When the PPAR-α agonist clofibrate was administered prior to daily sessions when rats were first allowed to self-administer nicotine, rats did not did not develop nicotine self-administration behavior (67). When nicotine self-administration was established in rats or monkeys before they were ever treated with the PPAR-α agonists WY1463 or clofibrate, these PPAR-α treatments decreased nicotine intake (67, 68); these effects were reversed by the PPAR-α antagonist MK886 (67, 68), which had no effect on nicotine self-administration on its own. As clearly indicated in Figure 2, the number of active lever presses by rats for nicotine was lower following pretreatment with clofibrate than following pretreatment with vehicle. Clofibrate did not affect pressing of an inactive lever that was used to detect possible non-specific changes in activity levels during acquisition of nicotine self-administration. Although clofibrate (67) and WY1463 (68) blocked the rewarding effects of nicotine, they did not block all of the interoceptive effects of nicotine (some of which may actually be aversive) in the nicotine drug-discrimination test. In sum, these studies suggest that PPAR-α agonists specifically reduce nicotine intake by interfering directly with nicotine’s rewarding/reinforcing pharmacological effects.
