Cholecystokinin in animal models of anxiety

S-57 Cholecystokinin in Anxiety: Overview and Update

regions. D I-dopamine receptors in the prefrontal cortex of the monkeyhave been suggested to regulate working memory and also to playa rolein schizophrenia. Striatal modulation of cortical output through D I andD2 dopamine receptors may also be involved in schizophrenia. Previouspost mortem studies in schizophrenic patients have given inconsistentresults concerning striatal Dl-dopamine receptor densities. In the presentstudy we examined Dl-dopamine receptor binding in the striatum andfrontal neocortex of neuroleptic naive schizophrenic patients and healthycontrol subjects using PET and the radioligand [IIC]SCH 23390. Sixteenhealthy subjects (14 men, 2 women; 21-32 years) and ten neurolepticnaive schizophrenic patients (8 men, 2 women; 21-32 years) (DSM-IV)were recruited. Psychopathology was rated using the BPRS at the time ofPET (median score 44.5, range 33-65). The IIC-labelled selective DI­dopamine receptor antagonist SCH 23390 with high specific radioactivitywas injected IV into each subject. Radioactivity was measured for 33 min.using the Scanditronix PC2048-15B PET-camera. The four peak pixelvalues were selected from each the striatal and frontal cortical regionsrespectively and normalized by division with the mean pixel value forthe cerebellum region. The peak pixel ratios for the striatum and thefrontal cortex respectively were 16% and 11% (p < 0.01) lower in theneuroleptic naive schizophrenic patients. The reduced peak pixel ratiosfound in the present study should represent reduced [IIC]SCH 23390binding to Dl-dopamine receptors. A putative reduction of Dl-dopaminereceptors in schizophrenia provides theurapeutic opportunities for D1­agonists. The sum of scores for the BPRS items reflecting psychoticsymptoms (4, 11, 12 and 15) was significantly inversely related to bothD J-binding ratios (p < 0.05). This inverse correlation may suggest thatthe intensity of psychotic symptoms is coupled to mechanisms causingreduced DI-receptor binding.

15-571 Cholecystokinin in Anxiety:Overview and Update

I6-57-1 I Human CSFCCKin Anxiety Disorders andCCKAgonist Challenge in GAD

R.B. Lydiard, O. Brawman-Mintzer, 1. Bradwejn, N. Emmanuel,M.R. Johnson, M.R. Ware, 1.c. Ballenger. Departments of Psychiatry,MUSC, Charleston, South Carolina

Preclinical and clinical studies support the hypothesis that cholecys­tokinin (CCK) is a potent neuromodulator/neurotransmitter in the CNS.We present here data relevant to the hypotheses that a) CCK CSF levelsmay be abnormal in anxious patients and b) that peripherally administeredCCK agonists may be panicogenic in patients with GAD as has beenshown in PD patients. To test the hypothesis that CCK function may beabnormal in anxiety states, we measured CCK-8S via radioimmunoassayin the cerebrospinal fluid of 25 subjects with DSM-IIIR panic disorder(PD) and 16 normals (N). CCK-8S was significantly lower (p < 0.05)in the CSF of the PD group than in the Ns. Since CCK-8S and thetetrapeptide CCK-4, our findings might reflect increased CCK-4 "tone"in PD vs Ns.

To explore the anxiogenic potential of the CCK agonist pentagastrin,we administered 0.6 uglkg bolus i.v. or normal saline (single blind) to 7patients with DSMlII-R - GAD and 7 age-and sex-matched Ns. 5/7 GADpatients vs In Ns had a panic attack after infusion (p < 0.05). Thus,it appears that GAD patients, like PD patients are significantly moresensitive to the anxiogenic effects of CCK agonists than are normals.These data support the hypothesis that CCK may play an important rolein human anxiety states.

I6-57-21 CCK·B Agonists and Panic Induction in Humans

J. Bradwejn, D. Koszycki. ClarkeInstituteof Psychiatry, Toronto,Canada

Cholecystokinin-tetrapeptide (CCK-4) and pentagastrin induce panic at­tacks in healthy volunteers, with patients with panic disorder (PD)

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showing an enhanced sensitivity to these agonists. In PD, the effectsof CCK-4 and pentagastrin can be blocked by chronic treatment withimipramine or f1uvoxamine. In dogs and in healthy human volunteers,CCK-4 induces increases in heart rate, blood pressure, tidal volume andrespiratory frequency in parallel with behavioral changes, thus mimickingcardinal physiological changes associated with panic attacks. In PD andin healthy volunteers, CCK-4-induced panic attacks are antagonized byCCK-B receptor antagonists suggesting a role for CCK-B receptors.The contribution of psychological factors to CCK-4-induced anxiety hasalso been evaluated. Studies have revealed that individual differencesin anxiety sensitivity, a trait characterized by the propensity to appraisesymptomatology of anxiety as threatening, does not predict panicogenicresponse in healthy subjects or PD patients treated with CCK-4. On theother hand, the MMPI Social Introversion scale, a measure of neuroticintroversion. has been found to be a significant predictor of CCK-4­induced anxiety. The contribution of different neurotransmitter systemsin the effects of CCK-4 are not known. Pre-treatment with f1umazenil,the benzodiazepine receptor antagonist, or tryptophan depletion have notbeen found to alter response to CCK-4 in healthy volunteers. Preliminarystudies with B-adrenergic blockers suggest that the B-adrenergic systemmight mediate some of the effects of CCK-4. It is possible that endoge­nous anomalies of the CCK system exist in PD. For example, decreasedCSF and lymphocyte concentrations of CCK-8S in PD, as comparedto controls has been reported. This could suggest anomalies in CCKsynthesis and/or metabolism. An important step in testing the hypothesisof a role for CCK in PD and anxiety will be to evaluate the action ofpharmacokinetically-viable CCK-B antagonists in blocking or preventingspontaneous panic attacks and in relieving symptoms of anxiety.

16-57-31 Cholecystokinin in Animal Models of Anxiety

E. Vasar. Departmentof Physiology, University ofTartu, Estonia

The systemic administration of cholecystokinin (CCK), a brain-gut pep­tide, induces anxiety in different animal species, including mouse, rat,cat, sheep and monkey. However, CCK is shown to be much morepotent in the ethological models (elevated plus-maze, social interactiontest) than in the models based on conflict or conditioned fear (condi­tioned conflict test, punished drinking test). CCK agonists (caerulein,CCK-8, pentagastrin and CCK-4) suppressed the exploratory behaviorof rodents at doses not affecting their locomotor activity. Moreover, theanti-exploratory effect of caerulein in the plus-maze, differently from itslocomotor depressant action, was not affected by the subdiaphragmaticvagotomy. The anxiogenic-Iike action of CCK agonists was antagonizedby the CCK B (brain subtype), but not by CCK A (peripheral subtype)receptor antagonists. This is in good accordance with the human studiessuggesting the role of brainstem CCK B receptors in CCK-induced anxi­ety. Nevertheless, the systemic or intracerebroventricular administrationof CCK antagonists (L-365 ,260, devazepide) as single treatments didnot cause anxiolytic action in rats. This finding is not in favor of directinvolvement of CCK in the neural networks mediating anxiety. However,CCK seems to modulate the activity of various nerve cells responsiblefor anxiety, including serotonin-, norepinephrine-, GABA- and NO-ergicneurons.

16-57-41 A Primate Model for Assessment of CCKAgonistsandAntagonists

R. Palmour, F. Ervin. Departmentof Psychiatry, McGill University,Montreal

The authors will describe evidence for a dose-related, CCK-agonist (CCKtetrapeptide CCK-4) -mediated increase in anxiety-related behaviors inprimates. In this model, agents which have been shown to block theCCKB receptor reliably attenuate these CCK-4 -induced anxiogenic ef­fects selectively. One important variable which modulates the anxiogenicresponse appears to be the baseline arousal of the individual animal.Monkeys in which "anxious" behavior at baseline is observed frequentlyare more susceptible to the anxiogenic effects of CCK-4. The usefulnessof the primate model in assessing selective CCK agonists and antagonistswill be discussed.