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Thursday, May 23, 2013

Dissociable Effects of Kappa-Opioid Receptor Activation on Impulsive Phenotypes in Wistar Rats

The kappa-opioid receptor (KOR) is the primary target for the endogenous opioid peptide dynorphin (DYN) and KORs reside within brain circuitry underlying the complex integration of information related to different behavioral domains such as motivation, negative affect and decision-making.

Alterations in extended amygdala dynorphins (DYN) and kappa-opioid receptor (KOR) function following chronic alcohol exposure have been shown to mediate escalated alcohol self-administration during acute withdrawal. In addition to excessive alcohol consumption and increased negative affect, other symptoms of alcohol dependence include compromised impulse control.

Given that DYN and KOR expression are dysregulated within prefrontal brain circuitry associated with decision-making and impulse control in alcohol-dependent humans and rodents and have been shown to modify multiple neurotransmitter systems associated with impulse control disorders, we hypothesized that KOR activation could contribute to impulsive phenotypes.

To test this hypothesis, separate cohorts of male Wistar rats were trained in one of two animal models of impulsivity: delay discounting (DD) or stop-signal reaction time (SSRT) tasks and once stable responding was observed, received intracerebroventricular infusions of the KOR agonist U50,488 (0-50μg) according to a within-subject dosing regimen.

The results demonstrated a dissociable effect of U50488 on impulsive phenotypes related to intolerance to delay or response inhibition with selective effects in the SSRT. Furthermore, the pro-impulsive effects of KOR activation were rescued by pretreatment with the KOR antagonist nor-binaltorphimine (norBNI). Therefore, KOR activation was shown to induce an impulsive phenotype that was norBNI-sensitive.

Dysregulation of impulsive behavior by increased DYN/ KOR activity could serve to increase vulnerability for the initiation, or perpetuate existing patterns of excessive alcohol abuse and can enhance the probability of relapse in dependent individuals. Furthermore, KOR-mediated impulsivity has implications for numerous neuropsychiatric disorders.

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