When relapse was modeled using a reinstatement procedure, the nicotine-seeking response (nose poking in rats, lever pressing in monkeys) was reinstated by a non-contingent priming injection of nicotine before the session (Fig. 3). WY14643 significantly reduced this reinstatement in rats (Fig. 3A: main effect of active vs. inactive nose-poking hole, F(1,14)=20.4, p<.0005; interaction of WY14643 dose and nicotine, F(2,13)=7.7, p<.01) and monkeys (Fig. 3B: 20 mg/kg WY14643: F(3,6)=15.4, p<.005; 40 mg/kg WY14643: F(3,6)=93.5, p<.001). WY14643 alone did not reinstate drug-seeking. In rats, nicotine also increased responding in the inactive hole, and WY14643 prevented this increase. However, it should be noted that responding in the active hole remained higher than the inactive hole under all testing conditions, indicating that the nicotine-induced increases in active-hole responding were due to reward rather than nonspecific increases in locomotor activity. Pretreatment of monkeys with the PPAR-α antagonist MK886 prevented the effects of WY14643 in this model of relapse, demonstrating the receptor-specificity of these effects (Fig. 3B).
