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).