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).