global, contiguous decrease in volume of distribution was detected in the whole brain according to spatial extent criteria (41627 of 55839 total voxels; P<.001 for fully corrected statistical parametric mapping extent criteria), with peak decreases in the right orbitofrontal cortex, right insula, right lingual gyrus, left fusiform gyrus, right superior temporal gyrus, left middle temporal gyrus, right middle temporal gyrus, left dorsolateral frontal cortex, left anterior medial frontal cortex, and left frontal pole. Benzodiazepine volume of distribution maps of a middle brain slice (z=+12 mm, ie, 12 mm above the anterior commissure–posterior commissure plane) are shown for the median volume of distribution value in each group (Figure 1).

Place holder to copy figure label and caption
Figure 1.

Middle brain (12 mm above the anterior commisure–posterior commisure plane) median volume of distribution map for controls (left) and patients with panic disorder (right). Note the generalized decrease in volume of distribution affecting the thalami and the heads of the caudate nucleus. FC indicates frontal cortex; CN, caudate nucleus; Th, thalamus; Ins, insula; TC, temporal cortex; and OC, occipital cortex.

Graphic Jump Location

The mean volume of distribution values for single brain voxels in the panic disorder group are between 76% and 82% of the mean values in the control group, as shown for the voxels with the maximal (right orbitofrontal cortex) and minimal (left retrosplenial isthmus–posterior cingulate) differences within the spatial extent significance volume (Figure 2).

Place holder to copy figure label and caption
Figure 2.

Volume of distribution values for the panic disorder and control groups at the voxels with the greatest (left, z=4.22) and least (right, z=1.96) significant difference within the gray matter.

Graphic Jump Location

Comparison of the pooled regional averages for the 26 regions for which we have ROI values using the nonparametric Wilcoxon–Mann-Whitney test also shows significant global reduction in binding (z=6.99; P<.001). Individual regional z scores using a Wilcoxon–Mann-Whitney test are shown (Table 3). Nonparametric comparison of male participants (8 controls vs 4 patients with panic disorder) shows similar (if not greater) differences, and these data are also presented in Table 3. This comparison is important, as it argues against the notion that the observed differences are due to the sex differences between the samples.

Table Graphic Jump LocationTable 3. Volume of Distribution Values Using [11C]Flumenazil by Region of Interest

Nobody experienced a panic attack either during the scanning session or during the preparation period.

We have demonstrated significantly decreased benzodiazepine receptor binding. This is consistent with the idea that panic disorder may be due to defective brain inhibition that leads to or allows paroxysmal elevations in anxiety during panic attacks. The fact that no one experienced a panic attack during a scan suggests that the observed changes are due either to baseline changes in receptor binding (a decrease in the maximum number of binding sites or an increase in the dissociation constant) or to increased occupancy of the receptor by an endogenous ligand, perhaps in the context of the increased anxiety tone. The peak decreases in benzodiazepine binding were in anatomical areas thought to be involved in the experience of anxiety in man (eg, the orbitofrontal cortex and insula).4952 If panic disorder is caused by a dysfunctional alarm system,53 global alterations in brain chemistry might be expected, because an effective extreme danger reaction has to involve the whole brain, and interruption of other ongoing behaviors is potentially vital for the survival of the whole organism.

Previously, other groups have attempted to examine the theory of reduced binding at the benzodiazepine-GABAA receptor by using iomazenil single photon-emission computed tomography.5456 Some of these studies have methodologic limitations (inappropriate control groups, relative quantitation only, presence of medication, and, most important, too short an interval between injection and scanning to separate the effects of delivery from binding) that result in considerable difficulty in interpreting the data. In addition, none of these studies measured plasma concentrations of iomazenil and therefore cannot produce fully quantitative data. Our study is itself limited by the small numbers studied and the imbalance in the sex ratio between the groups. The sex ratio, however, is unlikely to explain the results, as a separate comparison excluding women led to the same conclusions.

Small numbers and an imbalance in the sex mix reflect the difficulty in recruiting these patients for imaging studies. In the present study, it took more than 2 years to accrue this number of well-screened patients with the necessary characteristics and whose scans were fully quantitative.

There are 3 main types of mechanisms that could account for the widespread reduction in binding that are not mutually exclusive. First, an alteration of the subunit composition of the benzodiazepine-GABAA complex could indicate an a priori differential expression of GABAA-benzodiazepine receptors in patients with panic disorder. For instance, increased expression of α6 subunits, to which [11C]flumazenil does not bind, would produce the current findings. Polymorphisms of benzodiazepine-GABAA receptors might result in distinct receptor variants being more prevalent in panic disorder57; rat strains that are more anxious have been observed to have decreased benzodiazepine binding30 and decreased anticonflict effects from the same doses of benzodiazepine agonist.58 Decreased binding secondary to subunit composition modification could also be due to environmentally induced modification in receptor configuration59 or endocytic loop phosphorylation.60

Second, the presence of putative endogenous benzodiazepine ligands, increased GABA concentration,61 or neurosteroid inverse agonists62 can induce reduced benzodiazepine binding and may mediate the corticosteroid-dependent reduced binding observed with long-term stress in mice.6365 Finally, changes in serotonergic66,67 or noradrenergic68,69 tone are known to affect benzodiazepine receptor binding. Other explanations are possible but less plausible: a global decrease due to gray-matter atrophy is very unlikely, and magnetic resonance imaging studies of panic disorder have only found minimal changes, mostly in the temporal lobe.70 Changes in nonspecific binding of flumazenil in the brain, which would also decrease the volume of distribution, would not be of this magnitude, as nonspecific binding accounts for only about 10% of the total volume of distribution.71 Decreased binding due to occupancy by an anxiogenic endogenous inverse agonist is also unlikely to explain these findings because the pure antagonist flumazenil would be anxiolytic and not panicogenic, as previously demonstrated.14

Because of the complex system interactions in the brain, it is likely that a number of neurotransmitters are involved, and other receptors could be altered in panic disorder. Thus, future investigation should include the mapping of monoaminergic receptor density in patients with panic disorder as well as a comparison of benzodiazepine-GABAA receptors using subtype specific ligands. In addition, the technology is now mature for the measurement of the effects of stress on benzodiazepine binding in man in vivo.

In conclusion, this study has shown probable decreased binding at the brain GABAA-benzodiazepine site in panic disorder, strengthening the case that abnormalities in basal or adaptive inhibitory neuromodulation are of pathologic significance in this condition.

Accepted for publication April 9, 1998.

Dr Malizia was a Wellcome Training Fellow at the Psychopharmacology Unit, University of Bristol, Bristol, England.

We thank Simon Waters, Leonard Schnorr, the chemistry team, Andrew Blythe, Andreanna Willams, David Griffiths; Suren Rajeswaran, Mark Richardson, and Sean Spence at the Cyclotron Unit, Medical Research Council, Clinical Research Centre, Hammersmith Hospital, London, England; and Sue Wilson at the Psychopharmacology Unit, University of Bristol, for their invaluable help. We also thank the patients, volunteers, and the Panic and Agoraphobia Support Group for their support and patience.

Reprints: Andrea L. Malizia, MBBS, MRCPsych, Clinical Pharmacology Unit, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park South, Third Ave, Harlow CM19 5AW, England.

American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.  Washington, DC American Psychiatric Association1994;
Weissman  MMBland  RCCanino  GJFaravelli  CGreenwald  SHwu  H-GJoyce  PRKaram  EGLee  C-KLellouch  JLépine  J-PNewman  SCOakley-Browne  MARubio-Stipec  MWells  JEWickramaratne  PJWittchen  H-UYeh  E-K The cross-national epidemiology of panic disorder. Arch Gen Psychiatry. 1997;54305- 309
Katerndahl  DARealini  JP Lifetime prevalence of panic states. Am J Psychiatry. 1993;150246- 249
Katon  W Panic disorder: relationship to high medical utilization, unexplained physical symptoms, and medical costs. J Clin Psychiatry. 1996;57(suppl 10)11- 18
Coryell  W Panic disorder and mortality. Psychiatr Clin North Am. 1988;11433- 440
Lesch  KPWiesmann  MHoh  AMuller  TDisselkamp Tietze  JOsterheider  MSchulte  HM 5-HT1A receptor effector system responsivity in panic disorder. Psychopharmacology (Berl). 1992;106111- 117
Den Boer  JAWestenberg  HG Serotonin function in panic disorder: a double blind placebo controlled study with fluvoxamine and ritanserin. Psychopharmacology (Berl). 1990;10285- 94
George  DTNutt  DJRawlings  RRPhillips  MJEckardt  MJPotter  WZLinnoila  M Behavioral and endocrine responses to clomipramine in panic disorder patients with or without alcoholism. Biol Psychiatry. 1995;37112- 119
Charney  DSHeninger  GR Abnormal regulation of noradrenergic function in panic disorders: effects of clonidine in healthy subjects and patients with agoraphobia and panic disorder. Arch Gen Psychiatry. 1986;431042- 1054
Charney  DSHeninger  GRBreier  A Noradrenergic function in panic anxiety: effects of yohimbine in healthy subjects and patients with agoraphobia and panic disorder. Arch Gen Psychiatry. 1984;41751- 763
Nutt  DJ Altered central alpha2-adrenoceptor sensitivity in panic disorder. Arch Gen Psychiatry. 1989;46165- 169
Nesse  RMCameron  OGCurtis  GCMcCann  DSHuber-Smith  MJ Adrenergic function in patients with panic anxiety. Arch Gen Psychiatry. 1984;41771- 776
Roy-Byrne  PPCowley  DSGreenblatt  DJShader  RIHommer  D Reduced benzodiazepine sensitivity in panic disorder. Arch Gen Psychiatry. 1990;47534- 538
Nutt  DJGlue  PLawson  CWilson  S Flumazenil provocation of panic attacks: evidence for altered benzodiazepine receptor sensitivity in panic disorder. Arch Gen Psychiatry. 1990;47917- 925
Bradwejn  JKoszycki  DAnnable  LCouetoux du Tertre  AReines  SKarkanias  C A dose-ranging study of the behavioral and cardiovascular effects of CCK-tetrapeptide in panic disorder. Biol Psychiatry. 1992;32903- 912
Bradwejn  JKoszycki  DShriqui  C Enhanced sensitivity to cholecystokinin tetrapeptide in panic disorder: clinical and behavioral findings. Arch Gen Psychiatry. 1991;48603- 610
Abelson  JLCurtis  GC Hypothalamic-pituitary-adrenal axis activity in panic disorder: 24-hour secretion of corticotropin and cortisol. Arch Gen Psychiatry. 1996;53323- 331
Gorman  JMPapp  LACoplan  JDMartinez  JMLennon  SGoetz  RRRoss  DKlein  DF Anxiogenic effects of CO2 and hyperventilation in patients with panic disorder. Am J Psychiatry. 1994;151547- 553
Gorman  JMFyer  MRGoetz  RAskanazi  JLiebowitz  MRFyer  AJKinney  JKlein  DF Ventilatory physiology of patients with panic disorder. Arch Gen Psychiatry. 1988;4531- 39
Liebowitz  MRFyer  AJGorman  JMDillon  DAppleby  ILLevy  GAnderson  SLevitt  MPalij  MDavies  SOKlein  DF Lactate provocation of panic attacks, I: clinical and behavioral findings. Arch Gen Psychiatry. 1984;41764- 770
Reschke  AHMannuzza  SChapman  TFLipsitz  JDLiebowitz  MRGorman  JMKlein  DFFyer  AJ Sodium lactate response and familial risk for panic disorder. Am J Psychiatry. 1995;152277- 279
Rodin  EACalhoun  HD Metrazol tolerance in a "normal" volunteer population: a 10 year follow up report. J Nerv Ment Dis. 1970;150438- 443
File  SELister  RG Do the reductions in social interaction produced by picrotoxin and pentylenetetrazole indicate anxiogenic actions? Neuropharmacology. 1984;23793- 796
Corbett  RFielding  SCornfeldt  MDunn  RW GABAmimetic agents display anxiolytic-like effects in the social interaction and elevated plus maze procedures. Psychopharmacology (Berl). 1991;104312- 316
Hoehn Saric  R Effects of THIP on chronic anxiety. Psychopharmacology (Berl). 1983;80338- 341
Dorow  RHorowski  RPaschelke  GAmin  M Severe anxiety induced by FG 7142, a beta carboline ligand for benzodiazepine receptors. Lancet. 1983;298- 99
Drugan  RCMaier  SFSkolnick  PPaul  SMCrawley  JN An anxiogenic benzodiazepine receptor ligand induces learned helplessness. Eur J Pharmacol. 1985;113453- 457
Primus  RJGallager  DW GABAA receptor subunit mRNA levels are differentially influenced by chronic FG 7142 and diazepam exposure. Eur J Pharmacol. 1992;22621- 28
Rago  LKiivet  RAHarro  JPold  M Behavioral differences in an elevated plus maze: correlation between anxiety and decreased number of GABA and benzodiazepine receptors in mouse cerebral cortex. Naunyn Schmiedebergs Arch Pharmacol. 1988;337675- 678
Robertson  HAMartin  ILCandy  JM Differences in benzodiazepine receptor binding in Maudsley reactive and Maudsley non-reactive rats. Eur J Pharmacol. 1978;50455- 457
Roy-Byrne  PPLewis  NVillacres  EDiem  HGreenblatt  DJShader  RIVeith  R Preliminary evidence of benzodiazepine subsensitivity in panic disorder. Biol Psychiatry. 1989;26744- 748
Elsworth  JDDewar  DGlover  VGoodwin  BLClow  ASandler  M Purification and characterization of tribulin, and endogenous inhibitor of monoamine oxidase and of benzodiazepine receptor binding. J Neural Transm. 1986;6745- 56
Corda  MGFerrari  MGuidotti  AKonkel  DCosta  E Isolation, purification and partial sequence of a neuropeptide (diazepam binding inhibitor) precursor of an anxiogenic putative ligand for benzodiazepine recognition site. Neurosci Lett. 1984;47319- 324
Ulrichsen  JBech  BEbert  BDiemer  NHAllerup  PHemmingsen  R Glutamate and benzodiazepine receptor autoradiography in rat brain after repetition of alcohol dependence. Psychopharmacology (Berl). 1996;12631- 41
Flick  SNRoy-Byrne  PPCowley  DSShores  MMDunner  DL DSM III-R personality disorders in a mood and anxiety disorders clinic: prevalence, comorbidity and clinical correlates. J Affect Disord. 1993;2771- 79
Spielberger  CDGorsuch  RLLushene  R State Trait Anxiety Inventory Manual.  Palo Alto, Calif Consulting Psychologist Press1970;
Chambless  DLCaputo  GCBright  PGallagher  R The assessment of fear in agoraphobics: the Body Sensations Questionnaire and the Agoraphobic Cognitions Questionnaire. J Consult Clin Psychol. 1984;521090- 1097
Sheehan  DV The Anxiety Neuroses.  New York, NY Charles Scribner's Sons1983;144- 153
Spinks  TJJones  TBailey  DLTownsend  DWGrootoonk  SBloomfield  PMGilardi  MCCasey  MESipe  BReed  J Physical performance of a positron tomograph for brain imaging with retractable septa. Phys Med Biol. 1992;371637- 1655
Grootoonk  SSpinks  TJSashin  DSpyrou  NMJones  T Correction for scatter in 3D brain PET using a dual energy window method. Phys Med Biol. 1996;412757- 2774
Ranicar  ASWilliams  CWSchnorr  LClark  JCRhodes  CGBloomfield  PMJones  T The on-line monitoring of continuously withdrawn arterial blood during PET studies using a single BGO/photomultiplier assembly and non stick tubing. Med Prog Technol. 1991;17259- 264
Cunningham  VJJones  T Spectral analysis of dynamic PET studies. J Cereb Blood Flow Metab. 1993;1315- 23
Halldin  CStone Elander  SThorell  JOPersson  ASedvall  G 11C labelling of Ro 15-1788 in two different positions, and also 11C labelling of its main metabolite Ro 15-3890, for PET studies of benzodiazepine receptors. Int J Rad Appl Instrum [A]. 1988;39993- 997
Friston  KJAshburner  JFrith  CDPoline  J-BHeather  JFrackowiak  RSJ Spatial registration and normalisation of images. Hum Brain Mapping. 1995;2165- 189
Friston  KJHolmes  APWorsley  KJPoline  J-BFrith  CDFrackowiak  RSJ Statistical parametric maps in functional imaging: a general linear approach. Hum Brain Mapping. 1995;2189- 210
Friston  KJWorsley  KJFrackowiak  RSJMazziota  JCEvans  AC Assessing the significance of focal activations using their spatial extent. Hum Brain Mapping. 1994;1214- 220
Friston  KJHolmes  APoline  J-BPrice  CJFrith  CD Detecting activations in PET and fMRI: levels of inference and power. Neuroimage. 1996;4223- 235
Malizia  ALGunn  RGWilson  SJWaters  SHBloomfield  PCunningham  VJNutt  DJ Benzodiazepine site pharmacokinetic/pharmacodynamic quantification in man: direct measurement of drug occupancy and effects on the human brain in vivo. Neuropharmacology. 1996;351483- 1491
Nordahl  TESemple  WEGross  MMellman  TAStein  MBGoyer  PKing  ACUhde  TWCohen  RM Cerebral glucose metabolic differences in patients with panic disorder. Neuropsychopharmacology. 1990;3261- 272
Rauch  SLSavage  CRAlpert  NMMiguel  ECBaer  LBreiter  HCFischman  AJManzo  PAMoretti  CJenike  MA A positron emission tomographic study of simple phobic symptom provocation. Arch Gen Psychiatry. 1995;5220- 28
Fischer  HWik  GFredrikson  M Functional neuroanatomy of robbery re-experience: affective memories studied with PET. Neuroreport. 1996;72081- 2086
Bremner  JDInnis  RBNg  CKStaib  LHSalomon  RMBronen  RADuncan  JSouthwick  SMKrystal  JHRich  DZubal  GDey  HSoufer  RCharney  DS Positron emission tomography measurement of cerebral metabolic correlates of yohimbine administration in combat-related posttraumatic stress disorder. Arch Gen Psychiatry. 1997;54246- 254
Klein  DF False suffocation alarms, spontaneous panics, and related conditions: an integrative hypothesis. Arch Gen Psychiatry. 1993;50306- 317
Schlegel  SSteinert  HBockisch  AHahn  KSchloesser  RBenkert  O Decreased benzodiazepine receptor binding in panic disorder measured by iomazenil SPECT: a preliminary report. Eur Arch Psychiatry Clin Neurosci. 1994;24449- 51
Kaschka  WFeistel  HEbert  D Reduced benzodiazepine receptor binding in panic disorders measured by iomazenil SPECT. J Psychiatr Res. 1995;29427- 423
Kuikka  JTPitkanen  ALepola  UPartanen  KVainio  PBergstrom  KAWieler  HJKaiser  KPMittelbach  LKoponen  H Abnormal regional benzodiazepine receptor uptake in the prefrontal cortex in patients with panic disorder. Nucl Med Commun. 1995;16273- 280
Haefely  WFacklam  MSchoch  PMartin  JRBonetti  EPMoreau  JLJenck  FRichards  JG Partial agonists of benzodiazepine receptors for the treatment of epilepsy, sleep, and anxiety disorders. Adv Biochem Psychopharmacol. 1992;47379- 394
Commissaris  RLHarrington  GMAltman  HJ Benzodiazepine anti conflict effects in Maudsley reactive (MR/Har) and non-reactive (MNRA/Har) rats. Psychopharmacology (Berl). 1990;100287- 292
Kang  IMiller  LG Decreased GABAA receptor subunit mRNA concentrations following chronic lorazepam administration. Br J Pharmacol. 1991;1031285- 1287
Moss  SJSmart  TGBlackstone  CDHuganir  RL Functional modulation of GABAA receptors by cAMP dependent protein phosphorylation. Science. 1992;257661- 665
Maloteaux  JMOctave  JNGossuin  ALaterre  CTrouet  A GABA induces down regulation of the benzodiazepine GABA receptor complex in the rat cultured neurons. Eur J Pharmacol. 1987;144173- 183
Demirgoren  SMajewska  MDSpivak  CELondon  ED Receptor binding and electrophysiological effects of dehydroepiandrosterone sulfate, an antagonist of the GABAA receptor. Neuroscience. 1991;45127- 135
Weizman  RWeizman  AKook  KAVocci  FDeutsch  SIPaul  SM Repeated swim stress alters brain benzodiazepine receptors measured in vivo. J Pharmacol Exp Ther. 1989;249701- 707
Weizman  AWeizman  RKook  KAVocci  FDeutsch  SIPaul  SM Adrenalectomy prevents the stress induced decrease in in vivo [3H]Ro 151788 binding to GABAA benzodiazepine receptors in the mouse. Brain Res. 1990;519347- 350
Inoue  OAkimoto  YHashimoto  KYamasaki  T Alterations in biodistribution of [3H]Ro 151788 in mice by acute stress: possible changes in in vivo binding availability of brain benzodiazepine receptor. Int J Nucl Med Biol. 1985;12369- 374
Doudet  DHommer  DHigley  JDAndreason  PJMoneman  RSuomi  SJLinnoila  M Cerebral glucose metabolism, CSF 5 HIAA levels, and aggressive behavior in rhesus monkeys. Am J Psychiatry. 1995;1521782- 1787
Huidobro-Toro  JValenzuela  CFHarris  RA Modulation of GABAA receptor function by G protein coupled 5 HT2C receptors. Neuropharmacology. 1996;351355- 1363
Medina  JHNovas  ML Parallel changes in brain flunitrazepam binding and density of noradrenergic innervation. Eur J Pharmacol. 1983;88377- 382
Doble  AIversen  LLBowery  NGHill  DRHudson  AL 6-OHDA lesions decreases benzodiazepine but not GABA receptor binding in rat cerebellum. Neurosci Lett. 1981;27199- 204
Fontaine  RBreton  GDery  RFontaine  SElie  R Temporal lobe abnormalities in panic disorder: an MRI study. Biol Psychiatry. 1990;27304- 310
Lassen  NABartenstein  PALammertsma  AAPrevett  MCTurton  DRLuthra  SKOsman  SBloomfield  PJones  TPatsalos  PNO'Connell  MTDuncan  JSAndersen  JV Benzodiazepine receptor quantification in vivo in humans using [C-11] flumazenil and PET: application of the steady state principle. J Cereb Blood Flow Metab. 1995;15152- 165

Figures

Place holder to copy figure label and caption
Figure 1.

Middle brain (12 mm above the anterior commisure–posterior commisure plane) median volume of distribution map for controls (left) and patients with panic disorder (right). Note the generalized decrease in volume of distribution affecting the thalami and the heads of the caudate nucleus. FC indicates frontal cortex; CN, caudate nucleus; Th, thalamus; Ins, insula; TC, temporal cortex; and OC, occipital cortex.

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

Volume of distribution values for the panic disorder and control groups at the voxels with the greatest (left, z=4.22) and least (right, z=1.96) significant difference within the gray matter.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Clinical Indices for Patients*
Table Graphic Jump LocationTable 2. Characteristics of Healthy Volunteers*
Table Graphic Jump LocationTable 3. Volume of Distribution Values Using [11C]Flumenazil by Region of Interest

References

American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.  Washington, DC American Psychiatric Association1994;
Weissman  MMBland  RCCanino  GJFaravelli  CGreenwald  SHwu  H-GJoyce  PRKaram  EGLee  C-KLellouch  JLépine  J-PNewman  SCOakley-Browne  MARubio-Stipec  MWells  JEWickramaratne  PJWittchen  H-UYeh  E-K The cross-national epidemiology of panic disorder. Arch Gen Psychiatry. 1997;54305- 309
Katerndahl  DARealini  JP Lifetime prevalence of panic states. Am J Psychiatry. 1993;150246- 249
Katon  W Panic disorder: relationship to high medical utilization, unexplained physical symptoms, and medical costs. J Clin Psychiatry. 1996;57(suppl 10)11- 18
Coryell  W Panic disorder and mortality. Psychiatr Clin North Am. 1988;11433- 440
Lesch  KPWiesmann  MHoh  AMuller  TDisselkamp Tietze  JOsterheider  MSchulte  HM 5-HT1A receptor effector system responsivity in panic disorder. Psychopharmacology (Berl). 1992;106111- 117
Den Boer  JAWestenberg  HG Serotonin function in panic disorder: a double blind placebo controlled study with fluvoxamine and ritanserin. Psychopharmacology (Berl). 1990;10285- 94
George  DTNutt  DJRawlings  RRPhillips  MJEckardt  MJPotter  WZLinnoila  M Behavioral and endocrine responses to clomipramine in panic disorder patients with or without alcoholism. Biol Psychiatry. 1995;37112- 119
Charney  DSHeninger  GR Abnormal regulation of noradrenergic function in panic disorders: effects of clonidine in healthy subjects and patients with agoraphobia and panic disorder. Arch Gen Psychiatry. 1986;431042- 1054
Charney  DSHeninger  GRBreier  A Noradrenergic function in panic anxiety: effects of yohimbine in healthy subjects and patients with agoraphobia and panic disorder. Arch Gen Psychiatry. 1984;41751- 763
Nutt  DJ Altered central alpha2-adrenoceptor sensitivity in panic disorder. Arch Gen Psychiatry. 1989;46165- 169
Nesse  RMCameron  OGCurtis  GCMcCann  DSHuber-Smith  MJ Adrenergic function in patients with panic anxiety. Arch Gen Psychiatry. 1984;41771- 776
Roy-Byrne  PPCowley  DSGreenblatt  DJShader  RIHommer  D Reduced benzodiazepine sensitivity in panic disorder. Arch Gen Psychiatry. 1990;47534- 538
Nutt  DJGlue  PLawson  CWilson  S Flumazenil provocation of panic attacks: evidence for altered benzodiazepine receptor sensitivity in panic disorder. Arch Gen Psychiatry. 1990;47917- 925
Bradwejn  JKoszycki  DAnnable  LCouetoux du Tertre  AReines  SKarkanias  C A dose-ranging study of the behavioral and cardiovascular effects of CCK-tetrapeptide in panic disorder. Biol Psychiatry. 1992;32903- 912
Bradwejn  JKoszycki  DShriqui  C Enhanced sensitivity to cholecystokinin tetrapeptide in panic disorder: clinical and behavioral findings. Arch Gen Psychiatry. 1991;48603- 610
Abelson  JLCurtis  GC Hypothalamic-pituitary-adrenal axis activity in panic disorder: 24-hour secretion of corticotropin and cortisol. Arch Gen Psychiatry. 1996;53323- 331
Gorman  JMPapp  LACoplan  JDMartinez  JMLennon  SGoetz  RRRoss  DKlein  DF Anxiogenic effects of CO2 and hyperventilation in patients with panic disorder. Am J Psychiatry. 1994;151547- 553
Gorman  JMFyer  MRGoetz  RAskanazi  JLiebowitz  MRFyer  AJKinney  JKlein  DF Ventilatory physiology of patients with panic disorder. Arch Gen Psychiatry. 1988;4531- 39
Liebowitz  MRFyer  AJGorman  JMDillon  DAppleby  ILLevy  GAnderson  SLevitt  MPalij  MDavies  SOKlein  DF Lactate provocation of panic attacks, I: clinical and behavioral findings. Arch Gen Psychiatry. 1984;41764- 770
Reschke  AHMannuzza  SChapman  TFLipsitz  JDLiebowitz  MRGorman  JMKlein  DFFyer  AJ Sodium lactate response and familial risk for panic disorder. Am J Psychiatry. 1995;152277- 279
Rodin  EACalhoun  HD Metrazol tolerance in a "normal" volunteer population: a 10 year follow up report. J Nerv Ment Dis. 1970;150438- 443
File  SELister  RG Do the reductions in social interaction produced by picrotoxin and pentylenetetrazole indicate anxiogenic actions? Neuropharmacology. 1984;23793- 796
Corbett  RFielding  SCornfeldt  MDunn  RW GABAmimetic agents display anxiolytic-like effects in the social interaction and elevated plus maze procedures. Psychopharmacology (Berl). 1991;104312- 316
Hoehn Saric  R Effects of THIP on chronic anxiety. Psychopharmacology (Berl). 1983;80338- 341
Dorow  RHorowski  RPaschelke  GAmin  M Severe anxiety induced by FG 7142, a beta carboline ligand for benzodiazepine receptors. Lancet. 1983;298- 99
Drugan  RCMaier  SFSkolnick  PPaul  SMCrawley  JN An anxiogenic benzodiazepine receptor ligand induces learned helplessness. Eur J Pharmacol. 1985;113453- 457
Primus  RJGallager  DW GABAA receptor subunit mRNA levels are differentially influenced by chronic FG 7142 and diazepam exposure. Eur J Pharmacol. 1992;22621- 28
Rago  LKiivet  RAHarro  JPold  M Behavioral differences in an elevated plus maze: correlation between anxiety and decreased number of GABA and benzodiazepine receptors in mouse cerebral cortex. Naunyn Schmiedebergs Arch Pharmacol. 1988;337675- 678
Robertson  HAMartin  ILCandy  JM Differences in benzodiazepine receptor binding in Maudsley reactive and Maudsley non-reactive rats. Eur J Pharmacol. 1978;50455- 457
Roy-Byrne  PPLewis  NVillacres  EDiem  HGreenblatt  DJShader  RIVeith  R Preliminary evidence of benzodiazepine subsensitivity in panic disorder. Biol Psychiatry. 1989;26744- 748
Elsworth  JDDewar  DGlover  VGoodwin  BLClow  ASandler  M Purification and characterization of tribulin, and endogenous inhibitor of monoamine oxidase and of benzodiazepine receptor binding. J Neural Transm. 1986;6745- 56
Corda  MGFerrari  MGuidotti  AKonkel  DCosta  E Isolation, purification and partial sequence of a neuropeptide (diazepam binding inhibitor) precursor of an anxiogenic putative ligand for benzodiazepine recognition site. Neurosci Lett. 1984;47319- 324
Ulrichsen  JBech  BEbert  BDiemer  NHAllerup  PHemmingsen  R Glutamate and benzodiazepine receptor autoradiography in rat brain after repetition of alcohol dependence. Psychopharmacology (Berl). 1996;12631- 41
Flick  SNRoy-Byrne  PPCowley  DSShores  MMDunner  DL DSM III-R personality disorders in a mood and anxiety disorders clinic: prevalence, comorbidity and clinical correlates. J Affect Disord. 1993;2771- 79
Spielberger  CDGorsuch  RLLushene  R State Trait Anxiety Inventory Manual.  Palo Alto, Calif Consulting Psychologist Press1970;
Chambless  DLCaputo  GCBright  PGallagher  R The assessment of fear in agoraphobics: the Body Sensations Questionnaire and the Agoraphobic Cognitions Questionnaire. J Consult Clin Psychol. 1984;521090- 1097
Sheehan  DV The Anxiety Neuroses.  New York, NY Charles Scribner's Sons1983;144- 153
Spinks  TJJones  TBailey  DLTownsend  DWGrootoonk  SBloomfield  PMGilardi  MCCasey  MESipe  BReed  J Physical performance of a positron tomograph for brain imaging with retractable septa. Phys Med Biol. 1992;371637- 1655
Grootoonk  SSpinks  TJSashin  DSpyrou  NMJones  T Correction for scatter in 3D brain PET using a dual energy window method. Phys Med Biol. 1996;412757- 2774
Ranicar  ASWilliams  CWSchnorr  LClark  JCRhodes  CGBloomfield  PMJones  T The on-line monitoring of continuously withdrawn arterial blood during PET studies using a single BGO/photomultiplier assembly and non stick tubing. Med Prog Technol. 1991;17259- 264
Cunningham  VJJones  T Spectral analysis of dynamic PET studies. J Cereb Blood Flow Metab. 1993;1315- 23
Halldin  CStone Elander  SThorell  JOPersson  ASedvall  G 11C labelling of Ro 15-1788 in two different positions, and also 11C labelling of its main metabolite Ro 15-3890, for PET studies of benzodiazepine receptors. Int J Rad Appl Instrum [A]. 1988;39993- 997
Friston  KJAshburner  JFrith  CDPoline  J-BHeather  JFrackowiak  RSJ Spatial registration and normalisation of images. Hum Brain Mapping. 1995;2165- 189
Friston  KJHolmes  APWorsley  KJPoline  J-BFrith  CDFrackowiak  RSJ Statistical parametric maps in functional imaging: a general linear approach. Hum Brain Mapping. 1995;2189- 210
Friston  KJWorsley  KJFrackowiak  RSJMazziota  JCEvans  AC Assessing the significance of focal activations using their spatial extent. Hum Brain Mapping. 1994;1214- 220
Friston  KJHolmes  APoline  J-BPrice  CJFrith  CD Detecting activations in PET and fMRI: levels of inference and power. Neuroimage. 1996;4223- 235
Malizia  ALGunn  RGWilson  SJWaters  SHBloomfield  PCunningham  VJNutt  DJ Benzodiazepine site pharmacokinetic/pharmacodynamic quantification in man: direct measurement of drug occupancy and effects on the human brain in vivo. Neuropharmacology. 1996;351483- 1491
Nordahl  TESemple  WEGross  MMellman  TAStein  MBGoyer  PKing  ACUhde  TWCohen  RM Cerebral glucose metabolic differences in patients with panic disorder. Neuropsychopharmacology. 1990;3261- 272
Rauch  SLSavage  CRAlpert  NMMiguel  ECBaer  LBreiter  HCFischman  AJManzo  PAMoretti  CJenike  MA A positron emission tomographic study of simple phobic symptom provocation. Arch Gen Psychiatry. 1995;5220- 28
Fischer  HWik  GFredrikson  M Functional neuroanatomy of robbery re-experience: affective memories studied with PET. Neuroreport. 1996;72081- 2086
Bremner  JDInnis  RBNg  CKStaib  LHSalomon  RMBronen  RADuncan  JSouthwick  SMKrystal  JHRich  DZubal  GDey  HSoufer  RCharney  DS Positron emission tomography measurement of cerebral metabolic correlates of yohimbine administration in combat-related posttraumatic stress disorder. Arch Gen Psychiatry. 1997;54246- 254
Klein  DF False suffocation alarms, spontaneous panics, and related conditions: an integrative hypothesis. Arch Gen Psychiatry. 1993;50306- 317
Schlegel  SSteinert  HBockisch  AHahn  KSchloesser  RBenkert  O Decreased benzodiazepine receptor binding in panic disorder measured by iomazenil SPECT: a preliminary report. Eur Arch Psychiatry Clin Neurosci. 1994;24449- 51
Kaschka  WFeistel  HEbert  D Reduced benzodiazepine receptor binding in panic disorders measured by iomazenil SPECT. J Psychiatr Res. 1995;29427- 423
Kuikka  JTPitkanen  ALepola  UPartanen  KVainio  PBergstrom  KAWieler  HJKaiser  KPMittelbach  LKoponen  H Abnormal regional benzodiazepine receptor uptake in the prefrontal cortex in patients with panic disorder. Nucl Med Commun. 1995;16273- 280
Haefely  WFacklam  MSchoch  PMartin  JRBonetti  EPMoreau  JLJenck  FRichards  JG Partial agonists of benzodiazepine receptors for the treatment of epilepsy, sleep, and anxiety disorders. Adv Biochem Psychopharmacol. 1992;47379- 394
Commissaris  RLHarrington  GMAltman  HJ Benzodiazepine anti conflict effects in Maudsley reactive (MR/Har) and non-reactive (MNRA/Har) rats. Psychopharmacology (Berl). 1990;100287- 292
Kang  IMiller  LG Decreased GABAA receptor subunit mRNA concentrations following chronic lorazepam administration. Br J Pharmacol. 1991;1031285- 1287
Moss  SJSmart  TGBlackstone  CDHuganir  RL Functional modulation of GABAA receptors by cAMP dependent protein phosphorylation. Science. 1992;257661- 665
Maloteaux  JMOctave  JNGossuin  ALaterre  CTrouet  A GABA induces down regulation of the benzodiazepine GABA receptor complex in the rat cultured neurons. Eur J Pharmacol. 1987;144173- 183
Demirgoren  SMajewska  MDSpivak  CELondon  ED Receptor binding and electrophysiological effects of dehydroepiandrosterone sulfate, an antagonist of the GABAA receptor. Neuroscience. 1991;45127- 135
Weizman  RWeizman  AKook  KAVocci  FDeutsch  SIPaul  SM Repeated swim stress alters brain benzodiazepine receptors measured in vivo. J Pharmacol Exp Ther. 1989;249701- 707
Weizman  AWeizman  RKook  KAVocci  FDeutsch  SIPaul  SM Adrenalectomy prevents the stress induced decrease in in vivo [3H]Ro 151788 binding to GABAA benzodiazepine receptors in the mouse. Brain Res. 1990;519347- 350
Inoue  OAkimoto  YHashimoto  KYamasaki  T Alterations in biodistribution of [3H]Ro 151788 in mice by acute stress: possible changes in in vivo binding availability of brain benzodiazepine receptor. Int J Nucl Med Biol. 1985;12369- 374
Doudet  DHommer  DHigley  JDAndreason  PJMoneman  RSuomi  SJLinnoila  M Cerebral glucose metabolism, CSF 5 HIAA levels, and aggressive behavior in rhesus monkeys. Am J Psychiatry. 1995;1521782- 1787
Huidobro-Toro  JValenzuela  CFHarris  RA Modulation of GABAA receptor function by G protein coupled 5 HT2C receptors. Neuropharmacology. 1996;351355- 1363
Medina  JHNovas  ML Parallel changes in brain flunitrazepam binding and density of noradrenergic innervation. Eur J Pharmacol. 1983;88377- 382
Doble  AIversen  LLBowery  NGHill  DRHudson  AL 6-OHDA lesions decreases benzodiazepine but not GABA receptor binding in rat cerebellum. Neurosci Lett. 1981;27199- 204
Fontaine  RBreton  GDery  RFontaine  SElie  R Temporal lobe abnormalities in panic disorder: an MRI study. Biol Psychiatry. 1990;27304- 310
Lassen  NABartenstein  PALammertsma  AAPrevett  MCTurton  DRLuthra  SKOsman  SBloomfield  PJones  TPatsalos  PNO'Connell  MTDuncan  JSAndersen  JV Benzodiazepine receptor quantification in vivo in humans using [C-11] flumazenil and PET: application of the steady state principle. J Cereb Blood Flow Metab. 1995;15152- 165

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