5-47 Chromic Treatment of Anxiety: Benzodiazepines and Beyond I 5 -46-41 Interactions between NMDAlNitric Oxide Systems and CT Receptors in Learning and Memory in Mice T. Nabeshima, Y. Noda, T. Marniya, K. Yamada, T. Maurice. Dept. of Neuropsychopharmacology and Hosp. Pharm., Nagoya Univ. Sch.of Med. It is well known that N-methyl-D-aspartate (NMDA) receptors and nitric oxide (NO) play an important role in learning and memory. Since it has been reported that activation of NMDA receptors produces the activation of NO synthesis and that a receptor ligands potentiate the NMDA- induced excitation of the hippocampal neurons. it is possible that there is an interaction between NMDAINO systems and 0 receptors in learning and memory. Thu s, we investigated ( I) whether NO andJor 0 receptors are involved in (+)MK-801 (a non-competitive NMDA receptor antagonist)- induced impairment of working memory in mice, and (2) whether 0 receptors are involved in NO synthase inhibitor-induced impairment of working memory in mice. Performance of working memory was assessed by recording spontaneous alternation (SA) behavior in single session, in a Y-maze. (+)MK-80 1 (0.1 mg/kg i.p.)- and NG-nitro-L-arginine methyl ester (L-NAME; an NO synthase inhibitor; 100 mg/kg i.p.)-induced impairment of SA behavior were ameliorated by the pretreatment with dibutyryl cyclic GMP (10 nmoll5 I_ d/mouse i.e.v.) and L-arginine (an NO precursor; 1 glkg i.p.), suggesting that NO/cyclic GMP systems play a role in impairment of working memory induced by (+)MK-801 in mice. Further, (+)MK-80l (0.1 mglkg i.p.)-induced impairment of SA behavior was ameliorated by (+)SKF- IO,047 (a prototype 0 I receptor ligand; 0.1 and OJ mglkg s.c.) and l.3-d i-(2-tolyl) guanidine (DTG; a prototype 0 1/2 receptor ligand; 0.01-0.1 mglkg s.c.). The ameliorating effects of 0 receptor ligands were attenuated by 0 I receptor antagonists, NE- l 00 ( I mglkg i.p.) and BMY-14802 (5 and 10 mglkg i.p.), suggesting that 0 1 receptors are involved in (+)MK-80 l- induced impairment of SA behavior. Like (+)MK-801. L-NAME (100 mglkg i.p.)-induced impairment of SA behavior was also ameliorated by (+)SKF-IO,047 (I mglkg s.c.). The ameliorating effects of (+)SKF- IO,047 were attenuated by NE-100 (3 mglkg i.p.) and BMY-14802 (3 and 10 mglkg i.p.), suggesting that 0 I receptors is involved in L-NAME-induced impairment of SA behavior in mice. These findings demonstrated that there is the functional interaction between NMDAINO systems and a I receptors in the learning and memory process. I 5-46-5 1Roleof Sigma Receptors in MotorControl Michael 1. Walker. Brown University, Providence, Rhode Island, 02912, USA Sigma receptors are found in many areas of the brain, but the highest levels are found in areas that are associated with the control of movement: the oculomotor. trigeminal motor, facial, and hypoglossal nuclei, as well as the cerebellum, red nucleus and substantia nigra. Because of the high levels of sigma receptors in these areas of the brain, we have examined the possibility that sigma ligands play a functional role in movement. Our studies have focused on two systems the rubrocerebellar system, and the nigrostriatal system; significant motor effects of sigma ligands have been observed in both. In the rubro-cerebellar system. we have found that sigma ligands inhibit neurons in the red nucleus and produce acute dystonic reactions upon microinjection. The role of sigma receptors in this effect is suggested by its antagonism by certain putative sigma antagonists. The possibility that sigma receptors are involved in the motor side effects of antipsychotic drugs is suggested by that finding that reduced haloperidol. a sigma active metabolite of haloperidol, is neurotoxic in the red nucleus. Th is observation is consistent with recent findings from other laboratories demonstrating similar effects in cell culture. In the nigrostriatal system, a consistent set of findings indicate that sigma ligands cause dopamine release. Direct studies of dopamine levels indicate increased DA in the extracellular space following i.p. injections of relatively low doses of the sigma ligands 1,3 di-O-tolylguanidine (DTG) or (+)-pentazocine. These findings are consistent with I) rota- tional behavior following intranigral administration of sigma ligands; 2) increased firing rate of A9 DA neurons following i.v. (+)-pentazocine and its antagonism of (+)-3-PPP inhibition of DA firing; and 3) increased 159 utilization of glucose In the substantia nigra following i.p. administration of DTG. 15-4 71 Chromic Treatment of Anxiety: Benzodiazepines and Beyond I 5-47-1 I Chronic Benzodiazepine Use in the General Population P. Boyer. J.P. Lepine, W. Rein. J.e. Bisserbe. INSERM, Hopital Sainte Anile, Paris, France In order to assess the benzodiazepine use in the french general population a national representative sample of 4438 adults has been interviewed ac- cording to a two phase procedure. In a first stage the pattern of anxiolytic andJor hypnotic used was assessed using a 17 items self-questionnaire. In a second stage subsamples of chronic users (at least 5 days a week during the last year), sporadic users (less than 5 days a week) and non users were reinterviewed by professional investigators with a modified version of the CIDI (OMS, 1990). Current and lifetime mood, anxiety and somatoform disorders were rated. One year prevalence of regular anxiolytic usc was as high as 7%. This rate was more important in female (8%) than in male (5%) and increased significantly with age after 55 years (46% of chronic and sporadic users). No association with age was found for sporadic use. The current prevalence of depressive and anxiety disorders was two to threefold higher for chronic users than for non users. Registers of social insurance systems in France indicate than more than 15% of prescriptions (for any kind of diseases) correspond to an anxiolytic and than 7% correspond to an hypnotic. GPs represent 64% of the prescribers and deliver 86% of the total prescriptions of anxiolytics. 15-47-21 Benzodiazepines Use in the Medically III Population: Impact of Psychopathology and Somatic Morbidity A. Pelissolo, J.C. Bisserbe, E. Weiller, P. Boyer, Y. Lecrubier. INSERM U302, Hopital La Salpetriere, Paris, France The purpose of our study was to investigate the respective impact of somatic morbidity and psychopathology on anxiolyticsIhypnotics con- sumption in general hospital inpatients. 105 (38 males and 67 females) patients admitted during a 5-month period were consecutively included in the study. The assessment was made at admission and medical infor- mations was summarized and collected at discharge. Lifetime anxiolytics and hypnotics consumption was investigated with using a validated ques- tionnaire. Psychopathologic morbidity was assessed with the self-rated Hospital Anxiety and Depression scale (HAD) and 12-items General Health Questionnaire (GHQ-12). Somatic morbidity was rated indepen- dently using two global scales with 5 anchor points. Somatic Pronostic Scale and Somatic State Scale. Only 20% of the patients reported no lifetime anxiolytic/hypnotic use and were younger and mostly males (62%). 30% of the patients had used benzodiazepines daily in the last 3 months (26.3% in males; 32.8% in females) and 25% daily in the last years. BZD use was not associated with somatic disorder severity, patients using chronically BZD had higher HAD and GHQ-12 score, psychopathology rating were independent from somatic severity rating. 18-47-3 1 Receptor Mechanisms of Benzodiazepine Dependence J. Potokar. N. Coupland, J. Bailey, DJ . NUll . Psychopharmacology Unit, University of Bristol, UK Benzodiazepine tolerance is a major issue and of direct relevance to anxiety, sleep disorders, hypnotic prescriptions and epilepsy [I ]. Chron- ically benzodiazepines produce dependence with tolerance initially to the sedative and ataxic effects followed by the anticonvulsant and later the anxiolytic effects. Various mechanisms for this have been suggested including change in subunit composition and "receptor shift".