Blockade of nicotine reward and reinstatement by activation of alpha-type peroxisome proliferator-activated receptors - PubMed (original) (raw)

. 2011 Apr 1;69(7):633-41.

doi: 10.1016/j.biopsych.2010.07.009.

Marco Pistis, Zuzana Justinova, Leigh V Panlilio, Antonio Luchicchi, Salvatore Lecca, Maria Scherma, Walter Fratta, Paola Fadda, Chanel Barnes, Godfrey H Redhi, Sevil Yasar, Bernard Le Foll, Gianluigi Tanda, Daniele Piomelli, Steven R Goldberg

Affiliations

Blockade of nicotine reward and reinstatement by activation of alpha-type peroxisome proliferator-activated receptors

Paola Mascia et al. Biol Psychiatry. 2011.

Abstract

Background: Recent findings indicate that inhibitors of fatty acid amide hydrolase (FAAH) counteract the rewarding effects of nicotine in rats. Inhibition of FAAH increases levels of several endogenous substances in the brain, including the endocannabinoid anandamide and the noncannabinoid fatty acid ethanolamides oleoylethanolamide (OEA) and palmitoylethanolamide, which are ligands for alpha-type peroxisome proliferator-activated nuclear receptors (PPAR-α). Here, we evaluated whether directly acting PPAR-α agonists can modulate reward-related effects of nicotine.

Methods: We combined behavioral, neurochemical, and electrophysiological approaches to evaluate effects of the PPAR-α agonists [[4-Chloro-6-[(2,3-dimethylphenyl)amino]-2-pyrimidinyl]thio]acetic acid (WY14643) and methyl oleoylethanolamide (methOEA; a long-lasting form of OEA) on 1) nicotine self-administration in rats and squirrel monkeys; 2) reinstatement of nicotine-seeking behavior in rats and monkeys; 3) nicotine discrimination in rats; 4) nicotine-induced electrophysiological activity of ventral tegmental area dopamine neurons in anesthetized rats; and 5) nicotine-induced elevation of dopamine levels in the nucleus accumbens shell of freely moving rats.

Results: The PPAR-α agonists dose-dependently decreased nicotine self-administration and nicotine-induced reinstatement in rats and monkeys but did not alter food- or cocaine-reinforced operant behavior or the interoceptive effects of nicotine. The PPAR-α agonists also dose-dependently decreased nicotine-induced excitation of dopamine neurons in the ventral tegmental area and nicotine-induced elevations of dopamine levels in the nucleus accumbens shell of rats. The ability of WY14643 and methOEA to counteract the behavioral, electrophysiological, and neurochemical effects of nicotine was reversed by the PPAR-α antagonist 1-[(4-Chlorophenyl)methyl]-3-[(1,1-dimethylethyl)thio]-a,a-dimethyl-5-(1-methylethyl)-1H-Indole-2-propanoic acid (MK886).

Conclusions: These findings indicate that PPAR-α might provide a valuable new target for antismoking medications.

Published by Elsevier Inc.

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Figures

Figure 1

Figure 1

The PPAR-α agonists WY14643 (20 and 40 mg/kg) and methOEA (10 mg/kg) reduced nicotine self-administration in rats. PPAR-α agonists were given i.p. 20 minute (WY14643) or 40 min (methOEA) before three consecutive sessions in which rats self-administered nicotine (0.01 or 0.03 mg/kg/injection) under a FR5 schedule. (A) Average rate of injection over three test sessions, compared to average of three sessions of vehicle treatment. (B) Rates of nicotine self-administration during individual sessions under baseline conditions (sessions 1-3), after treatment with 40 mg/kg WY14643 (sessions 4-6), and after return to baseline conditions (sessions 7-9). N=6 for rats at the 0.01 mg/kg/injection nicotine dose; n=12 for rats at the 0.03 mg/kg/injection nicotine dose, except for methOEA, where n=5. Asterisks indicate a significant difference from vehicle treatment. Data are represented as group means ± SEM.

Figure 2

Figure 2

The PPAR-α agonists WY14643 (10, 20 and 40 mg/kg i.m., 20 min before session for 5 consecutive sessions) and methOEA (10 mg/kg i.m., 40 min before session) significantly reduced the rate of nicotine injections self-administered by squirrel monkeys under a FR10 schedule at a nicotine dose of 30 μg/kg/injection. The effects of WY14643 (20 mg/kg) were reversed by pretreatment with the PPAR-α antagonist MK866 (1 mg/kg i.m., 45 min before session), which had no significant effect when given alone. (A) Average rate of injection over five test sessions, compared to average of five sessions of vehicle treatment. (B, D) Rates of nicotine self-administration during individual sessions under baseline conditions (sessions 1-3), after treatment with 40 mg/kg WY14643 (sessions 4-8) or 10 mg/kg methOEA, and after return to baseline conditions (sessions 9-11). (C) WY14643 (20 or 40 mg/kg i.m., 20 min before session) did not alter the number of 30 μg/kg cocaine injections self administered or the number of food pellets obtained under an identical FR10 schedule in squirrel monkeys. N=3 for monkeys under all conditions except food reinforcement, where n=4. Asterisks indicate a significant difference from vehicle treatment. Data are represented as group means ± SEM.

Figure 3

Figure 3

The PPAR-α agonist WY14643 blocked reinstatement of nicotine self-administration after a period of abstinence in rats and monkeys. (A) In rats, WY14643 (20 mg/kg i.p, n=11; and 40 mg/kg i.p., n=15) dose-dependently reduced the reinstatement of extinguished nicotine-seeking responses produced by a priming injection of nicotine. (B) In squirrel monkeys, WY14643 (20 or 40 mg/kg i.m., 20 min before the session) dose-dependently reduced the reinstatement of extinguished nicotine-seeking responses produced by a priming injection of nicotine (0.1 mg/kg i.v.) before the session (n=3). This effect of WY14643 was prevented by pretreatment with the PPAR-α antagonist MK886 (1 mg/kg i.m., 45 min before session). Data are presented as group means ± SEM. Asterisks indicate a significant difference from vehicle pretreatment during a saline prime session. # signs represent a significant difference from vehicle pretreatment during a nicotine prime session. Diamond represents a significant difference from inactive-hole responding during a saline prime session.

Figure 4

Figure 4

The PPAR-α agonist WY14643 (40 mg/kg i.p., 20 min before session) did not alter the interoceptive effects of nicotine or the rate of food-maintained lever-pressing under a nicotine drug discrimination procedure in rats (n=12). When given alone or in combination with any dose of nicotine (0.01 to 0.4 mg/kg s.c.), WY14643 did not significantly affect the percentage of responses on the nicotine-appropriate lever (A) or the rate of lever responding (B). Data are presented as group means ± SEM.

Figure 5

Figure 5

PPAR-α agonists inhibited nicotine-induced activation of VTA dopamine neurons in anesthetized rats. Histograms show the stimulatory effects of nicotine (Nic, 0.2 mg/kg i.v., n=7) on discharge activity of an individual VTA dopamine neuron in a representative rat and the actions of PPAR-α agonists (A, C). Line graphs show the time course of nicotine's effects. WY14643 (40 mg/kg, i.p. injected ∼30 min before the start of recordings, n=7) significantly blocked nicotine-induced increases in firing rate (A) and burst firing (B). MK886 (3 mg/kg injected ∼45 min before the start of recordings, n=5) significantly abolished the effects produced by WY14643 (A, B). MethOEA (5 and 10 mg/kg i.v. injected 4 min before nicotine, n=7 both) mimicked the effects of WY14643, significantly blocking nicotine-induced increases in firing rate (C) and burst firing (D). Results are presented as mean ± SEM of firing rates and burst firing, expressed as percentages of or differences from baseline values, respectively. Note that data for vehicle in panel a are repeated in panel c, and that data for vehicle in panel b are repeated in panel d. Arrows indicate time of drug injections. The following treatments significantly reduced the effects of nicotine on firing rate (p's<.05, Dunnett's post-hoc comparisons): WY14643 40 mg/kg, methOEA 5 mg/kg, and methOEA 10 mg/kg. Burst firing was significantly reduced by WY14643 20 and 40 mg/kg, and by methOEA 5 and 10 mg/kg. Both firing rate and burst firing differed when WY14643 40 mg/kg was given with vs. without MK886 (p's<.05).

Figure 6

Figure 6

PPAR-α agonists inhibited nicotine-induced elevations in dopamine levels in the nucleus accumbens shell of freely-moving rats. Pre-treatment with WY14643 (20 and 40 mg/kg i.p., n=5 both) or methOEA (10 mg/kg i.p., n=5) but not their vehicle (n=5 both), given 20 and 40 min, respectively, before nicotine (0.4 mg/kg s.c., n=6), significantly reduced the increase in extracellular dopamine levels produced by nicotine (A, B). The PPAR-α antagonist MK886 (3 mg/kg i.p.) injected 20 min before 40 mg/kg WY14643 (n=6) or 10 mg/kg methOEA (n=6) completely reversed the reduction of nicotine-induced elevations in dopamine levels produced by WY14643 (40 mg/kg i.p.) and methOEA (10 mg/kg i.p.) (C, D). The following treatments significantly reduced the effects of nicotine (Tukey post-hoc comparisons): WY14643 20 mg/kg, (p<.05); WY14643 40 mg/kg, (p<.001; methOEA 10 mg/kg (p<.001). MK886 (3 mg/kg i.p., n=4) had no significant effect when given with the vehicle of WY14643 and saline (C), and methOEA (10 mg/kg i.p, n=4) had no significant effect when given with the vehicles of MK886 and saline (D). The following treatments significantly reduced the effects of nicotine (Tukey post-hoc comparisons): WY14643 20 mg/kg, (p<.05); WY14643 40 mg/kg, (p<.001; methOEA 10 mg/kg (p<.001). WY14643 (40 mg/kg i.p., n=5) injected 20 min before cocaine (3 mg/kg i.p.; n=5) did not significantly alter the effects of cocaine (E). Note that data for vehicle + nicotine and for WY14643 + nicotine in panel a are repeated in panel c, and that data for vehicle + nicotine and for methOEA + nicotine in panel b are repeated in panel d. Arrows indicate time of drug or vehicle injection. Results are presented as group means ± SEM, expressed as percent of basal values.

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