s304 1?3 Anxiety disorders and anxiolytics Ip.3.0161 The changing faces of nicotine’s effects on anxiety after acute and chronic administration E. Irvine, S. Cheeta, SE. File. Psychopharmacology Research Unit, Kings College London, Guy S Campus, London SE1 9RT UK The social interaction test of anxiety has proved sensitive to both anxi- olytic and anxiogenic effects of (-)-nicotine. When tested 30 min after intraperitoneal (i.p.) administration low doses were anxiolytic and high doses were anxiogenic (File et al, 1998). We have now investigated the time-course of effects following a single sub-cutaneous (s.c.) injection of 0.1 m&g (-)-nicotine. There was a complex pattern of effects with an initial anxiogenic effect at 5 rain being replaced with an anxiolytic action at 30 min, followed by a further anxiogenic effect at 1 hr, with a gradual return to control levels at 30 h. After 7 days of treatment with 0.1 mg/kg S.C. there was tolerance to both the anxiogenic effect observed at 5 min and to the anxiolytic effect observed at 30 min. 72 h after the last dose there was a significant anxiogenic response. A rapid modification in (-)-nicotine’s effects can also been seen after direct administration to the dorsal hippocampus. On the first occasion, (-)-nicotine (8 pg) had an anxiogenic effect. When rats were retested 48 h later with the same dose, it was ineffective. Thus, nicotinic modulation of anxiety is dependent on dose, time since administration, and length of treatment. References [l] File, SE., Kenny, P.J. & Ouagazzal, A-M. (1998) Bimodal modulation by nico- tine of anxiety in the social interaction test: Role of the dorsal hippocampus. Behaviouml Neuroscience zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA 112, 1423-1429. m] Development of the contingent tolerance to midarolam in FR30 reinforcement schedule H.B. Ayvasik, SC. Fowler, M.J. Kallman. Middle East Technical Uni- versity, Department of Psychology, Ankara, Turkey Unioersiv of Kansas, Department of Human Development, Kansas; Lilly Research Laboratories, Indiana, USA The purpose of the present study was to examine the effects of chronic treatment on the development of contingent (behavioral) tolerance to midazolam in FR30 reinforcement schedule. First, animals were trained for FR30 operant schedule. After an initial dose-effect determination with midazolam (O&30.0 mg/kg) (n = 16), midazolam (17.3 mg/kg) was given for 28 days chronically. During the chronic treatment, half of the rats received the drug before the session (PRE group) and the other half received the drug after the session (POST group). The control group (CONT group - n = 8) received vehicle 28 days throughout chronic treatment days. After the chronic treatment, a within-subject probe dose-effect was conducted for midazolam (0.0-30.0 m&g) to address the issue of loss of tolerance after withdrawal. After probe-dose effect determination, two weeks of withdrawal from chronic midazolam treatment started and all animals were given vehicle during the with- drawal days. Afier withdrawal, a second probe-dose effect determination was conducted (0.0-30.0 mg/kg). The results showed that response rate did not provide any evidence for the development of contingent tolerance. However, the PRE group displayed higher tolerance than the POST group for the mean response duration. After withdrawal, there was no difference between groups in terms of response rate and response duration. The results support the idea that behavioral experience under the drug contributes to the development of tolerance. Note: This study was a portion of the first author’s doctoral dissertation at the University of Mississippi. One part of the dis- sertation has been published. (Ayvasik, H.B., Fowler, S.C. and Kallman, M.J. (1996). Midazolam’s dose effects on fixed-ratio re- sponse rate in rats depend on amount of prior training experience. Experimental and Clinical Psychoparmacology, 4 (2), 151-156). How- )icle were completely different than those in this abstract. References [1] Fowler, SC., Bowen, S.E. and Kallman, M.J. (1993). Practice-augmented tolerance to triazolam: Evidence from an analysis of operant response durations and interresponse times. Behavioral Pharmacology, 4 (2), 147-157. [2] Tizzano, J.P., Parish, W.D. and Kallman, M.J. (1986). Pharmacological and behavioral tolerance to the sedative effects of diazepam and midazolam in rats. Federation Proceedings, 45, 428. -1 SSRls revert the inhibitory effect of PKC on the 5-HT transporter in OCD D. Marazziti, I. Masala, S. Baroni, A. Rossi, S. Presta, G. Giannaccini, L. Dell’Osso, A. Lucacchini, G.B. Cassano. Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, University of Piss, Piss, Italy While considerable evidence suggests that serotonin (5-HT) dysfunc- tion occurs in at least a subgroup of obsessive-compulsive disorder (OCD) patients, intracellular mechanisms that regulate or mediate 5- HT function have not been systematically examined in this disorder. Recently, a link between 5-HT reuptake and protein kinase C (PKC) has been observed. PKC is a class of phosphorylases present at high concentration in the brain. Diacylglycerol derived from the hydrolysis of phosphatidylinositol-4,5-bisphosphate (PIP2) stimulates PKC by increas- ing its affinity for calcium and membrane phospholipids, thus promoting its translocation from the cytosol to the particulate fraction. Following a previous observation that OCD untreated patients showed a decrease in platelet 5-HT reuptake by means of PKC activation in by 4-beta-12-tetradecanoylphorbol 13-acetate (p-TPA), a phorbol esther which mimics diacylglycerol, but at a greater extent than in a group of healthy controls, with this study we aimed to explore the effects of six-months’ treatments with different SSRIs on this effect. Fifteen out-patients of both sexes affected by OCD, according to DSM IV criteria, were included in the study and were treated with different SSRIs at adequate dosages for six months. The severity of OC symptoms was evaluated by the Yale Brown Obsessive-Compulsive Scale (Y-BOCS) at the beginning and at the end of the study. The determination of 5-HT uptake with and without P-TPA was carried out according to the method of Arora and Meltzer (1981) with slight modifications. At baseline, OCD patients showed a significant decrease in the maximal velocity (V,,) of 5-HT uptake, as compared with control subjects, with no change in the Michaelis-Menten constant (Km). The activation of PKC with p-TPA provoked a significant decrease in V, and an increase in K,,, values. After the treatment with SSRIs, the both Vmax and Km increased significantly. The activation of PKC with P-TPA did not provoke any more the decrease in Vmax. Taken together, these findings could indicate the presence of hyperac- tivity of PKC in OCD reverted by treatments with SSRIs. References [l] Anderson G, Home WC (1992): Activators of protein kinase C decrease serotonin transport in human platelets. Biochem Biophys Acta 1137: 331-337 [2] Marazziti D, Rossi A, Masala I, Rotondo A, Palego L, Mazzoni MR. Gi- annaccini G, Lucacchini A, Cassano GB (1999): Regulation of the platelet serotonin transporter by protein kinase C in the young. Biological Psychiatry 45: 443-447. Ip.3.0191 Relationship between anxiety disorders and (hypo)mania G. Perugi, C. Toni, F. Frare, B. Mata, B. Vitale. Institute of Psychiatry. University of Piss, Piss, Italy Objective: The relationship between anxiety and depressive disorders has been conventionally limited to unipolar depression. Recent studies from both clinical and epidemiologic samples have revealed intriguing associations between anxiety and bipolar (mainly bipolar II) disorders. The present report examines the temporal sequence of hypomania to