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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 monkey have been suggested to regulate working memory and also to playa role in schizophrenia. Striatal modulation of cortical output through D I and D2 dopamine receptors may also be involved in schizophrenia. Previous post mortem studies in schizophrenic patients have given inconsistent results concerning striatal Dl-dopamine receptor densities. In the present study we examined Dl-dopamine receptor binding in the striatum and frontal neocortex of neuroleptic naive schizophrenic patients and healthy control subjects using PET and the radioligand [IIC]SCH 23390. Sixteen healthy subjects (14 men, 2 women; 21-32 years) and ten neuroleptic naive schizophrenic patients (8 men, 2 women; 21-32 years) (DSM-IV) were recruited. Psychopathology was rated using the BPRS at the time of PET (median score 44.5, range 33-65). The IIC-labelled selective DIdopamine receptor antagonist SCH 23390 with high specific radioactivity was injected IV into each subject. Radioactivity was measured for 33 min. using the Scanditronix PC2048-15B PET-camera. The four peak pixel values were selected from each the striatal and frontal cortical regions respectively and normalized by division with the mean pixel value for the cerebellum region. The peak pixel ratios for the striatum and the frontal cortex respectively were 16% and 11% (p < 0.01) lower in the neuroleptic naive schizophrenic patients. The reduced peak pixel ratios found in the present study should represent reduced [IIC]SCH 23390 binding to Dl-dopamine receptors. A putative reduction of Dl-dopamine receptors in schizophrenia provides theurapeutic opportunities for D 1agonists. The sum of scores for the BPRS items reflecting psychotic symptoms (4, 11, 12 and 15) was significantly inversely related to both D J-binding ratios (p < 0.05). This inverse correlation may suggest that the intensity of psychotic symptoms is coupled to mechanisms causing reduced DI-receptor binding.
213 showing an enhanced sensitivity to these agonists. In PD, the effects of CCK-4 and pentagastrin can be blocked by chronic treatment with imipramine or f1uvoxamine. In dogs and in healthy human volunteers, CCK-4 induces increases in heart rate, blood pressure, tidal volume and respiratory frequency in parallel with behavioral changes, thus mimicking cardinal physiological changes associated with panic attacks. In PD and in healthy volunteers, CCK -4-induced panic attacks are antagonized by CCK-B receptor antagonists suggesting a role for CCK-B receptors. The contribution of psychological factors to CCK-4-induced anxiety has also been evaluated. Studies have revealed that individual differences in anxiety sensitivity, a trait characterized by the propensity to appraise symptomatology of anxiety as threatening, does not predict panicogenic response in healthy subjects or PD patients treated with CCK-4. On the other hand, the MMPI Social Introversion scale, a measure of neurotic introversion. has been found to be a significant predictor of CCK-4induced anxiety. The contribution of different neurotransmitter systems in the effects of CCK-4 are not known. Pre-treatment with f1umazenil, the benzodiazepine receptor antagonist, or tryptophan depletion have not been found to alter response to CCK-4 in healthy volunteers. Preliminary studies with B-adrenergic blockers suggest that the B-adrenergic system might mediate some of the effects of CCK-4. It is possible that endogenous anomalies of the CCK system exist in PD. For example, decreased CSF and lymphocyte concentrations of CCK-8S in PD, as compared to controls has been reported. This could suggest anomalies in CCK synthesis and/or metabolism. An important step in testing the hypothesis of a role for CCK in PD and anxiety will be to evaluate the action of pharmacokinetically-viable CCK-B antagonists in blocking or preventing spontaneous panic attacks and in relieving symptoms of anxiety.
16-57-31 Cholecystokinin in Animal Models of Anxiety
15-571 Cholecystokinin in Anxiety: Overview and Update
I6-57-1 I Human CSF CCKin Anxiety Disorders andCCK Agonist 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 levels may be abnormal in anxious patients and b) that peripherally administered CCK agonists may be panicogenic in patients with GAD as has been shown in PD patients. To test the hypothesis that CCK function may be abnormal in anxiety states, we measured CCK-8S via radioimmunoassay in 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 the tetrapeptide 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 7 patients with DSMlII-R - GAD and 7 age-and sex-matched Ns. 5/7 GAD patients vs In Ns had a panic attack after infusion (p < 0.05). Thus, it appears that GAD patients, like PD patients are significantly more sensitive to the anxiogenic effects of CCK agonists than are normals. These data support the hypothesis that CCK may play an important role in human anxiety states.
I6-57-21
CCK·B Agonists and Panic Induction in Humans
J. Bradwejn, D. Koszycki. Clarke Instituteof Psychiatry, Toronto,
Canada Cholecystokinin-tetrapeptide (CCK-4) and pentagastrin induce panic attacks in healthy volunteers, with patients with panic disorder (PD)
E. Vasar. Departmentof Physiology, University of Tartu, 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 more potent in the ethological models (elevated plus-maze, social interaction test) 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 behavior of rodents at doses not affecting their locomotor activity. Moreover, the anti-exploratory effect of caerulein in the plus-maze, differently from its locomotor depressant action, was not affected by the subdiaphragmatic vagotomy. The anxiogenic-Iike action of CCK agonists was antagonized by the CCK B (brain subtype), but not by CCK A (peripheral subtype) receptor antagonists. This is in good accordance with the human studies suggesting the role of brainstem CCK B receptors in CCK-induced anxiety. Nevertheless, the systemic or intracerebroventricular administration of CCK antagonists (L-365 ,260, devazepide) as single treatments did not cause anxiolytic action in rats. This finding is not in favor of direct involvement of CCK in the neural networks mediating anxiety. However, CCK seems to modulate the activity of various nerve cells responsible for anxiety, including serotonin-, norepinephrine-, GABA- and NO-ergic neurons.
16-57-41 A Primate Model for Assessment of CCK Agonists and Antagonists R. Palmour, F. Ervin. Departmentof Psychiatry, McGill University,
Montreal The authors will describe evidence for a dose-related, CCK-agonist (CCK tetrapeptide CCK-4) -mediated increase in anxiety-related behaviors in primates. In this model, agents which have been shown to block the CCKB receptor reliably attenuate these CCK-4 -induced anxiogenic effects selectively. One important variable which modulates the anxiogenic response appears to be the baseline arousal of the individual animal. Monkeys in which "anxious" behavior at baseline is observed frequently are more susceptible to the anxiogenic effects of CCK-4. The usefulness of the primate model in assessing selective CCK agonists and antagonists will be discussed.
213 showing an enhanced sensitivity to these agonists. In PD, the effects of CCK-4 and pentagastrin can be blocked by chronic treatment with imipramine or f1uvoxamine. In dogs and in healthy human volunteers, CCK-4 induces increases in heart rate, blood pressure, tidal volume and respiratory frequency in parallel with behavioral changes, thus mimicking cardinal physiological changes associated with panic attacks. In PD and in healthy volunteers, CCK -4-induced panic attacks are antagonized by CCK-B receptor antagonists suggesting a role for CCK-B receptors. The contribution of psychological factors to CCK-4-induced anxiety has also been evaluated. Studies have revealed that individual differences in anxiety sensitivity, a trait characterized by the propensity to appraise symptomatology of anxiety as threatening, does not predict panicogenic response in healthy subjects or PD patients treated with CCK-4. On the other hand, the MMPI Social Introversion scale, a measure of neurotic introversion. has been found to be a significant predictor of CCK-4induced anxiety. The contribution of different neurotransmitter systems in the effects of CCK-4 are not known. Pre-treatment with f1umazenil, the benzodiazepine receptor antagonist, or tryptophan depletion have not been found to alter response to CCK-4 in healthy volunteers. Preliminary studies with B-adrenergic blockers suggest that the B-adrenergic system might mediate some of the effects of CCK-4. It is possible that endogenous anomalies of the CCK system exist in PD. For example, decreased CSF and lymphocyte concentrations of CCK-8S in PD, as compared to controls has been reported. This could suggest anomalies in CCK synthesis and/or metabolism. An important step in testing the hypothesis of a role for CCK in PD and anxiety will be to evaluate the action of pharmacokinetically-viable CCK-B antagonists in blocking or preventing spontaneous panic attacks and in relieving symptoms of anxiety.
16-57-31 Cholecystokinin in Animal Models of Anxiety
15-571 Cholecystokinin in Anxiety: Overview and Update
I6-57-1 I Human CSF CCKin Anxiety Disorders andCCK Agonist 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 levels may be abnormal in anxious patients and b) that peripherally administered CCK agonists may be panicogenic in patients with GAD as has been shown in PD patients. To test the hypothesis that CCK function may be abnormal in anxiety states, we measured CCK-8S via radioimmunoassay in 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 the tetrapeptide 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 7 patients with DSMlII-R - GAD and 7 age-and sex-matched Ns. 5/7 GAD patients vs In Ns had a panic attack after infusion (p < 0.05). Thus, it appears that GAD patients, like PD patients are significantly more sensitive to the anxiogenic effects of CCK agonists than are normals. These data support the hypothesis that CCK may play an important role in human anxiety states.
I6-57-21
CCK·B Agonists and Panic Induction in Humans
J. Bradwejn, D. Koszycki. Clarke Instituteof Psychiatry, Toronto,
Canada Cholecystokinin-tetrapeptide (CCK-4) and pentagastrin induce panic attacks in healthy volunteers, with patients with panic disorder (PD)
E. Vasar. Departmentof Physiology, University of Tartu, 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 more potent in the ethological models (elevated plus-maze, social interaction test) 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 behavior of rodents at doses not affecting their locomotor activity. Moreover, the anti-exploratory effect of caerulein in the plus-maze, differently from its locomotor depressant action, was not affected by the subdiaphragmatic vagotomy. The anxiogenic-Iike action of CCK agonists was antagonized by the CCK B (brain subtype), but not by CCK A (peripheral subtype) receptor antagonists. This is in good accordance with the human studies suggesting the role of brainstem CCK B receptors in CCK-induced anxiety. Nevertheless, the systemic or intracerebroventricular administration of CCK antagonists (L-365 ,260, devazepide) as single treatments did not cause anxiolytic action in rats. This finding is not in favor of direct involvement of CCK in the neural networks mediating anxiety. However, CCK seems to modulate the activity of various nerve cells responsible for anxiety, including serotonin-, norepinephrine-, GABA- and NO-ergic neurons.
16-57-41 A Primate Model for Assessment of CCK Agonists and Antagonists R. Palmour, F. Ervin. Departmentof Psychiatry, McGill University,
Montreal The authors will describe evidence for a dose-related, CCK-agonist (CCK tetrapeptide CCK-4) -mediated increase in anxiety-related behaviors in primates. In this model, agents which have been shown to block the CCKB receptor reliably attenuate these CCK-4 -induced anxiogenic effects selectively. One important variable which modulates the anxiogenic response appears to be the baseline arousal of the individual animal. Monkeys in which "anxious" behavior at baseline is observed frequently are more susceptible to the anxiogenic effects of CCK-4. The usefulness of the primate model in assessing selective CCK agonists and antagonists will be discussed.