FAAH inhibition or directly by administration of a PPAR-α agonist, prevents nicotine-induced increases in firing rate and burst firing in dopamine neurons in the VTA and as a consequence prevents nicotine-induced elevations of dopamine levels in the shell of the nucleus accumbens. The mechanism underlying these effects was elucidated by our recent in vitro findings showing that activation of PPAR-α produces a non-genomic (rapid) modulation of nicotinic receptors on cell bodies of dopaminergic neurons in the VTA by promoting their phosphorylation by tyrosine kinases (8). Phosphorylated nicotinic receptors show diminished ionic conductance (41) and are rapidly internalized (42), reducing or abolishing the responses of dopamine neurons to nicotine, and we have demonstrated that the general tyrosine kinase inhibitor genistein reverses OEA's ability to block nicotine-induced excitation of VTA dopamine neurons (8). Additionally, we have found that the β2 subunit of nicotinic receptors is critical for PPAR-α effects, since deletion of this subunit abolished the effects of PPAR-α compounds, whereas its selective re-expression in VTA dopamine neurons restores both the behavioral effects of nicotine (motor activity) and PPAR-α actions (43). Taken together, all of these findings suggest a mechanism by which PPAR-α may modulate the reward-related dopaminergic effects of nicotine that
