Histamine mediates long-term potentiation of excitability in rat hippocampus

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Results: Before the therapy started, 58.3% of the patients took psychotropic drugs regularly (antidepressants 47.9%); benzodiazepines 27.1%; neuroleptics 19%). By the time they were discharged from hospital, this proportion was reduced to 12.5%. After their discharge, the consumption of psychotropic drugs amongst all patients first rose to 14.6%after six weeks and then significantly to 31.3%after six months. In order to study a connection between the extent of psychotherapeutic pre-treatment and the frequency of drug consumption, we observed three categories of patients separately; i.e, those with purely psychiatric pre-treatment, those with psychotherapeutic pre-treatment and those who where exclusively treated by their family doctor. Surprisingly there was no difference regardingthe frequency in taking drugs: in all three groups the averagepercentageof consumerswas about60%. Furthermore, a continuous out-patient treatment seemed to have no influence on the development of the utilisation of psychotropic drugs during the period after discharge: both in the group of patients who started or resumed out-patient psychotherapy after being discharged and in the group of patients who were not treated further, the drug consumption equallyrose again. Discussion: As far as the reductionof drug-related costs is concerned, the efficacy of psychtherapeutic treatment is challenged by the quickly renewed risein psychotropic drug consumption after in-patient treatment. The missing differences regarding the extent of drug consumption in groups of patients with different pre-treatments lead to the speculation that the majority of psychotropic drugs are prescribed by family doctors and internists with limited psychiatric or psychotherapeutic knowledge. This might be equally valid for numerous drug prescriptions after discharge from hospital, provided that patients don't fall back in their own drug supplies withoutconsultinga doctor. The results of the catamnestic study therefore suggest to especially monitor in detail the practice of prescriptions, while analysing the consumptionof psychotropic drugs. On the one hand, psychotropic drugsare often prescribedcarelesslyand inadequately, especially by non-specialist doctors. On the other hand, the strict refusalof psychotropic drugsin the treatment of psychoneurotic disorders contradicts the finding that there is no difference in the response to antidepressants, whether the genesis of the disorder is "neurotic" or "endogenous". Having the indication of the prescriptions during the periodafter discharge checkedby a specialist wouldalso reduce the dangerof wronglyinterpreting the prescriptions not indicated by specialists as a failure of the psychotherapeutic treatment.

IP.6.021 I Effects of sexandaging on3H-paroxetine binding to human platelets

O. Marazziti, A. Rossi, L. Palego, G. Giannaccini ' . A. Lucacchini I, G.B. Cassano. InstituteofPsychiatry and "Istituto Policattedra di Discipline Biologiche ", University ofPisa; via Roma67,56100 Pisa. Italy The striking similarities betweenthe sodium-and temperature dependent serotonin (5HT) transporter in human platelets and brain has led to the widespread use of these cells as a peripheral tool in the study of the central serotonergic neurons. Tricyclic antidepressants (TCAs) and selective 5HT reuptake inhibitors (SSRIs) are the most potent drugs interacting at the level of the 5HT transporterand, tritiated imipramine e H-IMI), a TCA, has been widelyused to label it. However, subsequently, it emerged that 3H-1MI binding was heterogenous, so that, in recent years, it has been demonstrated that the more selective ligand.3H-paroxetine e H-Par) binds to a singlesite probablycorresponding to the neuronal transporter. In order to clarify the possible effects of physiological factors such as age and sex on the specific binding of 3H-paroxetine, we compared it in plateletsof healthy youngand elederlysubjects. Twenty-one healthy young subjects (8 women and 13 men; age between 24 and 33 years, mean ± SD: 28 ± 4) and 20 elderly subjects (10 women and 10 men; age between 65 and 83 years, mean ± SO: 78 ± 3) who volunteered for the study.were included. Plateletmembranes and 3H-paroxetine binding assay were performed according to the method of Marazziti et al. (1995). The binding parameters (Bmax in frnollmg protein. and Kd in oM) were calculated by means of microcomputer programs (EBOA and UGAND). The difference bewteen the binding parameters of young and elderly subjects was measured according to

the Student's t-test, The possible influence of age and sex on binding parameters was analysed according to the methodof Pearson. The results showed that the Bmax values were not significantly different in the 2 groups (1539 ± 607 vs 1354 ± 517 frnollmflprotein in the young vs the aged subjects), as were not the Kd values (0.12 ± 0.5 vs 0.54 ± 0.57). When we compared the SUbjects according to the sex, it turned out that the young females had a statistically significant lower Kd than the males (0.081 ± 0.039 vs 0.14 ± 0.051. P < 0.02), while the contrary was true for the elderlywomen(0.13 ± 0.069 vs 0.078 ± 0.025, p < 0.02). In summary, the findings of the present study shows that sex appears to provoke significant age-related changes in the KD, that is the inverse of the affinity constant, of 3H-paroxetine binding to platelet membranes: young women had a significant lower KD which increased in the elderly age. This might reflect modifications in the 5-HT transporter that would constitute the basis for a different sex-related vulnerability to disorders, such as depression, where a dysfunction at this level is hypothesised. Reference Marazziti D., Rossi A., GiannacciniG., Martini C.. Castrogiovanni S., MicaliM.G.• Lucacchini A.. Cassano G.B. (1995)Correlation betweenthe sites labelledby3H_ 8 hydroxy-2·(di-N-propylamioo)tetralin and 3H-imipramine in humanplatelets. Human PsycbophannacoI. 100:417-421, 1995

IP.6.022I Histamine mediates long-term potentiation of excitability In rat hippocampus

O. Selbach, H.L. Haas. Institute of Physiology II, Heinrich-Heine-University; D4000] Dusseldorf, Germany The action of histamine (HA) on CAl pyramidal-cells in vitro was investigated in rat hippocampal slices perfused with solution containing 0.2 roM ea2+/4.0 roM Mg2+. Extracellular recordings of spontaneous discharges revealed that HA caused a long-lasting increase in cellexcitability, reminiscent the long-term potentiation (LTP) of population spikes [1]. The HA-mediated response was characterized by a quickly rising initial short-term (STPe) and a subsequent long-term potentiation of excitability (LTPe) consisting of an early (I) and later phases (IIIIII) withadditional increases in cell-firing. Low concentrations of HA (0.1 - I /LM) caused an HI-receptor mediated depression of excitability (STDe) which was mimicked by the Hj-receptor-agonist FPHA. Higher concentrations of HA (5 min; 1-10 /LM) exertedin an almost all-or-none manner strongnon-declining LTPe. All HA-induced excitations wereprevented by theH2-receptor-antagonist cimetidine (50--100 /LM). and mimicked by the H2-receptor-agonist impromidine (IMP; 3 /LM). Notably, in contrast to binding data., IMP was less effective than HA. 8-BrcAMP (50 to 100 /LM) and the protein-kinase A (pKA)-aetivator Sp-cAMPS (5- 50 /LM) mimicked IMP-mediated LTPe, whereas the adenylyl-cyclase (AC)inhibitorTHFA(50--500 /LM) or the PKA-inhibitor Rp-cAMPS (1-10 j1.M) blockedthem. Presynaptic Hj-recepror activation by R-a-methyl-histamine was ineffective in 0.2 roM Ca2+/4.0 roM Mg2+ , indicating predominantly postsynaptic actionsunder these conditions. However, the NMDA-receptor-antagonist APV and the Hj-receptorantagonist mepyramine (1-10 /LM) significantly attenuated HA-induced LTPe to a level of the isolated H2-receptor-response. The IMP-response wasnotsignificantly affected by APVor MEP, indicatingan H1·INMDAreceptor-conditioned potentiation of H2-receptor-mediated cAMPIPKAdependent LTPein low ea2+fhjgh Mg2+, presumably mediated by tonic ambientglutamate in the slice preparation. CAI-neurons were refractory for induction of additional LTPe during an early stage of ongoing LTPe. Second applications during this stages (phase I, 30 min) did not induce LTPe but STPe, whereas second applications during later phases (II1IIl, > 60 min) caused full additional non-declining LTPe. Remarkably, the refractoriness during early phases (I) for the LTPe-induction by Gs-Protein-coupled pathways could he removed by prior activation of Gi/q-Protein-coupJed Hj/a2-receptors. Lithium (2 roM) almost entirely blocked all HA- and IMP-mediated excitations, probablyby blocking G-proteins. Noradrenaline and the ,B-receptor-agonist isoprotenerol caused re-

P. 6 Othertopics sponses very similar to HA and IMP respectively, indicating common (convergent) signaltransduction-mechanisms underlying O!IIHI- and .B21H2-receptor mediated effects. HA as other biogenic amines can profoundly influence excitability and integration properties of hippocampal neurons and thus plays an important role in the regulation of neuronal information processing and plasticity according to behavioral state. Supported by DFG and HFSP.

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Miller, H.L., Delgado, P. L., Salomon, et al. (1992) Acute tryptophan depletion: a method of studying antidepressant action. J. Clin. Psychiatry 53, (10 Suppl), 28-35.

IP.6.024I Risperidone in thetreatment of Gilles de la ToureUe Syndrome

M. Stamenkovic, S. Schindler, H.N. Aschauer, S. Kasper. Department of

Reference

General Psychiatry, University Hospitalfor Psychiatry Vienna, Austria

[1] Kostopoulos et aI., Exp. Brain Res. 72: 45-50, 1988

I P.6.023I Acute tyrosine depletion reduces catecholamine synthesis in the rat brain S.F.B. McTavish, P.J. Cowen, T. Sharp. University Department of

Psychiatry, Littlemore Hospital, OxfordOX44XN, University Department ofClinical Pharmacology, Radcliffe Infirmary, OxfordOX2 6HE,UK Administration of an amino acid mixture lacking the 5-HT precursor tryptophan, lowers brain tryptophan levels and interferes with central 5-HT function. Tryptophan depletion has become a valuable tool for studying the role of 5-HT in psychiatric disorders and psychotropic drug function (Miller et al. 1992). Evidence suggests that catecholamine synthesis is also dependent upon the availability of its precursor tyrosine (Carlsson and Lindqvist, 1978; Fernstrom and Fernstrom, 1995). Therefore, a model based on tyrosine depletion could prove effective as a means of disrupting brain catecholamine function. Here, we have investigated the effects of a tyrosine-free amino acid mixture on brain tyrosine and catecholamine synthesis in the rat. Male Sprague Dawley rats (250-300 g) received a) a single injection of a tyrosine-free amino acid mixture, b) two injections of this mixture (or saline vehicle) one h apart or c) two injections of the tyrosine-free amino acid mixture (or saline vehicle) followed 30 min later by the DOPA decarboxylase inhibitor, NSD 1015 (100 mglkg i.p.). Rats were decapitated at various time points (0-6 h or 30 min after NSD 1015) and brain regions (frontal cortex, hippocampus, striatum, n. accumbens and hypothalamus) were dissected over ice and stored at -200 C before analysis of tissue extracts using HPLC with electrochemical detection. A single injection of the tyrosine-free amino acid load reduced tyrosine to about half the control values within 2 h of injection in all brain regions examined and levels returned to baseline within 6 h. No significant change in noradrenaline or dopamine levels was found in any brain region at any time point. The decrease in tyrosine was greater after two injections of the amino acid load. NSD 1015 caused DOPA and 5-HTP to accumulate in all brain regions. In rats pretreated with two injections of the tyrosine-free amino acid mixture (n = 5 rats) the accumulation of DOPA in all brain regions 6 was significantly less (p < 0.05) than saline-treated controls (n rats). This difference was most marked in striatum (controls 10.41 ± 0.65 versus treated 6.31 ± 0.57 pmol/mg tissue; means ± s.e.m) and n. accumbens (8.86 ± 0.38 versus 5.86 ± 0.18 pmol/mg), areas with a predominantly dopaminergic innervation. Smaller decreases in DOPA accumulation were found in cortex (0.70 ± 0.03 versus 0.53 ± 0.02 pmol/mg), hypothalamus (2.16 ± 0.0.15 versus 1.70 ± 0.09 pmol/mg) and hippocampus. (0.51 ± 0.04 versus 0.41 ± 0.01 pmol/mg). The accumulation of 5-HTP was not significantly different between treated and control animals, indicating that 5-HT synthesis was not affected. These studies indicate that administration of a tyrosine-free amino acid load to rats decreases regional brain levels of tyrosine and the rate of catecholamine synthesis. If this decrease in synthesis leads to decreased catecholamine release, then tyrosine depletion could have great value in the study of central catecholamine function in rats and potentially humans. S.F.B. McTavish is an MRC Clinical Training Fellow.

=

References Carlsson, A. and Lindqvist, M. (1978) Dependence of 5-HT and catecholamine synthesis on concentrations of precursor amino acids in rat brain. N. S. Arch. Pharmacol303, 157-164. Fernstrom, H.F. and Fernstrom, lD. Acute tyrosine depletion reduces tyrosine hydroxylation rates in rat central nervous system. (1995) Life Sci. 57, 97-102.

The treatment of Gilles de la Tourete Syndrome (GTS), a neuropsychiatric disorder, which is characterized by the occurrence of motoric and vocal tics, is often unsatisfactory. The etiopathogenesis is still unclear, but there are different discussions about the involvement of neurotransmitters such as Dopamine-(D) 2, 5-Hydroxytryptamine-(5HT) 2 and alpha-2 adrenoreceptors. Risperidone is a new neuroleptic drug which has a high affinity to D2 and 5-HT 2 receptors and a lower affinity to alpha-2 adrenoreceptors. 1994 we published a case report of Risperidone in the treatment of a GTS patient. Van der Linden et al. (1994) published the results of an open pilot study using Risperidone in 11 GTS patients. Both investigations showed an amelioration of GTS symptoms. The goal of our investigation was to confirm these preliminary observations. We included 6 patients (2 female/4 male) with an average age of 35 years (± 12.64) over a period of 8 weeks, that had not responded to or tolerated previous neuroleptic treatments. All patients received Risperidone in ascending dosage, following a washout period of one week. Initial dosage was 2 mg/d with a maximum dosage of 12 mg/d. Following rating scales were used: Yale Global Tic Severity Scale (YGTSS), Yale Brown Obsessive Compulsive Scale (YBOCS), Fischer Somatic and Unwanted Effects Check List (FSUCL), Extrapyramidale Symptom Scale (EPS) and the Clinical Global Impressions (CGI). All scales were assessed at days: -7,0,3, 14,28,42 and 56. Statistical analysis was done using the repeated measurements Analysis of Variance (ANOVA). Two of altogether six patients did not finish the study. One patient stopped taking the medication after 14 days because of a general distrust to all medication, the other patient droped out after 28 days because of the occurrence of akathisia. At day 14 of treatment with Risperidone 4 mg/d the tic symptomatology (YGTSS) ameliorated (p < 0.(01), obsessive-compulsive symptomatology (YBOCS) decreased (p < 0.05) and Clinical Global Impressions improved (p < 0.(01). At day 56 (end of study) patients received a mean dosage of 7.3 mg/d. At this time point all patients except the 2 drop outs ameliorated at least 60% of baseline (YGTSS) score. In our study we found, that Risperidone was a safe and effective treatment alternative in our patients, that previously had not responded to or tolerated "classical" neuroleptic drugs. In order to confirm these preliminary results, it seems necessary to conduct double blind placebo controlled trials.

References Stamenkovic, M., Aschauer, H.N. and Kasper, S. (1994) Risperidone for Tourette's Syndrome. The Lancet 344, 1577-1578. Van der Linden, C., Bruggeman, R. and Thee van Woerkom, C.A.M. (1994) Serotonin-Dopamine Antagonist andGilles de la Tourette's Syndrome: An Open Pilot Dose-TItration Study with Risperidone. Movement Disorders 9, 687-688.

I P.6.02SI Morphine counteracts theeffects of juvenile isolation on later social behaviour C'L, van den Berg, J.M. Van Ree, B.M. Spruijt. Department of

Pharmacology, RudolfMagnus Instituefor Neurosciences, Utrecht University, P. O. box 80040, 3508 TA Utrecht, TheNetherlands Social play is the earliest form of non-mother-directed social behaviour and consists of behavioural patterns related to social, sexual and agonistic behaviour. This specific type of behaviour is restricted to a short period of life between weaning and sexual maturation. Social play behaviour is of major importance for the normal development of social behaviour, because rats are very susceptible to the effects of social isolation during this period of life. Such an isolation causes both short- and long-term effects, such as abnormal patterns of social behaviour. Furthermore, play behaviour has rewarding properties. Opiates and opioid antagonists increase and decrease play behaviour respectively and playful interactions