Anxiogenesis in adult rats treated chronically with cocaine during adolescence: Effects of extended abstinence and 8-OH-DPAT treatment

Our laboratory has recently observed the development of an anxiogenic response after a short abstinence period (∼10 days) in young adult rats treated repeatedly with cocaine during adolescence. The present study was conducted to determine if this effect persists into adulthood following extended durations of abstinence and whether it could be modulated with the 5-HT_1A agonist (±)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide (8-OH-DPAT). Accordingly, 30-day-old rats were injected with either 10 mg/kg cocaine or saline for 8 consecutive days. Approximately 8 weeks after the final injection, anxiety levels in subjects were assessed with an elevated zero maze with a second assessment performed 4 weeks thereafter. Shortly prior to each test session, half the subjects in each of the two adolescent drug conditions received injections of 300 μg/kg 8-OH-DPAT while the other half received injections of the vehicle. Based on total time spent in the open areas of the maze, the results obtained at the first abstinent duration indicated that adolescent cocaine treatment did not induce an anxiogenic response. Assessment of maze behavior at the second abstinent duration was aided with a digital tracking and computerized scoring system (LimeLight, Actimetrics). Similar to the results obtained at the first abstinent duration, the amount of time spent in the open areas of the maze was unrelated to prior cocaine treatment. However, cocaine-treated rats did show evidence of an anxiogenic response at this abstinent duration based on more frequent entries into and out of the open and enclosed areas of the maze, more frequent and longer durations of exploratory bouts beyond the perimeter of the maze, excessive number of cautious protrusions into the open areas, and faster running velocities through the open areas. These results were not artifacts of generalized motor activation in that comparable total distance traveled scores were noted for all subjects. Treatment with 8-OH-DPAT shortly prior to elevated zero maze testing normalized these behaviors induced by adolescent cocaine. It is concluded that the anxiogenic response produced by cocaine exposure during adolescence persists 12 weeks beyond cessation of drug treatment and that this effect is reversible with 8-OH-DPAT. In addition, the results underscore the importance of taking multiple measures when assessing anxiety in experimental animals. Implications for the neurobiology of drug abuse and the role of serotonin are discussed.