Repeated intracerebroventricular forskolin administration enhances behavioral sensitization to cocaine

Repeated cocaine exposure produces behavioral sensitization expressed as an increased locomotor response to subsequent drug administration. Chronic cocaine administration also results in increased activity of adenylyl cyclase and cyclic-AMP (cAMP) dependent protein kinase (PKA) in the nucleus accumbens. To investigate the relationship between cocaine-induced behavioral sensitization and cAMP signaling, the present study examined the effect of forskolin, a direct adenylyl cyclase activator, on cocaine-induced hyperlocomotion and behavioral sensitization to cocaine. Rats were given intracerebroventricular (i.c.v.) injections of a water soluble form of forskolin (7DMB-forskolin) or vehicle 10 min prior to intraperitoneal (i.p.) cocaine or saline administration on 7 consecutive days. Acute or chronic forskolin alone had no effect on locomotor activity at the doses tested. On days 1 and 2, the activity of rats that received i.c.v. forskolin paired with cocaine was not significantly different from rats that received i.c.v. injections of vehicle co-administered with cocaine. By the third day of forskolin/cocaine co-administration, rats displayed enhanced cocaine-induced hyperlocomotor activity compared to rats that received cocaine alone, an effect that persisted through day 7. When challenged with cocaine on day 14, animals that had previously received forskolin paired with cocaine on days 1-7 displayed similar locomotor activity to animals that received cocaine only. These results suggest that alterations in adenylyl cyclase activity and/or cAMP levels may underlie the hyperlocomotor response to cocaine and may play a role in behavioral sensitization.