Biological Sex Influences the Contribution of Sign-Tracking and Anxiety-Like Behaviour toward Remifentanil Self-Administration

Most people sample addictive drugs, but use becomes disordered in only a small minority. Two important factors that influence susceptibility to addiction are individual differences in personality traits and biological sex. The influence of traits on addiction-like behaviour is well characterized in preclinical models of cocaine self-administration, but less is understood in regards to opioids. How biological sex influences trait susceptibility to opioid self-administration is likewise less studied than psychostimulants. Thus, we sought to elucidate how biological sex and several addiction-relevant traits interact with the propensity to self-administer the opioid remifentanil. We first screened female (n=19) and male (n=19) rats for four addiction-relevant traits: impulsivity, novelty place-preference, anxiety-like behaviour, and attribution of incentive value to reward cues. Rats were then trained to self-administer remifentanil in a "conflict model" of drug self-administration. Rats had to endure a mild electric shock to access the response manipulandum that triggered an intravenous infusion of remifentanil. In male rats, high anxiety-like behaviour was positively correlated with the number of drug infusions if the shock level was low or completely absent. In females, sign-tracking was predictive of greater resistance to punishment during drug seeking; an effect that was mediated by anxiety-like behaviour. Females consumed more remifentanil under all conditions, and their drug seeking persisted in the face of significantly greater current than males. These findings demonstrate that the influence of behavioural traits over the propensity to self-administer opioids is dependent upon biological sex.