HYPERACTIVITY AND SENSITIZATION TO PSYCHOSTIMULANTS FOLLOWING CHOLERA-TOXIN INFUSION INTO THE NUCLEUS-ACCUMBENS

Although manipulation of second messenger systems is widespread in cel l biology, there are few experiments examining the consequences of suc h manipulation on behavior. In three separate experiments, we extended earlier work by Miller and Kelly (1975) that examined the behavioral effects of microinfusion of cholera toxin (CTX) into the nucleus accum bens (N. Acc.) in rats. CTX is a bacterial toxin that ADP-ribosylates the G(s) transducer protein and stimulates production of cAMP. For Exp eriment I, three groups of rats received either saline or CTX (50 or 5 00 ng/mul) into the N. Acc. Locomotor activity was measured for 4 hr f ollowing a single CTX infusion and subsequently for 4 hr on 6 consecut ive days. No acute effects on motor activity were observed. However, t he 500 ng dose of CTX induced long-lasting hyperactivity that was appa rent 24 hr later and that lasted 4 d. A smaller but significant hyperm otility occurred on days 4 and 5 following infusion of the 50 ng dose. Site specificity of this effect was investigated in Experiment II by infusion of CTX (250 ng/mul) into either the N. Acc. or the posterior dorsal striatum (PDS). CTX treatment of the PDS had no behavioral effe cts while the long-lasting hyperactivity following treatment of the N. Acc. was replicated. In Experiment III the effect of intra-accumbens pretreatment with saline or CTX (10 ng/mul) on d-amphetamine (0.5 mg/k g, i.p.)- and cocaine (7 mg/kg, i.p.)-induced motor activity was inves tigated. This low dose of CTX did not increase baseline motor activity 1 d later; however, rats previously treated with CTX showed a sensiti zed locomotor response to amphetamine and cocaine but not saline chall enges. These data suggest that CTX-induced changes in G(s) proteins re sult in long-lasting upregulation of the cAMP system. This upregulatio n is reflected by enhanced motor responses normally mediated by the N. Acc. The results may have important implications for mechanisms under lying drug-induced sensitization and may also have potential as an ani mal model of mania.