PROTEIN-KINASES IN THE RAT NUCLEUS-ACCUMBENS ARE INVOLVED IN THE AVERSIVE COMPONENT OF OPIATE WITHDRAWAL

The specific participation of protein kinases in the expression of the somatic signs of morphine withdrawal has been previously demonstrated , suggesting that changes in intracellular signalling systems are invo lved in opioid addiction. In the present study, the involvement of pro tein kinases in the aversive/dysphoric effects of morphine abstinence has been investigated in the nucleus accumbens, because of the critica l role played by the mesolimbic system in the rewarding effects of opi oids. Rats were chronically treated with morphine, twice a day for 5 d ays, with doses progressively increased from 5 to 30 mg/kg (i.p.). In addition, microinjections into the nucleus accumbens of the serine-thr eonine kinase inhibitors H7 or H8 (1 or 10 nmol per side) or saline on ce daily were also given, both in control and in morphine-treated anim als. After these chronic treatments, withdrawal syndrome was induced b y naloxone administration (0.1 mg/kg, s.c.), and the motivational comp onent of morphine abstinence was studied using the place aversion para digm. When administered at the highest dose (10 nmol), H7 and H8 stron gly reduced the place aversion induced by naloxone in morphine depende nt animals. Protein kinase inhibitors did not induce significant behav ioural responses in non-dependent animals, Chronic morphine treatment induced a selective up-regulation of adenylate cyclase activity in the amygdala, without affecting other brain regions. The morphine-increas ed adenylate cyclase activity in amygdala was reversed by the chronic intra-accumbens microinjection of H7 or H8. These results suggest that serine-threonine kinases in the nucleus accumbens play an important r ole in the emotional/dysphoric properties which characterize opiate wi thdrawal.