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.