The PPAR-α agonists WY14643 and methOEA significantly decreased ongoing nicotine self-administration in both rats (Fig. 1A: main effect of WY14643, F(1,11)=5.4, p<.05; main effect of session F(1,11)=41.8, p<.0001; for 0.01 mg/kg nicotine baseline, t-test, t5=5.019, p<.05; methOEA: t4=5.4, p<.006) and monkeys (WY14643 in Fig. 2A: interaction of WY14643 and session F(2,4)=8.25, p<.05; methOEA in Fig. 2A: t2=25.8, p<.01). At the most effective doses, self-administration behavior was decreased significantly throughout the course of PPAR-α agonist treatment (Fig. 1B: F(3,27)=7.99, p<.001; Fig. 2B: F(5,10)=11.04, p<.001; Fig 2D: F(5,10)=6.23, p<.007) and rapidly returned to higher levels when treatment was discontinued. In rats, response rates in the inactive hole occurred at a fairly constant percentage of response rates in the active hole regardless of pretreatment (mean percentage±SEM=26±5 under vehicle treatment, 21±3 under 20 mg/kg WY14643, and 27±9 under 40 mg/kg WY14643). The specificity of WY14643's effects was verified by giving the PPAR-α antagonist MK886 as a pretreatment in monkeys. MK886 reversed the decreases in nicotine self-administration produced by WY14643, but had no effect on nicotine self-administration when given alone. On the final day of
