Modulatory effect of p-chlorophenylalanine microinjected into the dorsal and median raphe nuclei on cocaine-induced behaviour in the rat

The present study examined whether a potentiation of cocaine-induced behavi our in rats following peripheral pretreatment with the 5-hydroxytryptamine (5-HT) biosynthesis inhibitor p-chlorophenylalanine may be due to depletion of 5-HT in the dorsal raphe nucleus and/or median raphe nucleus. Following peripheral pretreatment with p-chlorophenylalanine (100 mg/kg, i.p.) for 3 consecutive days, a potentiation of cocaine-induced locomotor activity and rears was observed. To investigate a possible involvement of serotonergic neurones arising in the midbrain raphe nuclei in the observed potentiation, p-chlorophenylalanine (0.5 mu g) was microinjected in either the dorsal ra phe nucleus or median raphe nucleus followed by behavioural testing 48 h la ter. Application of p-chlorophenylalanine in the dorsal raphe nucleus resul ted in an enhancement of cocaine-induced locomotor activity and head bobs. Ln contrast, the stimulant effect of cocaine on behaviour was not altered b y microinjection of p-chlorophenylalanine in the median raphe nucleus. Peri pheral and central administration of p-chlorophenylalanine did not consiste ntly alter the baseline behaviour of saline-treated animals. Biochemical re sults indicated only a moderate depletion of 5-HT in the midbrain raphe nuc lei following peripheral p-chlorophenylalanine administration. Surprisingly , the central application of p-chlorophenylalanine in the dorsal raphe nucl eus and median raphe nucleus did not alter the 5-HT levels in the midbrain raphe nucleus investigated. Ln addition, peripheral and central administrat ion of p-chlorophenylalanine did not alter the 5-HT levels in the nucleus a ccumbens. In conclusion, the behavioural results suggest that the potentiat ion of cocaine-induced behaviour following peripheral p-chlorophenylalanine administration may be attributed to the dorsal raphe nucleus but not the m edian raphe nucleus suggesting that, serotonergic dorsal raphe nucleus neur ones may normally mediate a tonic inhibitory effect on cocaine-induced beha viour. Furthermore, the biochemical data may indicate the existence of neur ochemical resistance of the midbrain raphe nuclei to the 5-HT depleting eff ects of p-chlorophenylalanine. (C) 1999 Elsevier Science B.V. All rights re served.