Vol. 289, Issue 2, 791-799, May 1999

Effects of Luteinizing Hormone-Releasing Hormone on Plasma Cocaine Levels in Rhesus Monkeys¹

Jack H. Mendelson, Nancy K. Mello and S. Stevens Negus

Endocrine Unit, Alcohol and Drug Abuse Research Center, McLean Hospital-Harvard Medical School, Belmont, Massachusetts

No effective pharmacotherapy for the treatment of cocaine abuse is currently available. In addition to pharmacological approaches, immunologic methods that use specific antibodies to bind cocaine in blood and prevent it from reaching the central nervous system are also being evaluated. There is considerable evidence that cocaine binds to the dopamine transporter, and there are structural similarities between the dopamine transporter and an anterior pituitary hormone, luteinizing hormone (LH). These structural similarities led us to hypothesize that LH may bind cocaine and decrease plasma levels of free cocaine. Synthetic LH-releasing hormone (LHRH) was used to stimulate LH release from pituitary gonadotropes before i.v. cocaine administration to male and female rhesus monkeys. The effects of placebo-LHRH and 15 and 30 µg/kg LHRH on levels of free cocaine in plasma after i.v. administration of 0.8 mg/kg cocaine were studied. LHRH (15 and 30 µg/kg) significantly increased LH secretion in both males (P < .01-.001) and females (P < .01-.05). Peak plasma cocaine levels were significantly lower after both doses of LHRH than after placebo-LHRH in males and in females (P < .05). There was an inverse relationship between peak plasma cocaine levels and LHRH-stimulated LH levels in males (P < .01) but not in females. Pharmacokinetic analyses showed that the time to reach peak plasma cocaine levels, the elimination half-life, and the area under the plasma cocaine curve did not differ as a function of the LHRH dose compared with placebo LHRH. Moreover, there were no gender differences in any cocaine-related, pharmacokinetic parameter after placebo-LHRH administration. These data suggest the feasibility of reducing peak levels of free cocaine in plasma by stimulating secretion of LH. The functional consequences and underlying mechanisms of LHRH-induced decreases in peak plasma cocaine levels remain to be determined.