7.2 Kappa opioid receptors (KORs)
KORs are Gαi/o-coupled GPCRs that are expressed by midbrain dopamine neurons and SPNs and can exert complex control of dopamine transmission via both presynaptic and postsynaptic mechanisms (reviewed in Escobar et al., 2020). Pharmacological activation of KORs in the dorsal and ventral striatum decreases extracellular dopamine levels (Di Chiara & Imperato, 1988; Karkhanis et al., 2016; Spanagel et al., 1992), while KOR blockade or genetic deletion increases extracellular dopamine levels, suggesting tonic regulation of dopamine transmission by KORs (Chefer et al., 2005; Spanagel et al., 1992). KOR activation can decrease vesicular dopamine release by increasing K+ conductance and inhibiting voltage-gated calcium channels (Margolis & Karkhanis, 2019). In the VTA, KORs inhibit dopamine neuron activity by activating GIRK and possibly by decreasing excitatory input, although the degree of inhibition varies by projection target (Ford et al., 2006; Margolis et al., 2003, 2005). In addition, KOR activation with the atypical hallucinogen Salvinorin A and other KOR agonists increase DAT activity, representing another mechanism by which KORs constrain dopaminergic transmission (Atigari et al., 2019; Kivell et al., 2014; but see Escobar et al., 2020).
In addition to reducing dopamine transmission under normal conditions, acute KOR activation can also reduce dopamine release and associated behaviors evoked by psychoactive drugs including amphetamine and cocaine (Gray et al., 1999). Similarly, dopamine release in response to cocaine injection is increased in KOR knockout mice (Chefer et al., 2005). KOR agonists reduce cocaine self-administration in non-human primates, although this effect could be partially explained by side effects such as sedation (Negus et al., 1997). However, the regulation of drug-induced dopamine release by KORs is complex, and other studies have shown that repeated KOR activation can actually facilitate dopamine release in response to psychostimulants (see Escobar et al., 2020). Moreover, history of psychoactive drug exposure can modulate KOR-mediated inhibition of dopamine release in the NAc (Karkhanis et al., 2016). For example, alcohol exposure during adolescence can facilitate or impair KOR-mediated inhibition of dopamine release depending on the age of rats during alcohol exposure (i.e., early vs. late adolescence) (Spodnick et al., 2020). The ability of KORs to reduce drug-induced dopamine transmission suggested that KOR agonists could be a treatment for substance use disorders by reducing the primary reinforcing value of psychoactive drugs. However, activation of KORs promotes a dysphoric state that could facilitate drug seeking. More recently, findings that KOR activity contributes to negative affective states during drug withdrawal has led to interest in KOR antagonism as a pharmacological strategy to prevent reinstatement of drug use (Darcq & Kieffer, 2018).The ability of KOR antagonists to attenuate stress-induced drug seeking likely involves KOR effects in the VTA (Escobar et al., 2020; Graziane et al., 2013; Karkhanis et al., 2017; Polter et al., 2014).