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

Abstract

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 DYNs and 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 expressions are dysregulated within prefrontal brain circuitry associated with decision-making and impulse control in alcoholdependent 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 the two animal models of impulsivity: delay-discounting (DD) or stop-signal reaction time (SSRT) tasks, and once stable responding was observed, received intracerebroventricular (ICV) infusions of the KOR agonist U50,488 (0-50 mg) according to a within-subject dosing regimen. The results demonstrated a dissociable effect of U50,488 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 (nor-BNI). Therefore, KOR activation was shown to induce an impulsive phenotype that was nor-BNI-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.

Maturational alterations in constitutive activity of medial prefrontal cortex kappa‐opioid receptors in Wistar rats

“…2009). We have recently reported KOR activation-induce impulsive phenotypes in rats (Walker and Kissler 2013) and, well documented in both human and animal models, younger organisms engage in more impulsive and risky behaviors than their adult counterparts (Green et al . 1994;Doremus-Fitzwater et al .…”

“…2007) and given our previous experience with the compound, nor-BNI was selected for use in the present investigations as a putative negative efficacy antagonist. We previously demonstrated a KOR specific effect of nor-BNI in the GTPγS assay (Kissler and Walker, 2015) and initiated research on KOR involvement in executive function that implicated the KOR as being an important regulator of impulse control specific to stopping an already-initiated action (Walker and Kissler, 2013). Converging lines of evidence suggested that KORs in the mPFC could be important regulators of executive function: 1) The mPFC has been implicated as a substrate for stop-signal reaction time performance (e.g., Bari et al .…”

Upregulated dynorphin opioid peptides mediate alcohol-induced learning and memory impairment

“…75, 76 Furthermore, KOR activation was found to induce an impulsive phenotype that may contribute to the initiation of alcohol abuse and relapse in dependent individuals. 77 …”

Prefrontal Cortical Kappa Opioid Receptors Attenuate Responses to Amygdala Inputs

“…mPFC KOR upregulation may contribute to deficits in PFC-dependent decision-making and cognition in alcohol and drug addiction. Furthermore, KORs increase impulsive behavior (Walker and Kissler, 2013), which is inhibited by mPFC activation. As mPFC KOR signaling is sufficient to produce aversion and necessary for KOR-mediated aversion (BalsKubik et al, 1993;Tejeda et al, 2013), it is possible that heightened PFC KOR signaling contributes to a negative affective state during abstinence.…”