Fig. 7. Schematic diagram showing the effects of cocaine on CB₂R expression in the mesolimbic DA reward system.

This system originates from DA neurons in the VTA and projects to the NAc. Acute cocaine exposure blocks DA transporter (DAT) and elevates extracellular DA level in the NAc, which subsequently activates D₁-MSNs via Gs-coupled D₁Rs and inhibits D₂-MSNs via Gi-coupled D₂Rs, producing rewarding effects. Chronic cocaine administration increases CB₂R expression in VTA DA neurons as we reported previously [11] and also in NAc D₁-MSNs as shown in the present study. Accordingly, activation of CB₂Rs by CB₂R agonists would inhibit presynaptic VTA DA neurons and postsynaptic D₁-MSNs in the NAc, producing therapeutic anti-cocaine effects. VTA ventral tegmental area, NAc nucleus accumbens, (+) activation, (−) inhibition.