3 years ago

Fatty acid amide hydrolase (FAAH) inactivation confers enhanced sensitivity to nicotine-induced dopamine release in the mouse nucleus accumbens

Fatty acid amide hydrolase (FAAH) inactivation confers enhanced sensitivity to nicotine-induced dopamine release in the mouse nucleus accumbens
Benjamin F. Cravatt, Nimish Sidhpura, Ilham Polis, Antonia Serrano, David Stouffer, Loren H. Parsons, Fernando Rodriguez Fonseca, Francisco J. Pavon, Rémi Martin-Fardon
Nicotine exerts its rewarding effects by promoting an increase in dopamine (DA) release in the nucleus accumbens (NAc), and this process is influenced by the endocannabinoid system. Fatty acid amide hydrolase (FAAH) is the main enzyme responsible for the degradation of the endocannabinoid anandamide and other non-cannabinoid N-acylethanolamines. Previous research has reported that both genetic deletion and pharmacological inhibition of FAAH enhance nicotine-induced conditioned place preference at low doses. We conducted a microdialysis study to characterize nicotine-induced changes in DA and serotonin (5-HT) levels in the NAc of FAAH knockout (KO) mice using a conditioned place preference-like paradigm with three nicotine doses (0.1, 1 and 10 mg/kg, s.c.). Additionally, the effects of the selective FAAH inhibitor PF-3845 (10 mg/kg, i.p.) were also examined. Our data indicated that compared with wild-type mice, genetic deletion of FAAH selectively enhanced the effect of low-dose nicotine on DA release (p < 0.001) and resulted in a strong post-nicotine elevation in DA levels (p < 0.01). However, there were no differences between the genotypes at higher doses. Furthermore, FAAH KO mice displayed a moderate enhancement of the effect of low-dose nicotine on NAc 5-HT release (p < 0.05), with no differences between the genotypes at higher doses. Compared with vehicle-pretreated mice, mice pretreated with PF-3845 displayed an enhancement of the effect of low-dose nicotine on NAc DA release (p < 0.001), which resulted in a sustained increase in DA levels (p < 0.05). Similar to FAAH KO mice, PF-3845-pretreated mice displayed a moderate enhancement of the effect of low-dose nicotine on NAc 5-HT release (p < 0.01). These observations in mice suggest that enhanced nicotine-induced NAc DA release might contribute to increased sensitivity to the conditioned rewarding effects of low-dose nicotine following FAAH inhibition, which has been previously reported. Future studies combining behavioral and neurochemical approaches are needed to elucidate the precise mechanism of these effects. The present microdialysis study was designed to characterize nicotine-induced alterations in monoamine levels in the absence of fatty acid amide hydrolase (FAAH) activity in the mouse nucleus accumbens. Genetic deletion of FAAH enhanced the effect of low-dose nicotine (0.1 mg/kg) on dopamine and serotonin release but no differences between genotypes were found at higher doses (1 or 10 mg/kg). Similarly, FAAH inhibitor pretreatment (PF-3845) replicated the effects of low-dose nicotine on monoamine release observed in FAAH knockout mice.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/adb.12531

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