Affective Cue-Induced Escalation of Alcohol Self-Administration and Increased 22-kHz Ultrasonic Vocalizations during Alcohol Withdrawal: Role of Kappa-Opioid Receptors

Abstract

Negative affect promotes dysregulated alcohol consumption in non-dependent and alcohol-dependent animals, and cues associated with negative affective states induce withdrawal-like symptoms in rats. This study was designed to test the hypotheses that: (1) the kappaopioid receptor (KOR) system mediates phenotypes related to alcohol withdrawal and withdrawal-like negative affective states and (2) cues associated with negative affective states would result in dysregulated alcohol consumption when subsequently presented alone. To accomplish these goals, intracerebroventricular infusion of the KOR antagonist nor-binaltorphimine (nor-BNI) was assessed for the ability to attenuate the increase in 22-kHz ultrasonic vocalizations (USVs) associated with alcohol withdrawal and KOR activation in adult male wistar rats. Furthermore, cues associated with a KOR agonist-induced negative affective state were assessed for the ability to dysregulate alcohol consumption and the efficacy of intracerebroventricular KOR antagonism to reduce such dysregulation was evaluated. KOR antagonism blocked the increased number of 22-kHz USVs observed during acute alcohol withdrawal and a KOR agonist (U50,488) resulted in a nor-BNI reversible increase in 22-kHz USVs (mimicking an alcohol-dependent state). Additionally, cues associated with negative affective states resulted in escalated alcohol self-administration, an effect that was nor-BNI sensitive. Taken together, this study implicates negative affective states induced by both alcohol withdrawal and conditioned stimuli as being produced, in part, by activity of the DYN/KOR system.

Early-Life Social Isolation Stress Increases Kappa Opioid Receptor Responsiveness and Downregulates the Dopamine System

“…These data suggest that KOR activation is essential to drive stress-induced reward seeking and that functional upregulation of the KOR signaling increases the reinforcing efficacy of drugs of abuse, potentially through alleviation of a withdrawal-associated negative affective state. KOR antagonists reduce stress-associated escalation of ethanol intake and decrease the reinforcing efficacy of drugs of abuse (current study ;Berger et al, 2013;Funk et al, 2014). Likewise, in the current study, KOR blockade increased DA levels in SI rats, thus rescuing the animals from a hypodopaminergic state.…”

“…The KOR system modulates DA in the NAc and is involved in regulating both anxiety-like and drug-seeking behaviors (Sperling et al, 2010;Walker et al, 2012;Berger et al, 2013). Experiments in the current study examined the hypothesis that SI-induced alterations in NAc DA signaling involve an upregulation of the dynorphin/KOR system.…”

“…These behavioral data are also consistent with the selective enhancing effect of nor-BNI on baseline DA in SI rats observed in the current study. Adult rodents exposed to chronic ethanol (Becker, 2012;Berger et al, 2013;Rose et al, 2015) and rats exposed to adolescent SI (Karkhanis et al, 2014) exhibit increased anxiety-like behaviors. Thus it is possible that escalated ethanol intake in dependent and SI rats is driven, at least in part, by a persistent elevation of stress and anxiety.…”

“…Both repeated forced swim stress and pharmacological activation of KORs with U50,488 increases ethanol consumption in mice (Sperling et al, 2010;Rose et al, 2015). CIE exposure and withdrawal lead to increases in anxiety-like and anhedonic behaviors in addition to promoting an escalation in ethanol intake (Berger et al, 2013). Dynorphin A and KOR signaling is increased in ethanol-dependent adult rats (Kissler et al, 2014) that may contribute to the anhedonia associated with withdrawal.…”

“…Consistent with this, activation of KORs increases drug seeking and pharmacological inactivation of the dynorphin/ KOR system reduces drug seeking during withdrawal. For example, blockade of KORs with nor-binaltorphimine (nor-BNI) attenuates the augmented ethanol intake observed in adult-dependent animals (Berger et al, 2013). KOR blockade also reduces motivation for heroin and ethanol intake in adult-dependent animals, as measured by progressive ratio performance (Walker and Koob, 2008;Schlosburg et al, 2013).…”