Kappa opioid receptors mediate yohimbine-induced increases in impulsivity in the 5-choice serial reaction time task

Abstract

Dynorphin (DYN), and its receptor, the kappa opioid receptor (KOR) are involved in drug seeking and relapse but the mechanisms are poorly understood. One hypothesis is that DYN/KOR activation promotes drug seeking through increased impulsivity, because many stimuli that induce DYN release increase impulsivity. Here, we systematically compare the effects of drugs that activate DYN/KOR on performance on the 5-choice serial reaction time task (5-CSRTT), a test of sustained attention and impulsivity. In Experiment 1, we determined the effects of U50,488 (0, 2.5, 5 mg/kg), yohimbine (0, 1.25, 5 mg/kg), and nicotine (0, 0.15, 0.3 mg/kg) on 5-CSRTT performance. In Experiment 2, we determined the effects of alcohol (0, 0.5, 1.0, 1.5 g/kg) on 5-CSRTT performance before and after voluntary, intermittent alcohol exposure. In Experiment 3, we determined the potential role of KOR in the pro-impulsive effects of yohimbine (1.25 mg/kg) and nicotine (0.3 mg/kg) by the prior administration of the KOR antagonist nor-BNI (10 mg/kg). Premature responding, the primary measure of impulsivity, was reduced by U50,488 and alcohol, but these drugs had a general suppressive effect. Yohimbine and nicotine increased premature responding. Yohimbine-, but not nicotine-induced increases in premature responding were blocked by nor-BNI, suggesting that impulsivity induced by yohimbine is KOR dependent. This may suggests a potential role for KOR-mediated increases in impulsivity in yohimbine-induced reinstatement.

Pharmacological evidence of a cholinergic contribution to elevated impulsivity and risky decision-making caused by adding win-paired cues to a rat gambling task

“…Given that nicotine increases dopamine efflux in the mesolimbic dopamine system (Dani and Bertrand, 2007), we expected a dose-dependent increase in premature responding following administration of this drug, matching previous data using the 5CSRTT and similar tasks (e.g., Blondel et al, 2000;Funk et al, 2019;Higgins et al, 2020;Hosking et al, 2014;Stolerman et al, 2000). However, this just fell short of significance, whereas no sign of a linear increase in premature responding was observed on the uncued rGT (Silveira et al, 2015).…”

TA1 agonists attenuate extended‐access cocaine self‐administration and yohimbine‐induced reinstatement of cocaine‐seeking

“…Therefore, TA 1 activation may prevent yohimbine-induced relapse by inhibiting yohimbine-induced impulsivity. It should be noted that yohimbineand stress-induced reinstatement is a complicated process and also depends on other neurotransmitter systems such as the glutamatergic and κ opioid systems (Funk, Tamadon, Coen, Fletcher, & Le, 2019;Mantsch et al, 2016) A limitation of the present study is that we did not assess the pharmacological selectivity of the TA 1 agonists on cocaine-related behaviours. However, previous studies have clearly addressed this issue.…”

“…Therefore, TA 1 activation may prevent yohimbine‐induced relapse by inhibiting yohimbine‐induced impulsivity. It should be noted that yohimbine‐ and stress‐induced reinstatement is a complicated process and also depends on other neurotransmitter systems such as the glutamatergic and κ opioid systems (Funk, Tamadon, Coen, Fletcher, & Le, 2019; Mantsch et al, 2016). The inhibitory effects of TA 1 agonists on yohimbine‐induced reinstatement may not be generalizable to physical stressors.…”

Association of variants of prodynorphin promoter 68-bp repeats in caucasians with opioid dependence diagnosis: Effect on age trajectory of heroin use

“…Endogenous activation of KOR by dynorphins can result in aversion/dysphoria and anhedonia, and can also underlie relapse-like effects and escalation of drug self-exposure in animal models [33,34]. Furthermore, the KOR / dynorphin system modulates basic behavioral functions, including impulsivity, in animal models, and this could affect specific age trajectory phenotypes in OD (e.g., age of first heroin use) [35,36].…”