Session 12 : Neuro pharmacologie

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Session 12 : Neuro pharmacologie

125

ROLE OF THE DOPAMINE D3 RECEPTOR IN LEVODOPA-INDUCED BEHAVIORAL SENSITIZATION IN 6-OH-DA LESIONED RATS

R. Bordet*, S. Ridray, P. Sokoloff**, J.C. Schwartz**

Laboratoire de Physiologie, Université René Descartes, PARIS; ** Unité 109 de l’INSERM, PARIS; *Laboratoire de Pharmacologie, Faculté de Médecine, LILLE.

Chronic levodopa administration induces the dopamine D3 receptor (RD3) expression in 6-OH-DA-denervated caudate-putamen (CdPu), parallely to sensitization, suggesting a role for RD3 in this phenomenon, an hypothesis that we have investigated using a pharmacological approach.

Firstly, in unilateral 6-OH-DA lesioned rats (n=4-7/group), we studied expression in CdPu of RD3 using [3H]-7-OH-DPAT autoradiography (expressed as mean percent difference between lesion and control side) and rotation behavior (expressed as mean percent difference between first and last challenges) after a challenge dose of levodopa before and after various 7 day-treatments. Intermittent levodopa (50 mg/kg b.i.d. in combination with benserazide) induced RD3 expression in denervated CdPu (125

40 %; n.s.).

Secondly, in sensitized animals, the excess of rotation above pre-treatment level was dose-dependently blocked by nafadotride, a preferential RD3 antagonist, with an ID50 of 1.1 mg/kg (0.46-2.8, 95 % interval confidence), a dosage corresponding to selective RD3 occupancy.

Thirdly, rotation behavior induced by SKF 38393 (5 mg/kg i.p.), a selective D1 receptor agonist, was potentiated by administration of DO 897 (1 mg/kg), a selective RD3 agonist, in levodopa sensitized animals but not before levodopa treatment.

The parallelism between enhanced rotations and induction of RD3 expression and the modulation of the enhanced rotations by RD3 specific pharmacological agents strongly support the role of this receptor in behavioral sensitization to levodopa.

126

DIFFERENCES IN THE EFFICACY OF DOPAMINE D4 RECEPTOR LIGANDS ACCORDING TO THE EXPRESSION SYSTEM

L. Gazi, B. Sommer, D Hover, M. Tricklebank and P. Schoeffler

Nervous System Research, Novartis Pharma AG, S-386 7.44, CH-4002 Basel, Switzerland

The dopamine D2-like receptor family is an important target for intervention in psychiatric diseases. The dopamine D4 receptor subtype, the most recently identified member of the D2-like family, has stimulated much interest in schizophrenia research because the atypical neuroleptic, clozapine has high affinity and a small degree of selectivity for D4 over D2 receptors. Thus, many pharmaceutical companies have run programmes aimed at developing D4 receptor selective antagonists, in the hope of treating schizophrenia without eliciting side ffects. In the present work, we have characterised the functional activities of two D4 receptor ligands, L-745,870 (Merck, Sharp & Dohme), U-101958 (Pharmacia & Upjohn) at human recombinant D4 receptors stably expressed in two heterologous systems: human embryonic kidney (HEK) 293 cells and Chinese hamster ovary (CHO) cells. Dopamine induced a concentration-dependent inhibition of forskolin-stimulated cAMP accumulation in both transfected cell lines, but was 10 times more potent in HEK293/D4 cells (pEC50 8.59

7 %, n=4). In saturation binding studies using [3H]spiperone, Bmax values for D4 receptors were found to be in the range 330-570 and 210-220 fmol/mg protein in HEK293/D4 and CHO/D4, respectively. The results show that the efficacy of dopamine D4 receptor ligands can vary greatly according to the expression system.

127

CHARACTERISTICS OF CENTRAL 5-HTIA RECEPTORS IN MICE LACKING THE 5-HT TRANSPORTER

L. Lanfumey, C. Mannoury Lacour, A. Rioux, V. Fabre, M.P. Martres, K.P. Lesch* and M. Hamon.

INSERM U 288, CHU Pitié Salpêtrière, 91 Bd de l’Hôpital, 75634 Paris Cedex 13, France and *Dpt of Psychiatry, University of Wurzburg, Germany.

The serotonin transporter (5-HTT) plays a key role in the regulation of central serotoninergic neurotransmission, and has been implicated in the etiology of neuropsychiatric diseases such as depression or drug abuse. To further study the function of this transporter, knock-out mice lacking the 5-HTT (5-HTT-/-) have been generated by homologous recombination (1). We describe here the phenotypical characteristics of these mutant mice with special regard to 5-HT1A receptors that previous studies in our laboratory demonstrated the critical role in central 5-HT neurotransmission (2). Autoradiographic labeling of brain sections with [3H]citalopram first confirmed that the 5-HTT was not expressed in 5-HTT-/- mice. The specific labeling of 5-HT1A receptor binding sites by [3H]WAY 100635 showed a ~50% decrease in the dorsal raphe nucleus (DRN), with no differences in other brain regions, in 5-HTT -/- compared to wild-type mice. The fonctional status of 5-HT1A receptors in the DRN was then assessed by determining the potency A of the 5-HT1A agonist ipsapirone to decrease the firing rate of DRN 5-HT neurons in homozygote
(5-HTT-/-) and heterozygote (5-HTT+/-) mutant versus wild-type (5-HTT+/+) mice. In vitro electrophysiological experiments using brain stem slices showed that ipsapirone was markedly less potent to inhibit the cell firing in mutant compared to wild-type mice (EC50 = 2 µM in 5-HTT-/-; 300 nM in 5-HTT+/-; 40 nM in 5-HTT +/+). These first series of data demonstrated that major adaptive mechanisms have occurred at the level of 5-HT1A autoreceptors to compensate for the lack of 5-HT reuptake in 5-HTT-/- mice.

(1) Wickems, C.H. et al. Soc. Neurosci. 23:980 (389.1), 1997; (2) Le Poul, E. et al. Naunyn-Schmied. Arch. Pharmacol. 352:141-148, 1995.

128

DOSE-DEPENDENT INFLUENCE OF BUSPIRONE ON THE ACTIVITIES OF SSRIS IN THE MOUSE FORCED SWIMMING TEST

M Bourin, P. Redrobe, M.C. Colombel, G.B. Baker

GIS Medicament, J.E. Neurobiologie de l’anxiété, Faculté de Médecine, 44035 Nantes cedex 1, France

Recent clinical data suggest that buspirone may enhance the efficacy and/or reduce the latency to therapeutic effect of selective serotonin reuptake inhibitors (SSRIs) in unipolar major depressive disorder. The present study, using the mouse forced swimming test, was performed to further investigate the mechanisms involved in the potential antidepressant-enhancing effects of buspirone. Prior administration of buspirone (0.06 mg kg-1, i.p.) significantly enhanced the anti-immobility effects of subactive doses of fluvoxamine (4 mg kg-1, i.p.; p