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.