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).