Figure 3. Endocannabinoid influences in the VTA and NAc contributing to approach and avoidance behavior.

a. EC influences on VTA synaptic signaling. Endocannabinoids produced by dopaminergic VTA neurons act on CB₁Rs on nearby glutamatergic and GABAergic terminals before being degraded by ABHD6 or MAGL. CB₁Rs mediate robust inhibition of GABA inputs arising from the pallidus, RMTg nucleus and local interneurons onto VTA DA cells ²⁰⁵ and most evidence points to a role for 2-AG but not AEA in these processes^{109, 206}. CB₁Rs are also localized on glutamatergic terminals synapsing on VTA DA neurons, with relatively greater expression on VGLUT1-positive terminals of cortical origin compared with VGLUT2-expressing terminals of subcortical origin²⁰⁷. Extensive evidence demonstrates EC-mediated suppression of glutamate signaling in VTA²⁰⁸. Thus, ECs play a prominent role in fine-tuning the activity of the mesolimbic DA projection through modulation of both excitatory and inhibitory signaling in the VTA. b. EC influences on NAc synaptic signaling. The majority of NAc neurons (>90%) are GABAergic medium spiny neurons (MSNs) that comprise the direct and indirect projection pathways. Direct pathway MSNs (dMSNs) project to midbrain regions including the VTA and activation of this pathway increases behavior toward a stimulus (approach or appetitive behavior). Indirect pathway MSNs (iMSNs) project to the ventral pallidum (VP) and activation of this pathway increases the stimulus avoidance²⁰⁹. dMSNs express excitatory D₁ DA receptors and iMSNs express inhibitory D₂ DA receptors, and thus reward-related phasic DA release activates the direct pathway and inhibits the indirect pathway, thereby increasing approach behavior and reducing avoidance behavior²¹⁰. NAc MSN activity is also heavily modulated by glutamatergic inputs from the PFC, BLA and ventral hippocampus that express CB₁Rs²¹¹, CB₁-mediated suppression of excitatory signaling (EC-LTD) is preferentially active at iMSN synapses²¹² possibly resulting from D₂ receptor-mediated EC production from iMSN cell bodies²¹³. Thus, increased NAc EC formation preferentially reduces excitatory input to iMSNs vs. dMSNs, resulting in decreased avoidance behavior. Through these mechanisms, increased EC signaling in the NAc increases approach behavior while reducing avoidance-related processing thereby enhancing appetitive responding toward a stimulus. CB₁Rs are also expressed on terminals of fast-spiking interneurons (FSIs) in the NAc, the majority of which are electrically and chemically coupled and provide direct innervation to adjacent MSNs²¹⁴. FSIs exert important influence on the synchronization of neural ensemble activity and thus EC signaling may also exert critical influence on NAc output through feed-forward modulation of MSN network activity²¹⁴.