Endogenous fatty acid ethanolamides suppress nicotine-induced activation of mesolimbic dopamine neurons through nuclear receptors.
Nicotine stimulates the activity of mesolimbic dopamine neurons, which is believed to mediate the rewarding and addictive properties of tobacco use. Accumulating evidence suggests that the endocannabinoid system might play a major role in neuronal mechanisms underlying the rewarding properties of drugs of abuse, including nicotine. Here, we investigated the modulation of nicotine effects by the endocannabinoid system on dopamine neurons in the ventral tegmental area with electrophysiological techniques in vivo and in vitro. We discovered that pharmacological inhibition of fatty acid amide hydrolase (FAAH), the enzyme that catabolizes fatty acid ethanolamides, among which the endocannabinoid anandamide (AEA) is the best known, suppressed nicotine-induced excitation of dopamine cells. Importantly, this effect was mimicked by the administration of the FAAH substrates oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), but not methanandamide, the hydrolysis resistant analog of AEA. OEA and PEA are naturally occurring lipid signaling molecules structurally related to AEA, but devoid of affinity for cannabinoid receptors. They blocked the effects of nicotine by activation of the peroxisome proliferator-activated receptor-alpha (PPAR-alpha), a nuclear receptor transcription factor involved in several aspects of lipid metabolism and energy balance. Activation of PPAR-alpha triggered a nongenomic stimulation of tyrosine kinases, which might lead to phosphorylation and negative regulation of neuronal nicotinic acetylcholine receptors. These data indicate for the first time that the anorexic lipids OEA and PEA possess neuromodulatory properties as endogenous ligands of PPAR-alpha in the brain and provide a potential new target for the treatment of nicotine addiction.
Melis
Miriam
M
B. B. Brodie Department of Neuroscience, University of Cagliari, 09042 Monserrato, Italy.
Pillolla
Giuliano
G
Luchicchi
Antonio
A
Muntoni
Anna Lisa
AL
Yasar
Sevil
S
Goldberg
Steven R
SR
Pistis
Marco
M
D000577:Amides; D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001067:Appetite Depressants / Q000494:pharmacology; D001095:Arachidonic Acids / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D063387:Cannabinoid Receptor Antagonists; D002219:Carbamates / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D063388:Endocannabinoids; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004983:Ethanolamines; D007276:Injections, Intraventricular; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009538:Nicotine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D009829:Oleic Acids / Q000494:pharmacology; D009924:Organ Culture Techniques; D047493:PPAR alpha / Q000187:drug effects* / Q000378:metabolism; D010169:Palmitic Acids / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043882:Receptors, Cannabinoid / Q000378:metabolism; D000077285:Rimonabant; D017557:Ventral Tegmental Area / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000099252:Fatty Acid Amide Hydrolases
D000577:Amides; D000581:Amidohydrolases; D001067:Appetite Depressants; D001095:Arachidonic Acids; D001549:Benzamides; D063387:Cannabinoid Receptor Antagonists; D002219:Carbamates; D004298:Dopamine; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D004983:Ethanolamines; D016859:Lipoxygenase Inhibitors; D009538:Nicotine; D009829:Oleic Acids; D047493:PPAR alpha; D010169:Palmitic Acids; D010880:Piperidines; D011505:Protein-Tyrosine Kinases; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D000077285:Rimonabant; D000099252:Fatty Acid Amide Hydrolases; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C088155:methanandamide; C488250:oleoylethanolamide; C005958:palmidrol