These findings indicate that activation of PPAR-α receptors can counteract addiction-related effects of nicotine on the brain and behavior. In both rats and monkeys, the PPAR-α agonists WY14643 and methOEA significantly decreased nicotine self-administration and suppressed reinstatement of nicotine seeking, which models relapse, the main obstacle to smoking cessation. At the doses that produced these effects with nicotine self-administration, there was no indication that PPAR-α ligands had any effect on food- or cocaine maintained behavior. The reduction of nicotine self-administration and reinstatement by PPAR-α agonists was most likely due to these drugs' ability to prevent nicotine-induced excitation of dopaminergic transmission in reward-related areas of the brain. Specifically, PPAR-α agonists prevented nicotine-induced increases in firing rate and burst firing in dopamine neurons in the VTA, and they prevented nicotine-induced (but not cocaine-induced) elevations of dopamine levels in the shell of the nucleus accumbens. These potentially therapeutic behavioral, electrophysiological, and neurochemical effects of PPAR-α agonists were reversed by the PPAR-α antagonist MK886, verifying that they were indeed due to PPAR-α activation.
