Hyperactivity and sensitization to psychostimulants following cholera toxin infusion into the nucleus accumbens

Abstract

Although manipulation of second messenger systems is widespread in cell biology, there are few experiments examining the consequences of such 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 accumbens (N. Acc.) in rats. CTX is a bacterial toxin that ADP-ribosylates the G(s) transducer protein and stimulates production of cAMP. For Experiment I, three groups of rats received either saline or CTX (50 or 500 ng/μl) into the N. Acc. Locomotor activity was measured for 4 hr following a single CTX infusion and subsequently for 4 hr on 6 consecutive days. No acute effects on motor activity were observed. However, the 500 ng dose of CTX induced long-lasting hyperactivity that was apparent 24 hr later and that lasted 4 d. A smaller but significant hypermotility 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/μl) into either the N. Acc. or the posterior dorsal striatum (PDS). CTX treatment of the PDS had no behavioral effects 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/μl) on d-amphetamine (0.5 mg/kg, i.p.)- and cocaine (7 mg/kg, i.p.)-induced motor activity was investigated. This low dose of CTX did not increase baseline motor activity 1 d later; however, rats previously treated with CTX showed a sensitized locomotor response to amphetamine and cocaine but not saline challenges. These data suggest that CTX-induced changes in G(s) proteins result in long-lasting upregulation of the cAMP system. This upregulation is reflected by enhanced motor responses normally mediated by the N. Acc. The results may have important implications for mechanisms underlying drug-induced sensitization and may also have potential as an animal model of mania.