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 of psychostimulants. To elucidate the activity of the endogenous prodynorphin system upon treatment with psychostimulants, we investigated the effect of single and repeated cocaine and amphetamine on the prodynorphin messenger RNA level, the prodynorphin-derived peptide alpha-neoendorphin tissue level, and its in vitro release in the nucleus accumbens and striatum of rats. The density of kappa opioid receptors in those brain regions was also assessed. Rats were injected with cocaine following a "binge" administration pattern, 20 mg/kg i.p. every hour for 3 h, one (single treatment) or five days (chronic treatment). Amphetamine, 2.5 mg/kg i.p. was administered once (single treatment) or twice a day for five days (chronic treatment). As shown by an in situ hybridization study, the prodynorphin messenger RNA levels in the nucleus accumbens and striatum were raised following single (at 3 h) and chronic (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 observed in the striatum. Acute cocaine and amphetamine administration had no effect on the alpha-neoendorphin tissue level, whereas chronic administration of those drugs elevated the alpha-neoendorphin level in the nucleus accumbens and striatum at the late time-points studied. Acute and repeated cocaine administration had no effect on alpha-neoendorphin release in both the nucleus accumbens and striatum at 3 and 48 h after drug injection. In contrast, single and chronic (at 24 and 48 h) amphetamine administration profoundly elevated the release of alpha-neoendorphin in both these structures. Addition of cocaine or amphetamine to the incubation medium (10(-5)-10(-6) M) decreased the basal release of alpha-neoendorphin in the nucleus accumbens slices of naive rats, but it did not change the stimulated release (K+, 57 mM). On the other hand, in the striatum slices, addition of cocaine to the incubation medium depressed basal and stimulated release of the peptide; no significant 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 cocaine; only treatment with amphetamine markedly enhanced the release of prodynorphin-derived peptide. Furthermore, the psychostimulant-induced enhancement of biosynthetic activity of prodynorphin neurons was correlated with a marked and persistent decrease in the kappa opioid receptor density at a late withdrawal time.