Effects of the -2 Adrenergic Receptor Agonists Lofexidine and Guanfacine on Food-Cocaine Choice in Socially Housed Cynomolgus Monkeys.

Although norepinephrine (NE) does not appear to play a prominent role in mediating the abuse-related effects of cocaine, studies have indicated that NE -2 receptor agonists can attenuate reinstatement of extinguished cocaine self-administration in rats and monkeys and can decrease cocaine craving in humans. In the present studies, we examined the effects of two -2 receptor agonists, lofexidine and guanfacine, on choice between food and cocaine (0.0-0.1 mg/kg per injection) in cynomolgus monkeys. Male and female subjects were housed in stable same-sex social groups of four; social rank did not influence the effects of lofexidine and guanfacine. When administered acutely, lofexidine (0.03-3.0 mg/kg, i.v.) significantly decreased cocaine choice in females ( = 7) but not males ( = 8). However, in males, the same lofexidine doses produced dose-dependent decreases in core body temperature ( = 7), and acute guanfacine (0.003-1.0 mg/kg, i.v.) significantly decreased cocaine choice ( = 11). When lofexidine was administered for five consecutive days to a subset of the monkeys in whom lofexidine acutely decreased cocaine choice, tolerance to this effect developed to varying degrees of completeness in three of three males and two of four females. Taken together, these data suggest that -2 receptor agonists can produce small decreases in the reinforcing strength of cocaine relative to food and that, even when efficacy is observed after acute administration, tolerance to the decreases in cocaine choice are apparent and more likely in males compared with females. SIGNIFICANCE STATEMENT: Cocaine use disorder remains a significant public health problem with no US Food and Drug Administration-approved treatments. Although cocaine elevates dopamine, serotonin, and norepinephrine (NE), the latter target has received less research. The present study noted modest effects of NE agonists on the relative reinforcing strength of cocaine with greater efficacy in female compared with male monkeys.