6.1 CB1
CB1 receptors are Gαi/o-coupled GPCRs that are widely expressed on presynaptic terminals in various regions of the CNS, including in the midbrain. Until recently, evidence for CB1 receptor expression in midbrain dopamine neurons had not been established; however, CB1 can regulate inputs to dopamine neurons and therefore indirectly control their activity (reviewed in Peters, Cheer, et al., 2021; Peters, Oleson, et al., 2021). Endocannabinoids (eCBs), the endogenous ligands for CB receptors, are synthesized on-demand in response to neuronal activity and/or intracellular calcium mobilization in many types of neurons including midbrain dopamine neurons (Wang & Lupica, 2014; Yanovsky et al., 2003). The newly synthesized eCBs (anandamide or 2-arachidonylglycerol [2-AG]) then undergo retrograde transport and activate presynaptic CB1 receptors to inhibit neurotransmitter release (Kano et al., 2009). CB1 receptor activation resulting from retrograde eCB signaling or agonist administration can disinhibit dopamine neurons by reducing GABAergic transmission (De Luca et al., 2015; Wang & Lupica, 2014). For example, in the VTA, eCB mobilization from dopamine neurons can be triggered by activation of Gαq-coupled GPCRs including orexin 1 receptors, α1 adrenergic receptors, and type I mGlu receptors, thus reducing GABA transmission to disinhibit dopamine neurons (Tung et al., 2016; Wang et al., 2015).
Although the majority of studies have focused on inhibition of GABA inputs to dopamine neurons in the midbrain as the primary mechanism of CB1 regulation of dopamine transmission, a recent study identified CB1 mRNA in a subset of VTA neurons that co-express the glutamate neuron marker Vglut2, suggesting that direct presynaptic inhibition of dopamine release is another possible mechanism (Han et al., 2023). Supporting the behavioral relevance of this finding, CB1 receptor activation reduces optogenetic intracranial self-stimulation of these neurons, and this effect is lost when CB1 is conditionally deleted from these neurons (Han et al., 2023). CB1 receptors expressed on glutamatergic terminals in striatal regions are also poised to regulate local ACh-mediated dopamine release. For example, eCB action on prefrontal cortex terminals inhibits dopamine release evoked by optogenetic stimulation of PFC inputs or CINs, and activation of this population of CB1 receptors reducing optogenetic intracranial self-stimulation of PFC terminals in the NAc (Mateo et al., 2017).
Psychoactive drugs that activate CB1 receptors, such as Δ9-tetrahydrocannabinol (THC) and synthetic CB1 agonists, increase firing rates of VTA and SNc dopamine neurons (French et al., 1997; Gessa et al., 1998). Interestingly, CB1 receptors are also involved in dopamine release produced by several other classes of psychoactive drugs. For example, NAc dopamine transients evoked by systemic administration of nicotine, ethanol, cocaine, and amphetamine are reduced by CB1 blockade (Cheer et al., 2007; Covey et al., 2016). Activation of retrograde eCB signaling to reduce GABAergic transmission is likely to play a role, as fast-scan cyclic voltammetry experiments in midbrain slices demonstrate that cocaine application produces 2-AG synthesis and reduces inhibitory postsynaptic currents in VTA neurons (Wang et al., 2015). Findings from basic behavioral experiments suggest that engagement of the eCB system could contribute to many aspects of drug-associated reward, reinforcement, and addictive behaviors. For example, eCBs play a role in reward prediction, as disrupting VTA eCB signaling using antagonists attenuates cue-associated dopamine transients during a reward seeking task (Oleson et al., 2012). Activation of CB1 receptors modulates reward thresholds in intracranial self-stimulation task in a dose-dependent manner, as low doses of Δ9-THC decrease intracranial self-stimulation thresholds, while higher doses increase reward thresholds (Katsidoni et al., 2013). These findings raise interesting questions about how simultaneous cannabis use affects physiological and behavioral responses to other types of psychoactive drugs, including alcohol and psychostimulants.