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Anxiolytic effects found in the fear-potentiated startle response paradigm are not due to a non-specific disruption of startle behavior
P.5 Anxiety disordersand anxiolytics tensively studied throughout the world for the treatment of adults with depression, panic disorder and OCD.. The purpose of the study is to evaluatethe effects of fluvoxaminein children and adolescentswith OCD in a controlled, multicenter treatment trial. Methods: Subjects 8-17 years old with a minimum six month history of OCD (DSM-IllR) were recruited at 17 investigative sites throughout the United States. Exclusion criteria included significantmedical or psychiatric co-morbidity, or a past history of not responding to an adequate trial of another serotonin reuptake inhibitor. A 7-14 day single-blind, placebo washout/screening period occurred prior to randomization. To be randomized subjects were required to have a baseline score 2: 15 on the IQ-item Children's Yale-Brown ObsessiveCompulsiveScale (CY-BOCS) and 2: 7 on the NIMH Global Obsessive Compulsive Scale. Subjects who had not responded by week 6 of the 10 week trial could terminate the double-blind portion of the study and enter a long-term open trial of fluvoxamine. Outcome comparison of fluvoxamine vs. placebo used the intent-to-treat,last-observation-carried-forward method of analysis. Results: Of the 120 subjects randomized, 74 subjects (38 fluvoxamine, 36 placebo) completed the 1Q-week trial. The fluvoxamine and placebo groups were similar demographically. Each group had nearly equal number of boys and girls. About a third of the subjects had been on other medicines. Very few subjects had other co-morbid conditions. Most of the 44 subjects who terminated early, (22 placebo, 9 fluvoxamine) did so due to lack of improvement at week 6. Only 4 subjects (3 fluvoxamine, 1 placebo) discontinued due to side effects, none of which were considered serious; 9 subjects discontinuedfor "other" reasons.The primaryefficacy variable, CY-BOCS, showed significant differences from placebo (N = 120; P < 0.05) for the intent-to-treat, last-observation-carried-forward analysis at weeks 1-6 and week 10, with a trend toward significance at week 8. This finding was also supported by significant differences in the 3 secondary outcome measures. Side effects more common on fluvoxamineincluded insomnia, agitation, hyperkinesia, somnolenceand dyspepsia. There were no clinically significant changes in laboratory or EKG parameters during short-term fluvoxamine treatment. Conclusions: Fluvoxamine is rapidly effective and appears safe for the short-term treatment of OCD in children and adolescents as young as age 8. Improvement in OCD symptoms were uniformly identifiedby clinicians, parents as well as the children. The design, subjectsand results of this study will be compared with those of other published, controlled, medication trials for OCD in children and adolescents. References [I] De Veaugh-Geiss J, Moroz G, Biederman Jet al.:Clomipramine hydrochloride inchildhood andadolescent obsessive-compulsive disorder - a multicenter trial. J AmAcad Child Adolesc Psychiatry 1992, 31 (I), 45-49. [2] Riddle MA, Scahill L, King R et al.:Double-blind crossover trial of f1uoxetine andplacebo in children andadolescents with obsessive-compulsive disorder. J Am Acad Child Adolesc Psychiatry 1992.31 (6), 1062-1069.
IP.5.01S!
Discrimination between the S-HT1 receptor agonists flesinoxan and eltoprazine
J. Gommans I, T.H. Hijzen I, R.A. Maes z, B. Olivier t. 1 Departmentof Psychopharmacology, FacultyafPharmacy, Utrecht University, Sorbonnelaan16, 3584 CA Utrecht, The Netherlands; Z Departmentof Toxicology, Facultyof Pharmacy, Utrecht University, Sorbonnelaan 16, 3584 CA Utrecht, The Netherlands Flesinoxan and eltoprazine bind with high affinity to 5-HTt receptors, flesinoxan in particular to 5-HTIA receptors, and eltoprazine to 5-HT1A and 5-HT1B receptors. In previous operant, two lever, drugvehicle discrimination experiments, flesinoxan and eltoprazine partially cross-generalized to each other (59.9% and 49.4% respectively). The flesinoxan cue could be antagonized by the specific 5-HTtA receptor antagonistWAY-100635. The eltoprazine cue could not (Gommanset al., 1995; Gommans et al., submitted). Thus, despite the fact that there is considerable overlap between the mechanism of action of the two drugs, there are also salient differences. Therefore we investigated whether rats could learn to discriminate between flesinoxan and eltoprazine. Rats were trained to discriminate flesinoxan (1.0 mglkg p.o.) from eltoprazine (1.5 mglkg p.o.), using a two lever operant procedure with a FR 10 schedule of reinforcement. All rats learned the discrimination
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readily.Saline administration resulted in approximately50% lever presses on both levers; response rates were reduced and the latency to initiate lever pressing was increased.This indicates that the saline "cue" (or lack there of) is incompatable with both training cues. Dose response curves were obtained with both training drugs, the prototypical 5-HTIA receptor agonist 8-0H-DPAT, the 5-HTIB receptor agonist anpirtoline, and the 5-HT2A/2C receptor antagonist mianserin. Flesinoxan (dose range tested: 0.125-1.5 mglkg p.o.) and 8-0H-DPAT(0.01-{).1 mglkg s.c.) substituted completelyfor flesinoxan. Eltoprazine (0.125-1.5 mglkg) and anpirtoline (0.063-{).25 mglkg s.c.) substituted completely for eltoprazine. These results show that the cue of flesinoxan is mediated by activation of 5-HT1A receptors and the cue of eltoprazine by activation of 5-HTIB receptors. Mianserin (1.0-12.0 mglkg p.o.) yielded no more than 65% lever presses on either lever, i.e, was more comparable to saline than to one of the training drugs. We conclude that rats can easily learn to discriminate between the 5-HT receptor agonists flesinoxan and eltoprazine, and that the cues are mediated by 5-HTtA and 5-HT1B receptors respectively. References
Gommans, 1., Hijzen, T.H.•Maes, R.A., Mos, J. and Olivier, B. (1995) Discriminative stimulus properties of flesinoxan: effects of enantiomers, (S)-UH301 and WAY-l00635. Eur. 1. Phannacol. 284, 135-140. Gommans, 1., Hijzen, T.H., Maes, R.A and Olivier, B. Discriminative stimulus properties of eltoprazine. Submitted.
IP.5.019I Anxiolytic effects found in the fear-potentiated startle response paradigm are notdue to a non-specific disruption of startle behavior RJ.E. Joordens, T.H. Hijzen, B. Olivier. Department ofPsychopharmacology, FacultyofPharmacy, Rudolf Magnus Institute ofNeurosciences, UtrechtUniversity, Sorbonnelaan 16, 3584 CA, Utrecht, NL The startle response can be augmented by presenting the startle-eliciting noise in the presenceof a stimulusthat has previously been paired with an electric shock. The augmented startle response is called fear-potentiated startle response (FPS) and is considered to be a measure of a central state of fear (Davis et al. 1993). Clinically effective anxiolytic drugs usually reduce FPS, while anxiogenic drugs increase FPS (Davis et aI. 1993, Hijzen et al. 1995). The startle response can also be potentiated by a strychnine injection (SPS). Because no fear-conditioning takes place in SPS, no central state of fear exists. When anxiolytic drugs reduce FPS, but not SPS, the decrease in FPS after anxiolytic drugs can be attributed to the anxiolytic properties of the drug. In this study, the effects of the anxiolytic benzodiazepine alprazolam, the (putative) anxiolytic 5-HT1A receptor agonist flesinoxan and the anti-psychotic Dz receptor antagonist haloperidol on both the FPS and the SPS were investigated. Both fear-conditioning and strychnine injection significantly potentiate the startle response (see table I: main effect Potentiation). As expected, the anxiolytic drugs alprazolam and flesinoxan dose-dependently reduce FPS without affecting SPS (see table I: Potentiation x Dose interaction effect). On the other hand, the neuroleptic drug haloperidol is supposed to exert no effect on FPS, although anxiolyticeffects of haloperidolhave occasionally been reported. The findings of this study suggest that the dose-dependent reduction of the fear-potentiated startle response can be attributed to the anxiolytic properties of drugs and does not reflect a "non-specific" disruption of startle behavior. Table I: Summary of the main effects and interaction effect of alprazolam (ip), flesinoxan (po) andhaloperidol (ip) on theFPS andSPS (" P < 0.05). Drug Main effect Main effect Potentiation (dose in mglkg) Potentiation Dose x Dose FPS Alprazolam (0, 1,2,3) F (1,11)=41.4* F (3,9)=20.9* F (3,9)= 10.4' Flesinoxan (0. 1,3, 10) F (I, 11)=33.2' F (3,9)= 1.9 F (3,9)= 10.3' Haloperidol F (I, 11)=44.3" F (3.9)= 14.1" F (3,9)= 8.2' (0,0.06, 0.12. 0.24) SPS A1prazolam (0, 1.5, 3) F (1, II) =33.8' F (2, 10)= 14.4* F (2, 10) =0.6 Flesinoxan (0,10) F (I, 22)= 7.0' F (I, 22)= 0.0 F (I, 22)=0.6 Haloperidol (0,0.08, 0.24) F (1,11)=21.5* F (2,10)=3.2 F (2,10)=0.6
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P.5 Anxietydisorders and anxiolytics
References
Davis, M., Falls, W.A., Campeau, S. and Kim, M. (1993) Fear-potentiated startle: a neural and pbarmacoJogical analysis. Bebav. Brain.R;es. 58, 175-198. Hijzen, T.H., Houtzager, S.WJ., Joordens, RJ.E., Olivier, B. and Slangen,.n, (1995) Predictive validity of the potentiated startle response as a behavioral model foranxiolytic drugs. Psychopharmacology 118, 15(}-154.
IP.5.020 I Repeated tlesinoxan administration in rats:
Dissociation ot hormonaland behavioural effects
L. Groenink, I. vander Gugten, B. Olivier. Dept. Psychopharmacology;
Fac. Pharmacy and RudolfMagnus Institutefor Neurosciences, Utrecht University, Sorbonnelaan 16, 3584 CA Utrecht, TheNetherlands 5-HTIA receptor agonists exert anxiolytic effects, both in humans and animals. In humans, the beneficial effects of 5-HTIA receptor agonists show a delayed onset of action. Various hypotheses have been proposed to explain this slow onset of action, but most seem to relate this effect to adaptational processes at the receptor level (e.g. 5-HT1A or 5-HT2 ) . Functionality of 5-HT1A receptors may be visualized by measuring neuroendocrine parameters, an approachwhichis also clinically used. We used the clinically effective 5-HTlA receptoragonist f1esinoxan to study the effects of repeated administration of a 5-HT1A receptoragonist on the hypothalamic-pituitary-adrenal (HPA) axis and behaviour. The effectsweremeasuredboth after oneday and one weekof pretreatment (3 mg/kg SC once daily), to assess whether a potential adaptation develops gradually. The shock-probe buryingparadigm was used as animal model of anxiety. In this paradigm, rats are shocked when they touch an electrified probe. Rats may react with burying the probe or with immobility, whichcan be used as indices of anxiety. Acuteadministration of f1esinoxan (3 rng/kg SC) significantly enhanced plasmacorticosterone levels. After a single injection with flesinoxan, the effect of a second f1esinoxan injection (given 24 h later) on plasmacorticosterone levels was significantly reduced. After one week of f1esinoxan pretreatment the corticosterone response was completely absent, thus showing a gradual development of tolerance. Basal corticosterone levels were not affectedby the pretreatment. The effects of f1esinoxan-pretreatment on f1esinoxan-induced corticosterone secretion in rats which had been exposed to the shock-probe burying test, closely resembled those found in nonstressed rats. In the shock-probe buryingparadigm, f1esinoxan significantly enhanced plasma corticosterone levels in f1esinoxan-naive rats, both after one day and one week of vehicle-pretreatment. In rats pretreated with f1esinoxan for either one day or one week, the f1esinoxan-enhancing effects on plasma corticosterone were significantly reduced compared to f1esinoxan-naive rats. However, flesinoxan-pretreatment did not reduce the stress-induced rises in plasmacorticosterone levels. This may indicate that the HPA axis has become less sensitive to stimulation by 5-HT1A receptor agonists, whereas the HPAaxis is still responsive to stress. Acute t1esinoxan administration reduced burying and probe-directed behaviour. indicating potential anxiolytic effects of the drug. Following repeated f1esinoxan treatment (either one day or one week)these effects remained present,that is, no toleranceoccurredfor the behavioural effects of t1esinoxan. These results show that repeated administration of a 5-HTIA receptor agonist may indeed result in adaptation of 5-HT1A receptor mediated responses. However, it appears that not each response is affected similarly.
IP.5.021 I Monoaminergic systems in patients with
Obsessive-Compulsive Disorder(OCD) beforeand after f1uoxetine treatment
P. Prolo, U. Albert, G. Maina, L. Ravizza, F. Bogetto, C. Abrigo, M.C. Gennaro, P. Frattini, G. Santagostino. Chairof Psychiatry, Department of Neurosciences. University of Turin, via Cherasco II , 1-10126 Torino, Italy; Institute of AnaliticalChemistry, University of Turin. Italy; Institute ofPharmacology. University of Pavia, Italy The evaluation of the responsivity to orthostatic challenge represents a clue in the investigation of the Autonomic Nervous System (ANS) involvement in anxiety phenomena; this is of particular interest in Db-
sessive Compulsive Disorder (OCD), as the nosographic inclusion in Anxiety Disorders is not accepted by many authors and OCD seems to be an heterogeneous disorder. Orthostatic challengerepresentsa stress to the ANS that offers several advantages over pharmacologic means. First, orthostatic challenge is a 'natural' and physiologically relevant kind of stress. Second, it is an innocuous, pain-free procedure. As it does not induce any kind of disconfort, patients may be assured that they need not fear this procedure. Consequently, this challenge may be considered free of the artifacts of increased anticipatory anxiety that confounds interpretation of manypharmacologic challenges. This postural paradigm has been used previously in the study of patients with Depressive Disorders and Panic Disorders, but never, to our knowledge, in patients with OCD. Heart rate, blood pressure and plasma Norepinephrine (NE), Epinephrine (E), Dopamine (DA), L-dyhydroxyphenilalanine (L-DOPA), Serotonin(5-HT), Hydroxindolacetic Acid (5-HIAA) and Homovanillic Acid (HVA) responsivity to orthostasis have been evaluated in a group of 20 patients with OCD according to DSM IV criteria before and after two months therapy with f1uoxetine (2D--60 mg/day),and in 20 healthy age and sex-matched controls. While the two groups showed very similar supine heart rates and blood pressures, patients with OCD showed an atypical response to orthostatic challenge. At baseline, both at resting conditions and after the orthostatic challenge, DA plasma concentrations were significantly higher in patients than in controls (p < 0.02); HVA plasma levels were indeed significantly lower (p < 0.02). We found no clear cut abnormalities in NE, E, L-DOPA, 5-HT, 5-H!AA absolute values and their responses to orthostasis between patients and controls at baseline. All results were then correlated with the Yale-Brown ObsessiveCompulsive Scale, the NIMH Obsessive Compulsive Scale, the Stait and Trait Anxiety Inventory form X.l and X.2, the Hamilton Anxiety Rating Scale and the Hamilton Depression Rating Scale. Only NE levels showed a tendency to correlate positively with NIMH scores (p < 0.093). After treatment patients showeda bluntedresponsein L-DOPA(p < 0.04) and an increased heart rate response to orthostasis (p < 0.01); S-HT plasma concentrations were significantly lower (p < 0.001), while Fluoxetine and its major metabolite NOR-Fluoxetine plasma valuesdid not correlate withsymptoms improvement. Theseobservations suggestthat patternsof dopaminergic dysfunction may be present in OCD. References [I) Kopin, I.J. (1992) Origins aod significance of DOPA aod catecholamines metaholites in body fluids. Pharmacopsychiat. 25; 33-36; 1992. [2) Ravizza, L., Barzega, G., Bellino,S., Bogetto, F. andMaina, G. (1995) Predictors of drug treatment response in Obsessive-Compulsive Disorder. J. Clin. Psychiatry 56, 368-373. (3) Stein, M.B., Tancer, M.E. and Uhde, T.W. (1992) Hearth rate and plasma norepinephrine responsivity [0 orthostatic cballenge in anxiety disorders. Arch. Gen. Psyc. 49, 311-317.
IP.5.022I ejaCUlation Fluoxetlne treatmentof comorbid premature and panic disorder S. Kindler I , O.T.Dolberg I , M. Kotler2 . I Psychiatric Division, Anxiety Clinic, Sheba Medical Center, RamatGan52621. Israel; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv. Israel; 2 Beer-Sheva Mental Health Center; AnxietyandStressResearch Unit, and the Ben-Gurion University of the Negev, Beer-Sheva; Israel Premature ejaculation (PE) has been reported to occur in up to 30% of all men (I). Several clinical trials, both open-label and placebo controlled. have demonstrated the efficacy of serotonergic drugs in the treatment of PE (2). The results of these studies might suggest the possibility that the serotonergic system has a modulating effect on sexual responsivity, especially attainment of orgasm. Serotonergic dysfunction has also been implicated in the pathogenesis of panic disorder (PD). Numerous clinical trials have demonstrated the efficacy of serotonin reuptake inhibitors (SRI's) in the treatment of PD (3).
The purpose of this study was to assess the clinical efficacy of SRI medication in the treatment of patientswithcomorbid PD and PE. Included in thisopen-label, 8 weekstudy, were 10healthy, heterosexual men, mean age 35 years, withself-reported PE and diagnosedPD. Other
IP.5.01S!
Discrimination between the S-HT1 receptor agonists flesinoxan and eltoprazine
J. Gommans I, T.H. Hijzen I, R.A. Maes z, B. Olivier t. 1 Departmentof Psychopharmacology, FacultyafPharmacy, Utrecht University, Sorbonnelaan16, 3584 CA Utrecht, The Netherlands; Z Departmentof Toxicology, Facultyof Pharmacy, Utrecht University, Sorbonnelaan 16, 3584 CA Utrecht, The Netherlands Flesinoxan and eltoprazine bind with high affinity to 5-HTt receptors, flesinoxan in particular to 5-HTIA receptors, and eltoprazine to 5-HT1A and 5-HT1B receptors. In previous operant, two lever, drugvehicle discrimination experiments, flesinoxan and eltoprazine partially cross-generalized to each other (59.9% and 49.4% respectively). The flesinoxan cue could be antagonized by the specific 5-HTtA receptor antagonistWAY-100635. The eltoprazine cue could not (Gommanset al., 1995; Gommans et al., submitted). Thus, despite the fact that there is considerable overlap between the mechanism of action of the two drugs, there are also salient differences. Therefore we investigated whether rats could learn to discriminate between flesinoxan and eltoprazine. Rats were trained to discriminate flesinoxan (1.0 mglkg p.o.) from eltoprazine (1.5 mglkg p.o.), using a two lever operant procedure with a FR 10 schedule of reinforcement. All rats learned the discrimination
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readily.Saline administration resulted in approximately50% lever presses on both levers; response rates were reduced and the latency to initiate lever pressing was increased.This indicates that the saline "cue" (or lack there of) is incompatable with both training cues. Dose response curves were obtained with both training drugs, the prototypical 5-HTIA receptor agonist 8-0H-DPAT, the 5-HTIB receptor agonist anpirtoline, and the 5-HT2A/2C receptor antagonist mianserin. Flesinoxan (dose range tested: 0.125-1.5 mglkg p.o.) and 8-0H-DPAT(0.01-{).1 mglkg s.c.) substituted completelyfor flesinoxan. Eltoprazine (0.125-1.5 mglkg) and anpirtoline (0.063-{).25 mglkg s.c.) substituted completely for eltoprazine. These results show that the cue of flesinoxan is mediated by activation of 5-HT1A receptors and the cue of eltoprazine by activation of 5-HTIB receptors. Mianserin (1.0-12.0 mglkg p.o.) yielded no more than 65% lever presses on either lever, i.e, was more comparable to saline than to one of the training drugs. We conclude that rats can easily learn to discriminate between the 5-HT receptor agonists flesinoxan and eltoprazine, and that the cues are mediated by 5-HTtA and 5-HT1B receptors respectively. References
Gommans, 1., Hijzen, T.H.•Maes, R.A., Mos, J. and Olivier, B. (1995) Discriminative stimulus properties of flesinoxan: effects of enantiomers, (S)-UH301 and WAY-l00635. Eur. 1. Phannacol. 284, 135-140. Gommans, 1., Hijzen, T.H., Maes, R.A and Olivier, B. Discriminative stimulus properties of eltoprazine. Submitted.
IP.5.019I Anxiolytic effects found in the fear-potentiated startle response paradigm are notdue to a non-specific disruption of startle behavior RJ.E. Joordens, T.H. Hijzen, B. Olivier. Department ofPsychopharmacology, FacultyofPharmacy, Rudolf Magnus Institute ofNeurosciences, UtrechtUniversity, Sorbonnelaan 16, 3584 CA, Utrecht, NL The startle response can be augmented by presenting the startle-eliciting noise in the presenceof a stimulusthat has previously been paired with an electric shock. The augmented startle response is called fear-potentiated startle response (FPS) and is considered to be a measure of a central state of fear (Davis et al. 1993). Clinically effective anxiolytic drugs usually reduce FPS, while anxiogenic drugs increase FPS (Davis et aI. 1993, Hijzen et al. 1995). The startle response can also be potentiated by a strychnine injection (SPS). Because no fear-conditioning takes place in SPS, no central state of fear exists. When anxiolytic drugs reduce FPS, but not SPS, the decrease in FPS after anxiolytic drugs can be attributed to the anxiolytic properties of the drug. In this study, the effects of the anxiolytic benzodiazepine alprazolam, the (putative) anxiolytic 5-HT1A receptor agonist flesinoxan and the anti-psychotic Dz receptor antagonist haloperidol on both the FPS and the SPS were investigated. Both fear-conditioning and strychnine injection significantly potentiate the startle response (see table I: main effect Potentiation). As expected, the anxiolytic drugs alprazolam and flesinoxan dose-dependently reduce FPS without affecting SPS (see table I: Potentiation x Dose interaction effect). On the other hand, the neuroleptic drug haloperidol is supposed to exert no effect on FPS, although anxiolyticeffects of haloperidolhave occasionally been reported. The findings of this study suggest that the dose-dependent reduction of the fear-potentiated startle response can be attributed to the anxiolytic properties of drugs and does not reflect a "non-specific" disruption of startle behavior. Table I: Summary of the main effects and interaction effect of alprazolam (ip), flesinoxan (po) andhaloperidol (ip) on theFPS andSPS (" P < 0.05). Drug Main effect Main effect Potentiation (dose in mglkg) Potentiation Dose x Dose FPS Alprazolam (0, 1,2,3) F (1,11)=41.4* F (3,9)=20.9* F (3,9)= 10.4' Flesinoxan (0. 1,3, 10) F (I, 11)=33.2' F (3,9)= 1.9 F (3,9)= 10.3' Haloperidol F (I, 11)=44.3" F (3.9)= 14.1" F (3,9)= 8.2' (0,0.06, 0.12. 0.24) SPS A1prazolam (0, 1.5, 3) F (1, II) =33.8' F (2, 10)= 14.4* F (2, 10) =0.6 Flesinoxan (0,10) F (I, 22)= 7.0' F (I, 22)= 0.0 F (I, 22)=0.6 Haloperidol (0,0.08, 0.24) F (1,11)=21.5* F (2,10)=3.2 F (2,10)=0.6
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P.5 Anxietydisorders and anxiolytics
References
Davis, M., Falls, W.A., Campeau, S. and Kim, M. (1993) Fear-potentiated startle: a neural and pbarmacoJogical analysis. Bebav. Brain.R;es. 58, 175-198. Hijzen, T.H., Houtzager, S.WJ., Joordens, RJ.E., Olivier, B. and Slangen,.n, (1995) Predictive validity of the potentiated startle response as a behavioral model foranxiolytic drugs. Psychopharmacology 118, 15(}-154.
IP.5.020 I Repeated tlesinoxan administration in rats:
Dissociation ot hormonaland behavioural effects
L. Groenink, I. vander Gugten, B. Olivier. Dept. Psychopharmacology;
Fac. Pharmacy and RudolfMagnus Institutefor Neurosciences, Utrecht University, Sorbonnelaan 16, 3584 CA Utrecht, TheNetherlands 5-HTIA receptor agonists exert anxiolytic effects, both in humans and animals. In humans, the beneficial effects of 5-HTIA receptor agonists show a delayed onset of action. Various hypotheses have been proposed to explain this slow onset of action, but most seem to relate this effect to adaptational processes at the receptor level (e.g. 5-HT1A or 5-HT2 ) . Functionality of 5-HT1A receptors may be visualized by measuring neuroendocrine parameters, an approachwhichis also clinically used. We used the clinically effective 5-HTlA receptoragonist f1esinoxan to study the effects of repeated administration of a 5-HT1A receptoragonist on the hypothalamic-pituitary-adrenal (HPA) axis and behaviour. The effectsweremeasuredboth after oneday and one weekof pretreatment (3 mg/kg SC once daily), to assess whether a potential adaptation develops gradually. The shock-probe buryingparadigm was used as animal model of anxiety. In this paradigm, rats are shocked when they touch an electrified probe. Rats may react with burying the probe or with immobility, whichcan be used as indices of anxiety. Acuteadministration of f1esinoxan (3 rng/kg SC) significantly enhanced plasmacorticosterone levels. After a single injection with flesinoxan, the effect of a second f1esinoxan injection (given 24 h later) on plasmacorticosterone levels was significantly reduced. After one week of f1esinoxan pretreatment the corticosterone response was completely absent, thus showing a gradual development of tolerance. Basal corticosterone levels were not affectedby the pretreatment. The effects of f1esinoxan-pretreatment on f1esinoxan-induced corticosterone secretion in rats which had been exposed to the shock-probe burying test, closely resembled those found in nonstressed rats. In the shock-probe buryingparadigm, f1esinoxan significantly enhanced plasma corticosterone levels in f1esinoxan-naive rats, both after one day and one week of vehicle-pretreatment. In rats pretreated with f1esinoxan for either one day or one week, the f1esinoxan-enhancing effects on plasma corticosterone were significantly reduced compared to f1esinoxan-naive rats. However, flesinoxan-pretreatment did not reduce the stress-induced rises in plasmacorticosterone levels. This may indicate that the HPA axis has become less sensitive to stimulation by 5-HT1A receptor agonists, whereas the HPAaxis is still responsive to stress. Acute t1esinoxan administration reduced burying and probe-directed behaviour. indicating potential anxiolytic effects of the drug. Following repeated f1esinoxan treatment (either one day or one week)these effects remained present,that is, no toleranceoccurredfor the behavioural effects of t1esinoxan. These results show that repeated administration of a 5-HTIA receptor agonist may indeed result in adaptation of 5-HT1A receptor mediated responses. However, it appears that not each response is affected similarly.
IP.5.021 I Monoaminergic systems in patients with
Obsessive-Compulsive Disorder(OCD) beforeand after f1uoxetine treatment
P. Prolo, U. Albert, G. Maina, L. Ravizza, F. Bogetto, C. Abrigo, M.C. Gennaro, P. Frattini, G. Santagostino. Chairof Psychiatry, Department of Neurosciences. University of Turin, via Cherasco II , 1-10126 Torino, Italy; Institute of AnaliticalChemistry, University of Turin. Italy; Institute ofPharmacology. University of Pavia, Italy The evaluation of the responsivity to orthostatic challenge represents a clue in the investigation of the Autonomic Nervous System (ANS) involvement in anxiety phenomena; this is of particular interest in Db-
sessive Compulsive Disorder (OCD), as the nosographic inclusion in Anxiety Disorders is not accepted by many authors and OCD seems to be an heterogeneous disorder. Orthostatic challengerepresentsa stress to the ANS that offers several advantages over pharmacologic means. First, orthostatic challenge is a 'natural' and physiologically relevant kind of stress. Second, it is an innocuous, pain-free procedure. As it does not induce any kind of disconfort, patients may be assured that they need not fear this procedure. Consequently, this challenge may be considered free of the artifacts of increased anticipatory anxiety that confounds interpretation of manypharmacologic challenges. This postural paradigm has been used previously in the study of patients with Depressive Disorders and Panic Disorders, but never, to our knowledge, in patients with OCD. Heart rate, blood pressure and plasma Norepinephrine (NE), Epinephrine (E), Dopamine (DA), L-dyhydroxyphenilalanine (L-DOPA), Serotonin(5-HT), Hydroxindolacetic Acid (5-HIAA) and Homovanillic Acid (HVA) responsivity to orthostasis have been evaluated in a group of 20 patients with OCD according to DSM IV criteria before and after two months therapy with f1uoxetine (2D--60 mg/day),and in 20 healthy age and sex-matched controls. While the two groups showed very similar supine heart rates and blood pressures, patients with OCD showed an atypical response to orthostatic challenge. At baseline, both at resting conditions and after the orthostatic challenge, DA plasma concentrations were significantly higher in patients than in controls (p < 0.02); HVA plasma levels were indeed significantly lower (p < 0.02). We found no clear cut abnormalities in NE, E, L-DOPA, 5-HT, 5-H!AA absolute values and their responses to orthostasis between patients and controls at baseline. All results were then correlated with the Yale-Brown ObsessiveCompulsive Scale, the NIMH Obsessive Compulsive Scale, the Stait and Trait Anxiety Inventory form X.l and X.2, the Hamilton Anxiety Rating Scale and the Hamilton Depression Rating Scale. Only NE levels showed a tendency to correlate positively with NIMH scores (p < 0.093). After treatment patients showeda bluntedresponsein L-DOPA(p < 0.04) and an increased heart rate response to orthostasis (p < 0.01); S-HT plasma concentrations were significantly lower (p < 0.001), while Fluoxetine and its major metabolite NOR-Fluoxetine plasma valuesdid not correlate withsymptoms improvement. Theseobservations suggestthat patternsof dopaminergic dysfunction may be present in OCD. References [I) Kopin, I.J. (1992) Origins aod significance of DOPA aod catecholamines metaholites in body fluids. Pharmacopsychiat. 25; 33-36; 1992. [2) Ravizza, L., Barzega, G., Bellino,S., Bogetto, F. andMaina, G. (1995) Predictors of drug treatment response in Obsessive-Compulsive Disorder. J. Clin. Psychiatry 56, 368-373. (3) Stein, M.B., Tancer, M.E. and Uhde, T.W. (1992) Hearth rate and plasma norepinephrine responsivity [0 orthostatic cballenge in anxiety disorders. Arch. Gen. Psyc. 49, 311-317.
IP.5.022I ejaCUlation Fluoxetlne treatmentof comorbid premature and panic disorder S. Kindler I , O.T.Dolberg I , M. Kotler2 . I Psychiatric Division, Anxiety Clinic, Sheba Medical Center, RamatGan52621. Israel; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv. Israel; 2 Beer-Sheva Mental Health Center; AnxietyandStressResearch Unit, and the Ben-Gurion University of the Negev, Beer-Sheva; Israel Premature ejaculation (PE) has been reported to occur in up to 30% of all men (I). Several clinical trials, both open-label and placebo controlled. have demonstrated the efficacy of serotonergic drugs in the treatment of PE (2). The results of these studies might suggest the possibility that the serotonergic system has a modulating effect on sexual responsivity, especially attainment of orgasm. Serotonergic dysfunction has also been implicated in the pathogenesis of panic disorder (PD). Numerous clinical trials have demonstrated the efficacy of serotonin reuptake inhibitors (SRI's) in the treatment of PD (3).
The purpose of this study was to assess the clinical efficacy of SRI medication in the treatment of patientswithcomorbid PD and PE. Included in thisopen-label, 8 weekstudy, were 10healthy, heterosexual men, mean age 35 years, withself-reported PE and diagnosedPD. Other