EFFECTS OF REPEATED PSYCHOSTIMULANT ADMINISTRATION ON THE PRODYNORPHIN SYSTEM ACTIVITY AND KAPPA-OPIOID RECEPTOR DENSITY IN THE RAT-BRAIN

The prodynorphin system is implicated in the neurochemical mechanism o f psychostimulants. To elucidate the activity of the endogenous prodyn orphin system upon treatment with psychostimulants, we investigated th e effect of single and repealed cocaine and amphetamine on the prodyno rphin messenger RNA level, the prodynorphin-derived peptide alpha-neoe ndorphin tissue level, and its in vitro release in the nucleus accumbe ns and striatum of rats. The density of kappa opioid receptors in thos e brain regions was also assessed. Rats were injected with cocaine fol lowing a ''binge'' administration pattern, 20 mg/kg i.p. every hour fo r 3 h, one (single treatment) or five days (chronic treatment). Amphet amine, 2.5 mg/kg i.p. was administered once (single treatment) or twic e a day for five days (chronic treatment). As shown by an in situ hybr idization study, the prodynorphin messenger RNA levels in the nucleus accumbens and striatum were raised following single (at 3 h) and chron ic (at 3 and 24 h) cocaine administration. The prodynorphin messenger RNA level in the nucleus accumbens was markedly elevated after single or repeated amphetamine administration. A similar tendency was observe d in the striatum. Acute cocaine and amphetamine administration had no effect on the alpha-neoendorphin tissue level, whereas chronic admini stration of those drugs elevated the alpha-neoendorphin level in the n ucleus accumbens and striatum at the late time-points studied. Acute a nd repeated cocaine administration had no effect on alpha-neoendorphin release in both the nucleus accumbens and striatum at 3 and 48 h afte r drug injection. In contrast, single and chronic (at 24 and 48 h) amp hetamine administration profoundly elevated the release of alpha-neoen dorphin in both these structures. Addition of cocaine or amphetamine t o the incubation medium (10(-5)-10(-6) M) decreased the basal release of alpha-neoendorphin in the nucleus accumbens slices of naive rats, b ut it did not change the stimulated release (K+, 57 mM). On the other hand, in the striatum slices, addition of cocaine to the incubation me dium depressed basal and stimulated release of the peptide; no signifi cant changes were observed after addition of amphetamine. Cocaine and amphetamine evoked profound and long-term down-regulation of the kappa opioid receptors in both structures. The above data indicate that the amphetamine-induced changes were more abundant than those caused by c ocaine; only treatment with amphetamine markedly enhanced the release of prodynorphin-derived peptide. Furthermore, the psychostimulant-indu ced enhancement of biosynthetic activity of prodynorphin neurons was c orrelated with a marked and persistent decrease in the kappa opioid re ceptor density at a late withdrawal time. (C) 1998 IBRO. Published by Elsevier Science Ltd.