Effects of fatty acid amide hydrolase inhibition on neuronal responses to nicotine, cocaine and morphine in the nucleus accumbens shell and ventral tegmental area: involvement of PPAR-alpha nuclear receptors.
The endocannabinoid system regulates neurotransmission in brain regions relevant to neurobiological and behavioral actions of addicting drugs. We recently demonstrated that inhibition by URB597 of fatty acid amide hydrolase (FAAH), the main enzyme that degrades the endogenous cannabinoid N-acylethanolamine (NAE) anandamide and the endogenous non-cannabinoid NAEs oleoylethanolamide and palmitoylethanolamide, blocks nicotine-induced excitation of ventral tegmental area (VTA) dopamine (DA) neurons and DA release in the shell of the nucleus accumbens (ShNAc), as well as nicotine-induced drug self-administration, conditioned place preference and relapse in rats. Here, we studied whether effects of FAAH inhibition on nicotine-induced changes in activity of VTA DA neurons were specific for nicotine or extended to two drugs of abuse acting through different mechanisms, cocaine and morphine. We also evaluated whether FAAH inhibition affects nicotine-, cocaine- or morphine-induced actions in the ShNAc. Experiments involved single-unit electrophysiological recordings from DA neurons in the VTA and medium spiny neurons in the ShNAc in anesthetized rats. We found that URB597 blocked effects of nicotine and cocaine in the ShNAc through activation of both surface cannabinoid CB1-receptors and alpha-type peroxisome proliferator-activated nuclear receptor. URB597 did not alter the effects of either cocaine or morphine on VTA DA neurons. These results show that the blockade of nicotine-induced excitation of VTA DA neurons, which we previously described, is selective for nicotine and indicate novel mechanisms recruited to regulate the effects of addicting drugs within the ShNAc of the brain reward system.
Luchicchi
Antonio
A
B.B. Brodie Department of Neuroscience, University of Cagliari, 09042 Monserrato (CA), Italy.
Lecca
Salvatore
S
Carta
Stefano
S
Pillolla
Giuliano
G
Muntoni
Anna L
AL
Yasar
Sevil
S
Goldberg
Steven R
SR
Pistis
Marco
M
D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002219:Carbamates / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D005071:Evoked Potentials / Q000187:drug effects; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects*; D009538:Nicotine / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000187:drug effects*; D047493:PPAR alpha / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects*; D012201:Reward; D017557:Ventral Tegmental Area / Q000187:drug effects*; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D001549:Benzamides; D002219:Carbamates; D003042:Cocaine; D004298:Dopamine; D009020:Morphine; D009538:Nicotine; D047493:PPAR alpha; D018160:Receptors, Cytoplasmic and Nuclear; D000099252:Fatty Acid Amide Hydrolases; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester