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Ritanserin Reduces Abuse of Alcohol, Cocaine, and Fentanyl in Rats T. F. Meert, F. A wouters, C. J. E. Niemegeers, K. H L. Schellekens, P. A. J. Janssen Department ofNeuropsychopharmacology, Janssen Research Foundation, Beerse, Belgium

Rats that had received 3% alcohol, 0.0 I % cocaine, or 0.002% fentanyl as the only beverage over 10 days showed marked preference for the drug solution when water was made available as a second fluid in aseparate bottle. Treatment with low doses of ritanserin, a specific central serotonin 5-HT2 antagonist, rapidly reversed drug preference without changing total fluid intake. Quantitatively, the reduction in drug consumption was greater for alcohol than for cocaine and greater for cocaine than for fentanyl. This is probably related to difTerences in the reinforcing potential of the three drugs.

Introduction

Ritanserin is a potent and specific serotonin 5-HT2 antagonist, belonging to aseries of novel benzhydrylene piperidine derivatives (Leysen et al., 1985; Awouters et al., 1988). In rats, low doses in the order of 0.1 mgfkg antagonize the behavioral efTects induced by serotonergic stimulants such as tryptamine, mescaline, or 5-hydroxytryptophan. Similar doses increase deep slow-wave sleep (Dugovic et al., 1989) and markedly disinhibit behavior induced by natural aversive stimuli (Meert and Janssen, 1989; Meert et al. 1990). In drugdiscrimination procedures, ritanserin is devoid of internal stimulus properties and does not act as a substitute for any of the current types of drugs of abuse (Meert and Janssen, 1989; Meert et al., 1990). Normal behavior in rats is not afTected, even at high doses, which indicates that the central 5-HT2 antagonism alone is neurobehaviorally silent (Awouters et al., 1988; Leysen et al., 1989). In humans, ritanserin also markedly increases slow-wave sleep (Idzikowski et al., 1986) and improves mood and drive in dysthymic patients (Reyntjens et al., 1986). It has been suggested that the restoration of physio-Iogical sleep involves the improvement of neurotic symptoms (Janssen, 1987, 1988). Occasional observations in the past five years have also indicated that ritanserin may be

Pharmacopsychiat. 24 ( 1991) 159-163 © Georg Thieme Verlag Stuttgart . New York

Ritanserin vermindert die Präferenz von Alkohol, Kokain und Fentanyl bei Ratten

3% Alkohol, 0,01 % Kokain bzw. 0,002% Fentanyl wurde als einziges Getränk 10 Tage lang an Ratten verabreicht. Wenn Wasser als zweite Flüssigkeit in einer separaten Flasche bereit gestellt wurde, zeigten die Tiere eine ausgesprochene Vorliebe für die Arzneimittellösung. Bei Behandlung mit Ritanserin, einem spezifischen zentralen Serotonin-5-HT2-Antagonisten, in niedrigen Dosen, verschwand diese Vorliebe für das Arzneimittel, bei gleichbleibender gesamter Flüssigkeitsaufnahme, rasch. Die Verminderung des Arzneimittelverbrauchs war aus quantitativer Sicht für Alkohol größer als für Kokain, und für Kokain größer als für Fentanyl. Dies ist wahrscheinlich auf Unterschiede im Verstärkungspotential der drei Arzneimittel zurückzuführen.

of value in subjects withdrawing from abused drugs who may experience sirnilar problems of coping with daily life as dysthymic patients. The present experiments were set up to find out whether there is a pharmacological basis for more systematic c1inical studies, especially because conflicting results exist in the literature with regard to 5-HT and drug intake. Experimental results

Male Wistar rats (240± 20 g), bred at the authors' institute, were used. In preliminary experiments, using a procedure sirnilar to the one described below, different concentrations of each of the abused drugs were presented. Alcohol 3%, cocaine 0.01 %, and fentanyl 0.002% were found to possess the highest oral-reinforcing properties. In order to mimic the potential c1inical situations as c10sely as possible, the following standard procedure was adopted. Over aperiod of 10 days, the drug solution was the only available drinking fluid. In the first of three independent series of experiments, the fluid was 3% ethanol (wfv), in the second series it was 0.01 % cocaine, and in the third 0.002 % fentanyl. On day 11, the rats were randomly assigned to treatment groups of 10 animals and received a

Received: 26.10.1990 Revised version: 13. 3.1991 14. 5.1991 Accepted:

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Summary

Pharmacopsychiat. 24 (1991)

T. F. Meert, F. Awouters, C. J. E. Niemegeers, K. H. L. Schellekens, P. A. J. Janssen Fig. 1 Mesn fluid intake (% of total + S.E.M.) of drug solution (0 -0 ) or water (e -e )(upper panel) and preference for the drug solution (Iower panel during the period of treatment with vehicle or various doses of ntansenn. Statistical dlfferences from corresponding vehicle controls: • p

Ritanserin reduces abuse of alcohol, cocaine, and fentanyl in rats.

Rats that had received 3% alcohol, 0.01% cocaine, or 0.002% fentanyl as the only beverage over 10 days showed marked preference for the drug solution ...
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