Sex Differences in Heroin Self‐Administration Behaviors and Heroin‐Induced Receptor Alterations in Rats

Abstract

Despite reports that women are more vulnerable than men to certain features of heroin addiction, including craving and relapse, there are limited numbers of preclinical studies evaluating these phenomena. In addition, the published sex‐comparison studies in preclinical models of heroin addiction have shown conflicting results. For example, Lynch and Carroll (1999) report that female rats acquire heroin self‐administration faster than males, while Stewart et al. 1996 report no differences in acquisition rates between male and female rats. Therefore, this study examined sex differences in several heroin self‐administration behaviors and putative neural correlates. Adult male and female Sprague‐Dawley rats were implanted with jugular catheters and were given access to heroin (FR1 schedule of reinforcement, 0.025 mg/kg/inf; maximum 20 infusions) for 6 hours per day. Acquisition criteria were met when rodents earned all 20 infusions for 2 consecutive days. After acquisition, all animals were placed on a long access (LgA) paradigm, which included unlimited access to heroin (FR1) for 6 hours/day for 10 consecutive days. After completion of LgA, animals were tested for motivation to self‐administer heroin using a progressive ratio (PR) schedule. Finally, we measured basal dopamine dynamics and the ability of kappa opioid receptor (KOR) and D2/D3 autoreceptor agonism to reduce dopamine release in the nucleus accumbens following exposure to heroin self‐administration using ex vivo fast scan cyclic voltammetry (FSCV) in brain slices. Female and male rats acquired heroin self‐administration at similar rates, but females self‐administered more heroin during LgA, had increased loading doses of heroin during the first 10 minutes of LgA sessions, and increased escalation of intake across the 10 LgA sessions compared to males. PR data revealed a rightward shift in the dose‐response curve of the females, indicative of increased motivation to obtain higher doses of heroin. Using FSCV, we found that all rats displayed greater KOR‐ and D3 autoreceptor‐mediated dopamine release inhibition, however, females showed higher levels of activity for both receptors. These results reveal marked sex differences in specific heroin self‐administration behaviors that may be driven by altered receptor functioning within the nucleus accumbens. Future studies elucidating receptor interactions related to sexually dimorphic heroin self‐administration behaviors in rats will be highly informative.Support or Funding InformationT32 DA041349This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.