6.2 CB2
Although there are relatively few reports of CB2 regulation of neurotransmission, there is recent evidence that CB2 is expressed in midbrain dopamine neurons and plays a role in regulation of dopamine transmission (Aracil-Fernandez et al., 2012; Zhang et al., 2014). As mentioned above (see section 5.2), M4 activation in D1-expressing SPNs in the dorsal striatum promotes eCB production to reduce dopamine release, and this effect is absent in mice lacking CB2 receptors and blocked by a CB2-selective antagonist (Foster et al., 2016). In midbrain slice preparations and in vivo , CB2 activation decreased VTA dopamine neuron firing rates (Ma et al., 2019; Zhang et al., 2014). This effect was maintained in the presence of glutamatergic and GABAergic transmission blockers, but disrupted by blocking G protein signaling in the recorded cell, suggesting a direct effect on dopamine neurons. Conditional deletion of CB2 from DAT-expressing neurons produced complex effects on responses to a variety of psychoactive drugs, providing additional evidence that CB2 receptors expressed by dopamine neurons can directly modulate dopamine transmission (Canseco-Alba et al., 2019). In addition, a CB2 agonist inhibited optogenetic intracranial self-stimulation for activation of VTA dopamine neurons (Han et al., 2023). The ability of CB2 to reduce dopamine transmission by reducing dopamine neuron firing and decreasing release at terminals suggests that CB2 activation could reduce responses to psychoactive drugs. Supporting this idea, direct injection of a CB2 agonist into the VTA inhibits cocaine self-administration (Zhang et al., 2014). Transgenic mice with CB2 overexpression show reduced locomotor responses to cocaine and attenuated cocaine self-administration, providing further evidence that CB2 receptors can constrain the primary reinforcing effects of some psychoactive drugs (Aracil-Fernandez et al., 2012).