Acute versus chronic clonidine treatment effects on conflict behavior in the rat

The present study examined the effects of acute and chronic treatment with the alpha-2-adrenoceptor agonist clonidine on behavior in the Conditioned Suppression of Drinking (CSD) conflict paradigm, an animal model for the study of anti-anxiety treatments. In daily 10-min sessions, water-deprived rats were trained to drink from a tube which was occasionally electrified (0.25mA). Electrification was signalled by a tone. Within 3-4 weeks of 4 day/week CSD sessions, control (i.e. non-drug) CSD behavior had stabilized (approximately 40 shock/session and 11ml water/session). Acute treatment with clonidine across a range of doses (1.25-40µg/kg; 10-min pretreatment) did not exert an anti-conflict effect, with doses greater than 5µg/kg significantly depressing unpunished responding (i.e. water intake). Similarly, administration of a single dose of clonidine (40µg/kg) across a range of pretreatment times (10 to 120min) failed to increase punished responding. In contrast, chronic post-test treatment with clonidine (40µg/kg, twice daily for 18 weeks) resulted in a dramatic and time-dependent increase in punished responding, with a latency to onset of approximately 3-4 weeks. The response to an acute challenge with chlordiazepoxide (10mg/kg) or the benzodiazepine antagonist Ro 15-1788 (4.0mg/kg) did not differ in chronic clonidine-versus saline-treated subjects, indicating that benzodiazepine receptor sensitivity had not been affected by this chronic clonidine treatment. An acute challenge with a low dose of clonidine (10µg/kg) decreased punished and unpunished responding in chronic clonidine- or saline-treated subjects. Finally, an acute challenge with the alpha-2-antagonist yohimbine (1.25mg/kg) failed to block the increase in punished responding associated with chronic clonidine treatment, indicating that the anti-conflict effect of this chronic post-test clonidine treatment was not the result of alpha-2-adrenoceptor activation at the time of CSD testing (i.e. not due to drug accumulation). Discontinuation of chronic clonidine treatment resulted in a decline to near saline-treated levels of punished responding over the course of 3 weeks of conflict testing. The relationship of these findings to the anti-anxiety effects of clonidine in humans are discussed.