Early maternal separation and sex differences in the aversive effects of amphetamine in adult rats

Early life stress increases vulnerability to psychostimulant abuse, sometimes in a sex-dependent manner. These effects are presumably produced by modulation of neurobiological reward mechanisms; however, drug intake is also influenced by sensitivity to the drug's aversive properties, and little is known about the effects of early life stress on stimulant aversion. To assess this possibility, Sprague-Dawley rat litters experienced daily separation from the dam for 3 h (MS) or 15 min (H) on post-natal days 2-14; control litters (AFR) experienced twice-weekly routine animal facility care only. As adults, the animals were tested for conditioned taste aversions (CTA) induced by 1.5, 2.0 or 3.0 mg/kg d-amphetamine administered intraperitoneally over three acquisition trials followed by six drug-free extinction trials (n=7-8/sex/dose/rearing group). All groups acquired significant aversions compared to their vehicle-treated controls, but differential rearing had no effect on CTA acquisition or extinction. Collapsed across rearing groups, females exhibited significantly stronger aversions and slower extinction than their male counterparts at the low 1.5 mg/kg dose, and unlike the males, failed to fully extinguish relative to their vehicle controls at 1.5 and 2.0 mg/kg. These data underscore the importance of sex differences in assays of stimulant abuse liability, and further support the hypothesis that the effects of post-natal stress on the reinforcing efficacy of psychostimulants may be predominantly due to modulation of reward mechanisms.