Dissociation of intake and incentive sensitization during intermittent- and continuous-access heroin self-administration in rats

Abstract

Rationale Opioid misuse is a prominent public health concern, although patterns of use may confer different vulnerability to relapse. Continuous-access ( ContA ) self-administration has traditionally been used in preclinical models to study drug-motivated behaviors and produces robust escalation of intake and tolerance development. Alternatively, studies using intermittent access ( IntA ), where self-administration occurs in discrete drug-available periods, suggest that overall intake may be dissociable from subsequent increases in motivation (i.e., incentive sensitization). However, IntA paradigms have focused primarily on psychostimulants like cocaine and methamphetamine and have not been as comprehensively studied with opioids. Objective We compared two paradigms of heroin self-administration, ContA and IntA, to assess their effect on heroin intake and motivation. Methods Male and female rats were trained to self-administer heroin, then were transitioned to either ContA or IntA paradigms. Following self-administration, rats were tested in progressive-ratio, behavioral economics threshold probe, and conditioned reinforcement tests to measure motivation-related behaviors. Results Both patterns of intake evoked similar heroin-directed motivation during progressive-ratio and conditioned reinforcement tests, despite lower overall intake throughout IntA for male rats. Females had similar responding between treatments in self-administration and progressive-ratio even though IntA rats had less time to earn infusions. During threshold probe, IntA-trained subjects showed more inelastic responding (lower α values), suggesting a greater degree of dependence-like behavior. Conclusions These results suggest the importance of dissociating heroin intake from incentive sensitization and emphasize the significance of sex differences as a modifier of heroin consumption and motivation.

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