The mechanism by which PPAR-α agonists and FAAH inhibition exert these unanticipated anti-addictive actions is not completely understood. However, the following points are well-established. Mesolimbic dopamine plays a pivotal role in nicotine dependence, and the VTA and nucleus accumbens shell are critical brain areas for nicotine's rewarding effects (37-39). Nicotinic receptors in the VTA are located both on cell bodies of dopaminergic neurons and on presynaptic nerve endings of glutamatergic neurons which descend from the medial prefrontal cortex and impinge on these cell bodies (40). Nicotine facilitates dopaminergic neurotransmission and dopamine release in the nucleus accumbens shell by directly stimulating nicotinic receptors on cell bodies of dopaminergic neurons and by indirectly stimulating glutamate release, which in turn stimulates VTA dopaminergic neuron firing and dopamine release in the nucleus accumbens shell. Our data show that activation of PPAR-α, either indirectly through 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
