Sex differences in methamphetamine seeking in rats: Impact of oxytocin

Abstract

Previous evidence in an animal model of drug self-administration and drug seeking showed that acute oxytocin decreased methamphetamine (meth) seeking in male rats, suggesting potential clinical efficacy for the treatment of psychostimulant addiction. However, based on the well-established role of oxytocin in reproduction and pair bond formation, it is important to know how this effect extrapolates to females. Here, we tested whether oxytocin (1 mg/kg, IP) would decrease meth seeking in female rats across various stages of the estrous cycle (Experiment 1). Freely cycling Long Evans female rats self-administered meth (IV) in 2-h daily sessions, followed by daily extinction sessions. Following extinction, rats received oxytocin (0, 0.3, or 1 mg/kg, IP) 30 min before a meth priming injection (1 mg/kg, IP) to assess reinstatement of meth seeking. Next, we examined the effects of oxytocin on motivated meth- and sucrose-taking and seeking in male and female rats. In separate experiments, males and females self-administered meth (Experiment 2) or sucrose (Experiment 3) until responding was stabilized along a fixed ratio (FR) 5 schedule of reinforcement. Subsequently, rats received either oxytocin or vehicle prior to self-administration along a progressive ratio (PR) schedule of reinforcement. Rats were subsequently tested for cue-, meth-, and stress-induced reinstatement after pretreatment with oxytocin or vehicle. While oxytocin reduced meth seeking in females, we found that estrous cycle stage (as determined from vaginal cytology) did not influence meth-primed reinstatement or the ability of oxytocin to decrease reinstatement of meth seeking. Oxytocin reduced PR responding for meth only in females. Females responded more than males during cue-induced reinstatement of meth and sucrose seeking, and oxytocin reduced this responding only in meth females. In both sexes, oxytocin attenuated meth seeking in response to a meth prime and yohimbine (a pharmacological stressor). The results suggest that oxytocin may have efficacy as a treatment of meth addiction in both sexes; however, females may show greater response to oxytocin treatment for the prevention of relapse.

Economic demand predicts addiction-like behavior and therapeutic efficacy of oxytocin in the rat

“…There is strong preclinical evidence for oxytocin as a treatment for psychostimulant addiction (34,35,37), and early clinical studies have confirmed that oxytocin reduces craving for marijuana and alcohol (38,39). We found that oxytocin dramatically reduced cocaine demand in animals with a standard self-administration history; this finding, in view of the relationship between demand and addiction-like behavior reported here, predicts that oxytocin may effectively treat psychostimulant dependence in the clinic.…”

“…There is no current Food and Drug Administration-approved pharmacotherapy to evaluate the predictive validity of our economic demand procedures; however, oxytocin is a promising candidate (34,35). In preclinical testing oxytocin attenuates self-administration of psychostimulants as well as reinstatement to drug seeking (36,37), and early clinical testing confirmed that oxytocin attenuates drug craving (38,39). We tested the effect of oxytocin pretreatment on cocaine demand and reinstatement of cocaine seeking to evaluate its potential as a cocaine addiction treatment as well as to demonstrate utility of this economic approach.…”

Sex Differences in Animal Models: Focus on Addiction

“…Oxytocin suppressed methamphetamine-induced reinstatement in both sexes and cue-induced reinstatement in females only (Cox et al, 2013).…”

Methamphetamine abstinence induces changes in μ-opioid receptor, oxytocin and CRF systems: Association with an anxiogenic phenotype

“…(Qi et al, 2009) as well as intra-hippocampal and intra-medial prefrontal cortex (Han et al, 2014) administration of OT prevented stress-induced reinstatement of METH-seeking. Similarly, intra-AcbC , as well as peripheral (Carson et al, 2010;Cox et al, 2013) administration of OT attenuated METH-primed reinstatement in rodents. In addition, Hicks et al (2014) showed that a 10-day oxytocin administration during adolescence was able to decrease the motivation to self-administer METH and to attenuate priming-induced reinstatement of METH-seeking during adulthood in rats.…”