Abstract
Impulsivity is a primary feature of many psychiatric disorders, most notably attention deficit hyperactivity disorder and drug addiction. Impulsivity includes a number of processes such as the inability to delay gratification, the inability to withhold a motor response, or acting before all of the relevant information is available. These processes are mediated by neural systems that include dopamine, serotonin, norepinephrine, glutamate and cannabinoids. We examine, for the first time, the role of opioid systems in impulsivity by testing whether inactivation of the mu- (Oprm1) or delta- (Oprd1) opioid receptor gene alters motor impulsivity in mice. Wild-type and knockout mice were examined on either a pure C57BL6/J (BL6) or a hybrid 50% C57Bl/6J–50% 129Sv/pas (HYB) background. Mice were trained to respond for sucrose in a signaled nose poke task that provides independent measures of associative learning (responses to the reward-paired cue) and motor impulsivity (premature responses). Oprm1 knockout mice displayed a remarkable decrease in motor impulsivity. This was observed on the two genetic backgrounds and did not result from impaired associative learning, as responses to the cue signaling reward did not differ across genotypes. Furthermore, mutant mice were insensitive to the effects of ethanol, which increased disinhibition and decreased conditioned responding in wild-type mice. In sharp contrast, mice lacking the Oprd1 gene were more impulsive than controls. Again, mutant animals showed no deficit in associative learning. Ethanol completely disrupted performance in these animals. Together, our results suggest that mu-opioid receptors enhance, whereas delta-opioid receptors inhibit, motor impulsivity. This reveals an unanticipated contribution of endogenous opioid receptor activity to disinhibition. In a broader context, these data suggest that alterations in mu- or delta-opioid receptor function may contribute to impulse control disorders.
Highlights
Impulsivity is a behavioral trait that varies across the general population
All animals learned the significance of the reward presentation, evidenced by an increase in the proportion of magazine entries that occurred during sucrose availability: there were no genotype or background differences on this measure
Pairwise comparisons revealed that hybrid 50% C57Bl/6J–50% 129Sv/pas (HYB), but not BL6, knockout animals differed from their wild-type controls on session 6
Summary
Impulsivity is a behavioral trait that varies across the general population. Extreme manifestations of impulsivity are revealed in a variety of pathological conditions including antisocial and borderline personality disorders, attention deficit hyperactivity disorder (ADHD), pathological gambling, eating disorders, obsessive-compulsive disorder and substance abuse [1]. Patients with neurological impairments such as Parkinson’s disease, Schizophrenia, Tourette’s syndrome and frontal lobe dementia present with clinical features of impulsivity. The pervasiveness of this trait across patient populations, and the fact that it is a significant predictor of therapeutic efficacy for some disorders [2,3,4], provide compelling arguments for understanding the neuropharmacology of impulsivity. Altered serotoninergic transmission has long been associated with impulse control disorders [5], and an important role for dopamine (DA) has been inferred from the therapeutic efficacy of psychostimulants in the treatment of ADHD [6]. No one has investigated the role of opioid systems in impulsivity using animal models
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