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Abstract
The endogenous opioid system has long been implicated in acute drug reinforcement and addiction processes, as well as in the maintenance of a homeostatic reward system. The four experiments of Part I sought to elucidate the specific contributions of opioid receptor subtypes, by examining the responsiveness of mice deficient in these receptors using place-conditioning paradigms. In Experiment 1, δOR deficient mice demonstrated intact naloxone CPA, a phenomenon that is absent in mice lacking the µOR. This result supports the notion that tonic peptide agonism at δORs does not contribute to the maintenance of affective tone, consistent with other experiments finding little aversive impact of δOR-selective antagonists. Experiment 2 utilized the same strain of δOR KO mice to examine a putative role for the δOR in cocaine reinforcement, given an inconsistent and equivocal literature. δOR deficient mice exhibited comparable cocaine CPP (compared to WTs) at both 10 and 25 mg/kg, suggesting that the rewarding properties of cocaine are not mediated, in any part, at the δOR. Experiments 3 and 4 utilized µOR KO mice to investigate the neuroanatomical loci of affective tone, using a loss-of-function/gain-of-function model. Retroviral vectors were used to reintroduce the µOR into the VP or NACsh, in hopes of reversing the robust behavioral phenotype of diminished naloxone aversion in KO mice. Naloxone CPA remained absent in these animals, which may rule out these structures, although methodological limitations are a more likely explanation of the observed null result.
The four experiments of Part II sought to examine the contribution of endogenous opioids in the incentive motivational processes mediating the pursuit of food reward (operant paradigms), with implications for the fields of addiction and obesity. Experiment 5 revealed attenuated acquisition, and outcome devaluation by specific satiety following pre-training injections of naloxone in C57BL/6 mice, suggesting that opioid blockade not only modulates the value of a palatable outcome, but precipitates habitual responding that is independent of satiety-induced fluctuations in outcome value. Experiment 6 failed to reveal devaluation deficits in PENK and BEND KO mice, although BEND KO mice did exhibit depressed acquisition rates. Similar to BEND KO mice, µOR KO mice (Experiment 7) demonstrated a behavioral phenotype characterized by acquisition deficits, but intact devaluation. Additionally, these animals performed equivalent to WTs on a test of omission, while an overtraining phenotype proved inconclusive due to the absence of stimulus-driven responding in WTs. Finally, utilizing the same µOR strain in a seeking-taking chain of instrumental performance, Experiment 8 showed that pre-test naloxone had no effect on performance in KO mice during a rewarded test, in contrast to WT performance. This, along with the acquisition data, generally supports a role for the µOR in the incentive motivational control of goal-directed action under deprived conditions, although a palatability-based account cannot be excluded.
