Effects of Progesterone and Testosterone on Cocaine Self-Administration and Cocaine Discrimination by Female Rhesus Monkeys

Abstract

The neuroactive steroid hormone progesterone attenuates cocaine's abuse-related effects in women and in rodents under some conditions, but the effects of testosterone are unknown. We compared the acute effects of progesterone (0.1, 0.2, and 0.3 mg/kg, intramuscularly (i.m.)), testosterone (0.001, 0.003, and 0.01 mg/kg, i.m.), and placebo on cocaine self-administration and cocaine discrimination dose-effect curves in female rhesus monkeys. Cocaine self-administration (0.03 mg/kg per inj.) was maintained on a fixed ratio 30 schedule of reinforcement, and monkeys had unlimited access to cocaine for 2 h each day. Cocaine doses were administered in an irregular order during each dose-effect curve determination, and the same dose order was used in each subject in all treatment conditions. Blood samples for hormone analysis were collected at the end of each test session. Banana-flavored food pellets (1 g) were also available in three 1-h daily sessions. In drug discrimination studies, the effects of pretreatment with progesterone (0.032-0.32 mg/kg, i.m.) and testosterone (0.001-0.01 mg/kg, i.m.) on the discriminative stimulus effects of cocaine (0.18 mg/kg, i.m.) were examined. Progesterone and testosterone did not alter cocaine discrimination, and did not substitute for cocaine. In contrast, progesterone and testosterone each significantly decreased cocaine self-administration, and produced a downward and rightward shift in the cocaine self-administration dose-effect curve. These findings are concordant with clinical reports that progesterone administration may decrease ratings of positive subjective effects of cocaine in women, and suggest the possible value of neuroactive steroid hormones for the treatment of cocaine abuse and reduction of risk for relapse.

Acute Effects of 3,4-Methylenedioxymethamphetamine and Methylphenidate on Circulating Steroid Levels in Healthy Subjects

“…Steroids are involved in a wide range of central and peripheral physiological functions related to mood, cognition, adaptation to stress, immune function, and others. In the context of recreational drug use, cortisol, DHEA, and testosterone may contribute to or modulate substance-induced acute psychotropic and reinforcing effects [12,20,21]. For example, MDMA-induced increases in plasma cortisol levels have previously been shown to correlate with subjective drug liking in response to MDMA in a laboratory study [12].…”

“…Mineralocorticoids increase renal sodium absorption and blood pressure. Androgens may modulate the addictive effects of drugs of abuse [12,20,21]. We hypothesized that methylphenidate and MDMA would differentially affect the plasma levels of these steroids based on their different pharmacological profiles.…”

Emergence of sex differences in the development of substance use and abuse during adolescence

“…Numerous studies have shown that estradiol augments and progesterone inhibits self-administration and the reinforcing effects of psychostimulants, ethanol, nicotine and opioids (Anker & Carroll, 2011; Becker & Hu, 2008; Becker, Perry, & Westenbroek, 2012; Carroll & Anker, 2010; Carroll et al, 2004; Donny et al, 2000; Feltenstein et al, 2012; Levin et al, 2011; Lynch, 2009; O'Dell & Torres, 2014; Perkins et al, 1999). In contrast, the presence of testosterone was reported to have no effect on cocaine self-administration (Caine et al, 2004; Mello, Knudson, Kelly, Fivel, & Mendelson, 2011) self-administration of morphine (Cooper & Wood, 2014). However, testosterone could contribute to drug taking through actions on impulsive or risk-taking behavior rather than directly affecting the reinforcing properties of the drugs.…”

Exercise as a Potential Treatment for Drug Abuse: Evidence from Preclinical Studies

“…Two other studies reported no sex differences in the effects of exercise on measures of escalation, binge responding, extinction responding, drug-primed reinstatement, and cue-induced reinstatement (Smith et al, 2011a,b). Gonadal hormones are known to influence both drug self-administration (Roberts et al, 1989; Feltenstein and See, 2007; Larson and Carroll, 2007; Mello et al, 2011) and wheel running (Hertrampf et al, 2006; Hydock et al, 2007), but it is not known whether gonadal hormones influence the effects of exercise on drug self-administration. Studies that experimentally manipulate the hormonal milieu via gonadectomy and receptor-specific antagonists will be necessary to characterize the role of sex-specific hormones in this relationship.…”