Effects of the alpha-1 antagonist prazosin on KOR agonist-induced reinstatement of alcohol seeking

Abstract

Background Stress is associated with relapse to alcohol seeking during abstinence, but the processes underlying this relationship are poorly understood. Noradrenaline is a key transmitter in stress responses and in stress-induced drug seeking. The alpha-1 adrenoceptor antagonist prazosin has been investigated as a treatment for alcoholism and for chronic stress disorders that are frequently comorbid with alcoholism. In rats, we previously showed that prazosin blocks reinstatement of alcohol seeking induced by footshock and yohimbine stressors, and reduces yohimbine-induced brain activation. The role of alpha-1 adrenoceptors in reinstatement induced by other stressors is not known. Our most recent work is on the role of kappa opioid receptors (KOR) in stress-induced reinstatement of alcohol seeking and have reported that the selective KOR agonist U50,488 induces reinstatement and neuronal activation in stress- and relapse-related brain regions. Here we determine the involvement of alpha-1 receptors in reinstatement and brain activation induced by U50,488. Methods We trained male Long-Evans rats to self-administer alcohol (12% w/v), extinguished alcohol-reinforced responding and then determined the effects of prazosin (1 mg/kg) on U50,488 (2.5 mg/kg)-induced reinstatement and regional Fos expression. Results Prazosin blocked U50,488-induced reinstatement and decreased U50,488-induced Fos expression in the OFC, NAC core, ventral BNST, CeA, BLA and VTA. Conclusions These findings suggest that prazosin may reduce U50,488-induced relapse by inhibiting activity in one or more of these brain areas.