3. Modulation of dopamine transmission by D2 autoreceptors
Dopamine release modulates the physiology of dopamine neurons and
neurons in target regions by acting on GPCRs that include the
Gαs-coupled D1-like receptors (D1 and D5) and
Gαi/o-coupled D2-like receptors (D2, D3, D4) (Martel &
Gatti McArthur, 2020). D2 receptors are expressed in both axonal and
somatodendritic regions of dopamine neurons, and are thus poised to
exert negative feedback on dopamine release using several distinct
mechanisms (reviewed in Ford, 2014; Nolan et al., 2020). Activation of
somatodendritic D2 receptors expressed by VTA and SNc dopamine neurons
produces hyperpolarization via activation of GIRK channels and can
reduce firing rates (Beckstead et al., 2004; Courtney et al., 2012;
Ford, 2014; Lacey et al., 1987). In terminal regions, activation of D2
autoreceptors inhibits dopamine release due to activation of
K+ currents and inhibition of voltage-gated calcium
channels (Cardozo & Bean, 1995; Congar et al., 2002; Ford, 2014; Martel
et al., 2011; Nolan et al., 2020; Stamford et al., 1991). In addition,
D2 receptor activation can modulate dopamine transmission over a range
of timescales via effects on synthesis and clearance. D2 activation
reduces tyrosine hydroxylase activity and can increase activity of
dopamine transporters, particularly in the context of strong D2 receptor
activation (Anzalone et al., 2012; Benoit-Marand et al., 2011; Ford,
2014; Lee et al., 2007; Mayfield & Zahniser, 2001; Nolan et al., 2020;
Wolf & Roth, 1990).
Converging lines of evidence from pharmacological, genetic, and human
imaging studies provide substantial evidence that D2 receptors are
involved in acute responses to psychoactive drugs and that adaptations
in D2 receptor expression and function can occur following chronic drug
use (reviewed in Jordan & Xi, 2021; Urban & Martinez, 2012; Volkow &
Morales, 2015). Because D2 receptors are expressed by both dopaminergic
and non-dopaminergic neurons, the majority of studies do not delineate
specific roles for D2 autoreceptors vs. heteroreceptors expressed by
various striatal neurons and neurons in other target regions (e.g.,
cortex). Conditional knockout mice are an important tool for
interrogating cell-type specific receptor functions. Selective deletion
of D2 receptors from dopamine neurons enhances dopamine release,
increases locomotion while exploring a novel environment, and elevates
motivation for natural rewards (Anzalone et al., 2012; Bello et al.,
2011). In the context of psychoactive drug responsiveness, D2
autoreceptor deletion enhances responses to psychoactive drugs,
including enhanced cocaine-induced dopamine release and psychomotor
activation, conditioned place preference, acquisition of operant
self-administration, and cocaine-paired cue reactivity (Anzalone et al.,
2012; Bello et al., 2011; Holroyd et al., 2015). However, D2
autoreceptor deletion from the SNc of adult rats using RNA interference
blunted locomotor responses to cocaine, suggesting that it could be
important to consider the developmental effects, species dependence, and
region specificity when using the conditional knockout approach (Budygin
et al., 2016). Interestingly, human imaging studies suggest that
midbrain D2/D3 receptor availability is inversely correlated with trait
impulsivity, a potential vulnerability factor for psychoactive drug
misuse (Buckholtz et al., 2010). Lower human D2/D3 receptor binding is
also associated with enhanced amphetamine-induced striatal dopamine
release, supporting the translational relevance of preclinical evidence
for the autoinhibitory role of D2 receptors (Buckholtz et al., 2010). In
addition to the potential for D2 autoreceptor expression or function to
confer vulnerability to drug misuse, repeated exposure to drugs
including psychostimulants and alcohol can alter D2-mediated modulation
of dopaminergic transmission (Perra et al., 2011; Wolf et al., 1993).