1. Introduction
Dopamine transmission in the striatum plays critical roles in complex cognitive and behavioral processes including reward, motivation, reinforcement learning, effort, and responses to salience (Berke, 2018; Kutlu et al., 2021; Walton & Bouret, 2019). Dopamine neurons that project to striatal regions originate in the substantia nigra pars compacta (SNc), which densely innervates the dorsal striatum, and the ventral tegmental area (VTA), which projects to the ventral aspect of the striatum (the nucleus accumbens or NAc) and cortical areas that are important for executive functions (An et al., 2021; de Jong et al., 2022). Dopamine exerts several types of modulatory influence on striatal physiology (Yamada et al., 2016). Distinct populations of striatal projection neurons (SPNs; also known as medium spiny neurons) express D1 and D2 subtypes of dopamine receptors, which modulate their excitability and regulate neurotransmitter release. D2 receptors on striatal cholinergic interneurons are important regulators of firing patterns (Zhang & Cragg, 2017). In addition, dopaminergic transmission contributes to several forms of synaptic plasticity that influence corticostriatal transmission over longer time scales (Bamford et al., 2018).
Psychoactive drugs that are subject to misuse acutely increase dopamine release in striatal regions, although the mechanisms that mediate these transient increases in dopamine release vary depending on the molecular targets of each drug (Luscher et al., 2020). Drug-evoked dopamine release is an important mediator of the rewarding and reinforcing effects of psychoactive drugs, and is involved in many aspects of psychoactive drug misuse including behavioral reinforcement, habit formation, and aberrant responses to drug-associated stimuli (Koob & Volkow, 2016; Wise & Robble, 2020). GPCRs that regulate dopaminergic circuitry play various roles in psychoactive drug effects. Opioids and cannabinoids directly activate GPCRs, resulting in increased striatal dopamine transmission. In other cases, endogenous activation of GPCRs that inhibit dopamine release constrain the effects of psychoactive drugs (e.g., D2 dopamine receptors and kappa opioid receptors). Many GPCRs that modulate dopamine release in the striatum are current or proposed targets for treatment of substance use disorders based on their ability to reduce drug consumption in preclinical models and in human subjects. Reducing the primary reinforcing value of psychoactive drugs by attenuating their ability to evoke dopamine release is one potential mechanism by which GPCR modulation can reduce drug consumption. GPCR manipulations that reduce dopamine transmission evoked by drug-associated stimuli also have the potential to inhibit drug seeking caused by aberrant incentive salience. Understanding how GPCRs modulate striatal dopamine transmission under normal conditions, and the relevance of GPCR actions to psychoactive drug effects in the context of recreational-type use and substance use disorders, is critical to understanding the neurobiology of psychoactive drug use and developing novel treatment strategies for substance use disorders.
This review will highlight several types of GPCRs that regulate dopamine release, including dopamine release evoked by psychoactive drugs, in striatal regions. We will focus on examples that demonstrate the diverse mechanisms by which GPCRs can regulate striatal dopamine release, including D2 dopamine receptors, metabotropic glutamate receptor 2 (mGlu2), cannabinoid receptors (CB1 and CB2), muscarinic acetylcholine receptors (M1, M4, and M5), and opioid receptors (mu and kappa). For each receptor, we will review the synaptic mechanisms by which dopamine release is either enhanced or attenuated, and then highlight examples of how these receptors modulate psychoactive drug effects from a neurochemical and behavioral perspective.