Dopaminergic Cellular and Circuit Contributions to Kappa Opioid Receptor Mediated Aversion

Abstract

Neural circuits that enable an organism to protect itself by promoting escape from immediate threat and avoidance of future injury are conceptualized to carry an “aversive” signal. One of the key molecular elements of these circuits is the kappa opioid receptor (KOR) and its endogenous peptide agonist, dynorphin. In many cases, the aversive response to an experimental manipulation can be eliminated by selective blockade of KOR function, indicating its necessity in transmitting this signal. The dopamine system, through its contributions to reinforcement learning, is also involved in processing of aversive stimuli, and KOR control of dopamine in the context of aversive behavioral states has been intensely studied. In this review, we have discussed the multiple ways in which the KORs regulate dopamine dynamics with a central focus on dopamine neurons and projections from the ventral tegmental area. At the neuronal level, KOR agonists inhibit dopamine neurons both in the somatodendritic region as well as at terminal release sites, through various signaling pathways and ion channels, and these effects are specific to different synaptic sites. While the dominant hypotheses are that aversive states are driven by decreases in dopamine and increases in dynorphin, reported exceptions to these patterns indicate these ideas require refinement. This is critical given that KOR is being considered as a target for development of new therapeutics for anxiety, depression, pain, and other psychiatric disorders.

Effects of the alpha-1 antagonist prazosin on KOR agonist-induced reinstatement of alcohol seeking

“…We noted that prazosin significantly blocked U50,488-induced increases in Fos expression in the VTA, the site of origin of dopamine projections to the forebrain, suggesting the possible involvement of dopamine in U50,488-induced reinstatement and its blockade by prazosin. This is unlikely, however, because, in contrast to other common laboratory stressors that reliably increase dopamine release, U50,488 decreases basal and stimulated dopamine release (Cortez et al, 2010; Karkhanis et al, 2016), which may occur at the level of the dopaminergic cell bodies by decreasing dopamine cell firing or at the level of the terminals by inhibiting dopamine release (Margolis and Karkhanis, 2019). It is also possible that U50,488 activates non-dopaminergic neurons in the VTA; a double labeling approach would be necessary to verify this.…”

Cocaine self-administration augments kappa opioid receptor system-mediated inhibition of dopamine activity in the mesolimbic dopamine system

“…When KORs are activated by dynorphin or exogenous agonists, DA release is suppressed through multiple mechanisms ultimately leading to subsequent terminal hyperpolarization (for review, see Margolis and Karkhanis, 2019 ). This inhibition of DA release after chronic cocaine self-administration may contribute to a hypofunctioning DA system (for review, see Trifilieff and Martinez, 2013 ), and dopamine hypofunction is involved in the reward deficits and negative affective states seen during drug withdrawal, which may drive further cocaine use and promote relapse (for review see Koob et al, 2014 and Koob, 2021 ).…”