The endogenous PPAR-α agonists, oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) can block nicotine’s ability to stimulate mesolimbic dopamine neurons, thereby blocking nicotine’s rewarding and addictive properties (81). These effects of OEA and PEA are inhibited by the PPAR-α antagonist MK886, demonstrating specific PPAR-α involvement. Further, incubation of brain slices with the tyrosine hydroxylase inhibitor, genistein, also inhibited the effects of OEA on nicotine induced changes in firing rate of dopamine neurons, suggesting that tyrosine kinases contribute to the effects of PPARs on nicotine-induced changes in firing rate; phosphorylation of the nicotine receptor appears to mediate the PPAR-α inhibition of nicotine’s effects. The rapid onset of OEA/PEA effects suggested a nongenomic mechanism of PPAR-α stimulation of tyrosine kinases. Further work showed that PPAR-α agonists caused negative modulation of dopamine neurons, as WY14643, a PPAR-α agonist, reduced the number of spontaneously active dopamine neurons, while MK886, a PPAR-α antagonist, increased spontaneous activity of VTA dopamine neurons, an effect that was blocked by WY14643 and by nicotinic antagonists (82). The addictive potential of nicotine is believed to be mediated by dopamine neurons (6, 83), and thus these effects are key to its addictive potential.
