Endogenous fatty acid ethanolamides suppress nicotine-induced activation of mesolimbic dopamine neurons through nuclear receptors

Miriam Melis, Giuliano Pillolla, Antonio Luchicchi, Anna Lisa Muntoni, Sevil Yasar, Steven R. Goldberg, Marco Pistis

Research output: Contribution to journalArticle

Abstract

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-α (PPAR-α), a nuclear receptor transcription factor involved in several aspects of lipid metabolism and energy balance. Activation of PPAR-α 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-α in the brain and provide a potential new target for the treatment of nicotine addiction.

Original languageEnglish (US)
Pages (from-to)13985-13994
Number of pages10
JournalJournal of Neuroscience
Volume28
Issue number51
DOIs
StatePublished - Dec 17 2008

Fingerprint

Dopaminergic Neurons
Endocannabinoids
Cytoplasmic and Nuclear Receptors
Nicotine
Fatty Acids
Peroxisome Proliferator-Activated Receptors
Lipids
Cannabinoid Receptors
Ventral Tegmental Area
Nicotinic Receptors
Tobacco Use
Street Drugs
Lipid Metabolism
Protein-Tyrosine Kinases
Dopamine
Hydrolysis
Transcription Factors
Phosphorylation
Pharmacology
Ligands

Keywords

  • Dopamine neurons
  • Electrophysiology
  • Endocannabinoids
  • Fatty acid amide hydrolase
  • Nicotine
  • Patch clamp
  • Peroxisome proliferator-activated receptor

ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)

Cite this

Endogenous fatty acid ethanolamides suppress nicotine-induced activation of mesolimbic dopamine neurons through nuclear receptors. / Melis, Miriam; Pillolla, Giuliano; Luchicchi, Antonio; Muntoni, Anna Lisa; Yasar, Sevil; Goldberg, Steven R.; Pistis, Marco.

In: Journal of Neuroscience, Vol. 28, No. 51, 17.12.2008, p. 13985-13994.

Research output: Contribution to journalArticle

Melis, Miriam ; Pillolla, Giuliano ; Luchicchi, Antonio ; Muntoni, Anna Lisa ; Yasar, Sevil ; Goldberg, Steven R. ; Pistis, Marco. / Endogenous fatty acid ethanolamides suppress nicotine-induced activation of mesolimbic dopamine neurons through nuclear receptors. In: Journal of Neuroscience. 2008 ; Vol. 28, No. 51. pp. 13985-13994.
@article{6f4bce0d36594e859483cb62435200e6,
title = "Endogenous fatty acid ethanolamides suppress nicotine-induced activation of mesolimbic dopamine neurons through nuclear receptors",
abstract = "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-α (PPAR-α), a nuclear receptor transcription factor involved in several aspects of lipid metabolism and energy balance. Activation of PPAR-α 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-α in the brain and provide a potential new target for the treatment of nicotine addiction.",
keywords = "Dopamine neurons, Electrophysiology, Endocannabinoids, Fatty acid amide hydrolase, Nicotine, Patch clamp, Peroxisome proliferator-activated receptor",
author = "Miriam Melis and Giuliano Pillolla and Antonio Luchicchi and Muntoni, {Anna Lisa} and Sevil Yasar and Goldberg, {Steven R.} and Marco Pistis",
year = "2008",
month = "12",
day = "17",
doi = "10.1523/JNEUROSCI.3221-08.2008",
language = "English (US)",
volume = "28",
pages = "13985--13994",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "51",

}

TY - JOUR

T1 - Endogenous fatty acid ethanolamides suppress nicotine-induced activation of mesolimbic dopamine neurons through nuclear receptors

AU - Melis, Miriam

AU - Pillolla, Giuliano

AU - Luchicchi, Antonio

AU - Muntoni, Anna Lisa

AU - Yasar, Sevil

AU - Goldberg, Steven R.

AU - Pistis, Marco

PY - 2008/12/17

Y1 - 2008/12/17

N2 - 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-α (PPAR-α), a nuclear receptor transcription factor involved in several aspects of lipid metabolism and energy balance. Activation of PPAR-α 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-α in the brain and provide a potential new target for the treatment of nicotine addiction.

AB - 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-α (PPAR-α), a nuclear receptor transcription factor involved in several aspects of lipid metabolism and energy balance. Activation of PPAR-α 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-α in the brain and provide a potential new target for the treatment of nicotine addiction.

KW - Dopamine neurons

KW - Electrophysiology

KW - Endocannabinoids

KW - Fatty acid amide hydrolase

KW - Nicotine

KW - Patch clamp

KW - Peroxisome proliferator-activated receptor

UR - http://www.scopus.com/inward/record.url?scp=58149392527&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=58149392527&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.3221-08.2008

DO - 10.1523/JNEUROSCI.3221-08.2008

M3 - Article

C2 - 19091987

AN - SCOPUS:58149392527

VL - 28

SP - 13985

EP - 13994

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 51

ER -