RT Journal Article
SR Electronic
T1 Effects of the Alpha-2 Adrenergic Receptor Agonist Lofexidine on Food-Cocaine Choice in Socially Housed Cynomolgus Monkeys
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.120.266007
DO 10.1124/jpet.120.266007
A1 Paul W. Czoty
A1 Michael A. Nader
YR 2020
UL http://jpet.aspetjournals.org/content/early/2020/07/07/jpet.120.266007.abstract
AB Although norepinephrine (NE) does not appear to play prominent a role in mediating the abuse-related effects of cocaine, studies have indicated that NE alpha-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 alpha-2 receptor agonists, lofexidine and guanfacine, on choice between food and cocaine (0.0-0.1 mg/kg per injection) in male and female cynomolgus monkeys. Subjects were housed in stable same-sex social groups of four; social rank did not influence the effects of lofexidine and guanfacine on cocaine choice. When administered acutely, lofexidine (0.03-3.0 mg/kg, i.v.) significantly decreased cocaine choice in females (N=7), but not males (N=8); lofexidine produced dose-dependent decreases in core body temperature in males. When 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 3 of 3 males and 2 of 4 females. To further evaluate alpha-2 receptor agonists in males (N=11), guanfacine (0.003-1.0 mg/kg, i.v.) was tested acutely and significantly decreased cocaine choice. Taken together, these data suggest that alpha-2 receptor agonists can produce small decreases in the reinforcing strength of cocaine relative to food and that, even when efficacy is observed following acute administration, tolerance to the decreases in cocaine choice are apparent and more likely in males compared to females.SIGNIFICANCE STATEMENT Cocaine use disorder remains a significant public health problem with no FDA-approved treatments. While 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.