Figure 6.

Effects of O-1602 on nicotine self-administration in WT and GPR55-KO mice. A/B: Systemic administration of O-1602 (10 and 20 mg/kg) significantly inhibited nicotine self-administration in WT mice, but not in GPR55-KO mice. C/D: Representative records of nicotine infusions after the vehicle (C) or O-1602 administration (D), illustrate that O-1602, at 10 mg/kg, caused cessation of self-administration. E: A proposed working hypothesis explaining how GPR55 agonism reduces nicotine self-administration. Briefly, cocaine or nicotine may increase extracellular DA levels in the NAc by blockade of DA transporter (DAT) or activation of a₄b₂ nicotinic receptors located on midbrain DA neurons or NAc DA terminals, respectively, which has been thought to underlie intravenous drug self-administration. Activation of GPR55 expressed on glutamate terminals projected from the cortex and hippocampus increases glutamate release in the NAc, which subsequently counteracts DA effects on postsynaptic medium-spiny neurons (MSNs), particularly in D2 receptor-expressing MSNs (D2-MSNs) where glutamate and DA produce opposite effects on neuronal activity. ** p<0.01, compared to the vehicle control group.