Low dopamine D(2) receptor binding potential in social phobia.

[lulz]

This issue seems connected to how benzodiazepines work for people with social phobia.

When GABA is the main culprit for social phobia, it's because GABA receptors don't have a high enough affinity for GABA molecules, and less receptor binding means insufficient signals get transmitted along these pathways. Benzos work by binding to those receptor sites and increasing their affinity for GABA, so that the neuron becomes activated.

The research below seems to suggest that a similar problem might occur with dopamine binding. If benzodiazepines can increase receptor affinity for GABA, could maybe a similar drug be created to do the same thing for dopamine?

Am J Psychiatry 157:457-459, March 2000
© 2000 American Psychiatric Association

Low Dopamine D2 Receptor Binding Potential in Social Phobia

Franklin R. Schneier, M.D., Michael R. Liebowitz, M.D., Anissa Abi-Dargham, M.D., Yolanda Zea-Ponce, Ph.D., Shu-Hsing Lin, Ph.D. and Marc Laruelle, M.D.

ABSTRACT

OBJECTIVE: This study compared dopamine D2 receptor binding potential in patients with social phobia and healthy comparison subjects. METHOD: Dopamine D2 receptor binding potential was assessed in 10 unmedicated subjects with generalized social phobia and no significant lifetime psychiatric comorbidity and 10 healthy comparison subjects matched for age and sex. Binding potential was measured in the striatum by using single photon emission computerized tomography and constant infusion of the D2 receptor radiotracer [123I]iodobenzamide ([123I]IBZM). RESULTS: Mean D2 receptor binding potential was significantly lower in the subjects with social phobia than in the comparison subjects. Within the social phobia group, there was a nonsignificant correlation of binding potential with the Liebowitz Social Anxiety Scale score. CONCLUSIONS: Generalized social phobia may be associated with low binding of [123I]IBZM to D2 receptors in the striatum.

INTRODUCTION

The generalized subtype of social phobia, characterized by fear and/or avoidance of most social situations, is chronic (1), is heritable (2), and may share behavioral features with subordinate social status in animals (3), yet the biology of social phobia has been little studied. Evidence for an association of social phobia with subnormal transmission in the dopamine system includes treatment efficacy for monoamine oxidase inhibitors but not tricyclic antidepressants (4), low dopamine transporter density in generalized social phobia (5), low CSF levels of homovanillic acid among panic disorder patients with comorbid social phobia (6), a high rate of social phobia among patients with Parkinson’s disease (7), and increased social phobia symptoms during haloperidol treatment of patients with Tourette’s syndrome (8).

In this study we compared dopamine D2 receptor binding potential in patients with generalized social phobia and healthy comparison subjects.

METHOD

Ten subjects with social phobia were recruited by advertisement and clinical referrals; their mean age was 32.5 years (SD=10.4), and the group comprised five men and five women.

All subjects were physically healthy as determined by complete medical evaluation, with no current or lifetime psychosis, organic mental disorders, major depression, bipolar disorder, panic disorder, obsessive-compulsive disorder, posttraumatic stress disorder, eating disorders, attention deficit hyperactivity disorder, substance abuse or dependence, schizotypal or borderline personality disorder, or family history of schizophrenia. Ten healthy comparison subjects, matched by age and sex and with no current or past mental disorders, were recruited by advertisement. Diagnoses were confirmed by using the Structured Clinical Interview for DSM-IV Axis I Disorders (9). All subjects had been free of psychotropic medication for at least a year, and a drug screen was performed before scanning. After complete description of the study to the subjects, written informed consent was obtained.

The Liebowitz Social Anxiety Scale (10) was used to measure the severity of social phobia. D2 receptor binding potential was measured by using the radiotracer [123I]iodobenzamide ([123I]IBZM) with single photon emission computerized tomography, by means of the bolus plus constant infusion method, as previously described (11). A standard region-of-interest profile of constant size and shape was used to analyze the studies. Right and left striatal regions and occipital regions were positioned on summed images. Specific binding was calculated as the difference between striatal activity and occipital activity at equilibrium. [123I]IBZM binding potential (in ml/g), corresponding to the product of the free receptor density (Bmax, in nM or picomoles per gram of brain tissue) and affinity (1/KD, in 1/nM or milliliters of plasma per picomole of [123I]IBZM), was calculated as the ratio of striatal specific binding (in microcuries per gram of brain tissue) to steady-state free unmetabolized plasma tracer concentration (in microcuries per milliliter of plasma) (12).

The group comparisons used two-tailed unpaired t tests with an alpha of 0.05. Binding potential was related to clinical severity by means of rank-transformed data (Spearman rank correlation).

RESULTS

There were no significant group differences in age, sex, race, education, marital status, or handedness.

There was a significant difference in [123I]IBZM binding potential between groups (t=2.6, df=18, p=0.02), with lower binding potential in the patients with generalized social phobia (mean=93.6 ml/g, SD=29.8) than in the comparison subjects (mean=133.5 ml/g, SD=38.2) (figure 1). Within the social phobia group, there was a nonsignificant negative correlation of binding potential with the total score on the Liebowitz Social Anxiety Scale (rs=–0.59, N=10, p=0.07).

View larger version (28K):
[in this window]
[in a new window]

FIGURE 1. Dopamine D2 Receptor Binding Potential in Patients With Generalized Social Phobia and Healthy Comparison Subjects

DISCUSSION

These findings suggest that generalized social phobia may be associated with low D2 receptor binding potential in the striatum. Low D2 receptor binding potential would be consistent with the findings of low dopamine system activity in social phobia.

This study is limited by the small number of subjects. Also, because only one high-specific-activity experiment was performed with each subject, D2 receptor density and affinity could not be measured.

The findings appear to parallel those from animal studies of subordinate social status, which has been suggested to share behavioral features with human social phobia (3). For example, a recent positron emission tomography study of female cynomolgus monkeys (13) showed lower striatal D2 binding in subordinates, similar to our finding in generalized social phobia. Animals of subordinate social status may be a useful model for understanding the brain function underlying human social phobia.

Low D2 receptor binding seems at least partially specific to social phobia, rather than representing a nonspecific correlate of stress or mental disorder. D2 binding has not been found to be low in schizophrenia (14) or major depression (15). It has been reported to be low in substance abuse disorders (16), which may often be comorbid with social phobia (17).

These data suggest that low D2 receptor binding potential might be associated with social phobia. Combined with results from other centers, these data add to the growing evidence that D2 receptor function modulates social behavior in humans.

REFERENCES

1. Chartier MJ, Hazen AL, Stein MB: Lifetime patterns of social phobia: a retrospective study of the course of social phobia in a nonclinical population. Depress Anxiety 1998; 7:113–121[CrossRef][Medline]
2. Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ: The genetic epidemiology of phobias in women: the interrelations of agoraphobia, social phobia, situational phobia, and simple phobia. Arch Gen Psychiatry 1992; 49:273–281[Abstract]
3. Ohman A: Face the beast and fear the face: animal and social fears as prototypes for evolutionary analyses of emotion. Psychophysiol 1986; 23:123–145[Medline]
4. Liebowitz MR, Campeas R, Hollander E: Possible dopamine dysregulation in social phobia and atypical depression. Psychiatry Res 1987; 22:89–90[Medline]
5. Tiihonen J, Kuikka J, Bergström K, Lepola U, Koponen H, Leinonen E: Dopamine reuptake site densities in patients with social phobia. Am J Psychiatry 1997; 154:239–242[Abstract]
6. Johnson MR, Lydiard RB, Zealberg JJ, Fossey MD, Ballenger JC: Plasma and CSF levels in panic patients with comorbid social phobia. Biol Psychiatry 1994; 36:426–427
7. Stein MB, Heuser IJ, Juncos JL, Uhde TW: Anxiety disorders in patients with Parkinson’s disease. Am J Psychiatry 1990; 147:217–220[Abstract/Free Full Text]
8. Mikkelsen EJ, Detlor J, Cohen DJ: School avoidance and social phobia triggered by haloperidol in patients with Tourette’s disorder. Am J Psychiatry 1981; 138:1572–1576
9. First MB, Spitzer RL, Gibbon M, Williams JBW: Structured Clinical Interview for DSM-IV Axis I Disorders, Patient Edition (SCID-P), version 2. New York, New York State Psychiatric Institute, Biometrics Research, 1994
10. Heimberg RG, Horner KJ, Juster HR, Safren SA, Brown EJ, Schneier FR, Liebowitz MR: Psychometric properties of the Liebowitz Social Anxiety Scale. Psychol Med 1999; 29:199–212[CrossRef][Medline]
11. Laruelle M, Abi-Dargham A, van Dyck CH, Rosenblatt W, Zea-Ponce Y, Zoghbi SS, Baldwin RM, Charney DS, Hoffer PB, Kung HF, Innis RB: SPECT imaging of dopamine release after amphetamine challenge. J Nucl Med 1995; 36:1182–1190
12. Laruelle M, Abi-Dargham A, Al-Tikriti MS, Baldwin RM, Zea-Ponce Y, Zoghbi SS, Charney DS, Hoffer PB, Innis RB: SPECT quantification of [123I]iomazenil binding to benzodiazepine receptors in nonhuman primates, II: equilibrium analysis of constant infusion experiments and correlation with in vitro parameters. J Cereb Blood Flow Metab 1994; 14:453–465[Medline]
13. Grant KA, Shively CA, Nader MA, Ehrenkaufer RL, Line SW, Morton TE, Gage HD, Mach RH: Effect of social status on striatal DA D2 receptor binding characteristics in cynomolgus monkeys assessed with positron emission tomography. Synapse 1998; 29:80–83[CrossRef][Medline]
14. Laruelle M: Imaging dopamine transmission in schizophrenia: a review and meta-analysis. Q J Nucl Med 1998; 42:211–221[Medline]
15. Shah PJ, Ogilvie AD, Goodwin GM, Ebmeier KP: Clinical and psychometric correlates of dopamine D2 binding in depression. Psychol Med 1997; 27:1247–1256
16. Hietala J, West C, Syvalahti E, Nagren K, Lehikoinen P, Sonninen P, Ruotsalainen U: Striatal D2 dopamine receptor binding characteristics in vivo in patients with alcohol dependence. Psychopharmacology (Berl) 1994; 116:285–290[CrossRef][Medline]
17. Schneier FR, Martin LY, Liebowitz MR, Gorman JM, Klein DF, Fyer AJ: Alcohol abuse and social phobia. J Anxiety Disord 1989; 3:15–23

http://ajp.psychiatryonline.org/cgi/...full/157/3/457

PDF version available here: http://ajp.psychiatryonline.org/cgi/reprint/157/3/457

I downloaded a copy of the PDF in case it becomes unavailable.

Reputation Comments on this post:

interesting post.

[~lostgurl~]

Good find. Why don't you add it to the file archive?

[lulz]

Thanks lostgurl, will do.

[imyourlittlebare]

Thats why buspar works well. Without actually having to bind to the GABA receptors.

[Zaprenz]

Interesting read.

All anti-psychotics block D2 receptors to some degree and there are strong links between recreational/addictive drugs and D2 receptor functions.

D2 receptors are a very interesting topic but quite complicated and not entirely understood.