Peroxisome Proliferator-Activated Receptors-Alpha Modulate Dopamine Cell Activity Through Nicotinic Receptors

Melis, Miriam; Carta, Stefano Mariano; Fattore, Liana; Tolu, Stefania; Yaşar, Sevil; Goldberg, Steven R.; Fratta, Walter; Maskos, Uwe; Pistis, Marco

doi:10.1016/j.biopsych.2010.04.016

Cited by 82 publications

(90 citation statements)

References 54 publications

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“…This is presumably the mechanism by which PPARa activation blocks the dopaminergic effects of nicotine in the VTA and nucleus accumbens shell, which are believed to provide the primary basis for nicotine reward (Gotti et al, 2010;Corrigall et al, 1994;Lecca et al, 2006). This nicotineinduced dopaminergic signaling, and indeed the rewarding effects of nicotine in behavioral procedures, have been shown to be blocked by experimental drugs that activate PPARa directly (ie, the synthetic agonist WY14643, the endogenous ligands oleoylethanolamine and palmitoylethanolamide, and the longer-acting oleoylethanolamine derivative methyl oleoylethanolamine; Melis et al, 2008Melis et al, , 2010Mascia et al, 2011) or indirectly (ie, the fatty-acid amide hydrolase inhibitor URB597; Melis et al, 2008;Scherma et al, 2008;Forget et al, 2009;Luchicchi et al, 2010). The electrophysiology, microdialysis, and behavioral experiments of this study extend these findings to the fibrate class of medications.…”

Section: Discussionmentioning

confidence: 99%

Novel Use of a Lipid-Lowering Fibrate Medication to Prevent Nicotine Reward and Relapse: Preclinical Findings

Panlilio

Justinová

Mascia

et al. 2012

Neuropsychopharmacol

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Experimental drugs that activate a-type peroxisome proliferator-activated receptors (PPARa) have recently been shown to reduce the rewarding effects of nicotine in animals, but these drugs have not been approved for human use. The fibrates are a class of PPARa-activating medications that are widely prescribed to improve lipid profiles and prevent cardiovascular disease, but these drugs have not been tested in animal models of nicotine reward. Here, we examine the effects of clofibrate, a representative of the fibrate class, on reward-related behavioral, electrophysiological, and neurochemical effects of nicotine in rats and squirrel monkeys. Clofibrate prevented the acquisition of nicotine-taking behavior in naive animals, substantially decreased nicotine taking in experienced animals, and counteracted the relapse-inducing effects of re-exposure to nicotine or nicotine-associated cues after a period of abstinence. In the central nervous system, clofibrate blocked nicotine's effects on neuronal firing in the ventral tegmental area and on dopamine release in the nucleus accumbens shell. All of these results suggest that fibrate medications might promote smoking cessation. The fact that fibrates are already approved for human use could expedite clinical trials and subsequent implementation of fibrates as a treatment for tobacco dependence, especially in smokers with abnormal lipid profiles.

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Section: Discussionmentioning

confidence: 99%

Novel Use of a Lipid-Lowering Fibrate Medication to Prevent Nicotine Reward and Relapse: Preclinical Findings

Panlilio

Justinová

Mascia

et al. 2012

Neuropsychopharmacol

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“…PPAR a activation by OEA and other agonists reduces nicotine SA, prevents nicotine-induced increases in VTA DA cell burst firing, and attenuates nicotine-induced increases in NAc DA release (Mascia et al, 2010(Mascia et al, , 2011Melis et al, 2008). PPAR a receptors can exert tonic inhibition of DA cell activity, as their antagonism increases the spontaneous firing rate of VTA DA neurons (Melis et al, 2010). Accordingly, deficient OEA tone may contribute to enhanced spontaneous firing and burst activity of VTA DA cells that is more pronounced following a history of nicotine SA vs YA (Caille et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

“…Accordingly, deficient OEA tone may contribute to enhanced spontaneous firing and burst activity of VTA DA cells that is more pronounced following a history of nicotine SA vs YA (Caille et al, 2009). The PPAR a influence on VTA DA cell activity likely occurs through a negative modulation of a 4 b 2 -nACh receptor expression or function (Melis et al, 2010), and it is conceivable that reduced PPAR a activation resulting from deficient OEA tone contributes to enhanced VTA a 4 b 2 -nACh receptor expression that is more pronounced following nicotine SA vs YA (Metaxas et al, 2010). Although nicotine SA produced subtle nonsignificant elevations in dialysate OEA content, this was not sufficient to restore OEA to levels observed in nicotine-naïve controls.…”

Section: Discussionmentioning

confidence: 99%

The Volitional Nature of Nicotine Exposure Alters Anandamide and Oleoylethanolamide Levels in the Ventral Tegmental Area

Buczynski

Polis

Parsons

2012

Neuropsychopharmacol

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Cannabinoid-1 receptors (CB 1 ) have an important role in nicotine reward and their function is disrupted by chronic nicotine exposure, suggesting nicotine-induced alterations in endocannabinoid (eCB) signaling. However, the effects of nicotine on brain eCB levels have not been rigorously evaluated. Volitional intake of nicotine produces physiological and behavioral effects distinct from forced drug administration, although the mechanisms underlying these effects are not known. This study compared the effects of volitional nicotine self-administration (SA) and forced nicotine exposure (yoked administration (YA)) on levels of eCBs and related neuroactive lipids in the ventral tegmental area (VTA) and other brain regions. Brain lipid levels were indexed both by in vivo microdialysis in the VTA and lipid extractions from brain tissues. Nicotine SA, but not YA, reduced baseline VTA dialysate oleoylethanolamide (OEA) levels relative to nicotine-naïve controls, and increased anandamide (AEA) release during nicotine intake. In contrast, all nicotine exposure paradigms increased VTA dialysate 2-arachidonoyl glycerol (2-AG) levels. Thus, nicotine differentially modulates brain lipid (2-AG, AEA, and OEA) signaling, and these modulations are influenced by the volitional nature of the drug exposure. Corresponding bulk tissue analysis failed to identify these lipid changes. Nicotine exposure had no effect on fatty acid amide hydrolase activity in the VTA, suggesting that changes in AEA and OEA signaling result from alterations in their nicotine-induced biosynthesis. Both CB 1 (by AEA and 2-AG) and non-CB 1 (by OEA) targets can alter the excitability and activity of the dopaminergic neurons in the VTA. Collectively, these findings implicate disrupted lipid signaling in the motivational effects of nicotine.

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“…Nonetheless, previous anatomical, biochemical and electrophysiological studies have provided compelling evidence that the N-acylethanolamine anandamide and the endogenous ligands to peroxisome-proliferatoractivated receptor-alpha (PPARa; i.e. oleoylethanolamide, OEA; palmitoylethanolamide, PEA), as well as the endocannabinoid/vanilloid N-arachidonoyldopamine (NADA) are also present within the VTA [31,34,[38][39][40][41][42][43], thus suggesting discrete physiological roles for each endocannabinoid and cognate molecule in the modulation of DA neuron and its related behaviour.…”

Section: Endocannabinoid Systemmentioning

confidence: 99%

“…Additionally, preclinical studies strongly suggest that PPARa could be an effective target for antismoking medication [39,[41][42][43]73,111,112]. Noteworthy, being PPARa-mediated actions directed at controlling either function and/or number of b2*-nAChRs, their effects are restricted to nicotine.…”

Section: Review Endocannabinoids and Dopamine Neurons M Melis And Mmentioning

confidence: 99%

Hub and switches: endocannabinoid signalling in midbrain dopamine neurons

Melis

Pistis

2012

Phil. Trans. R. Soc. B

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The last decade has provided a wealth of experimental data on the role played by lipids belonging to the endocannabinoid family in several facets of physiopathology of dopamine neurons. We currently suggest that these molecules, being intimately connected with diverse metabolic and signalling pathways, might differently affect various functions of dopamine neurons through activation not only of surface receptors, but also of nuclear receptors. It is now emerging how dopamine neurons can regulate their constituent biomolecules to compensate for changes in either internal functions or external conditions. Consequently, dopamine neurons use these lipid molecules as metabolic and homeostatic signal detectors, which can dynamically impact cell function and fitness. Because dysfunctions of the dopamine system underlie diverse neuropsychiatric disorders, including schizophrenia and drug addiction, the importance of better understanding the correlation between an unbalanced endocannabinoid signal and the dopamine system is even greater. Particularly, because dopamine neurons are critical in controlling incentive-motivated behaviours, the involvement of endocannabinoid molecules in fine-tuning dopamine cell activity opened new avenues in both understanding and treating drug addiction. Here, we review recent advances that have shed new light on the understanding of differential roles of endocannabinoids and their cognate molecules in the regulation of the reward circuit, and discuss their anti-addicting properties, particularly with a focus on their potential engagement in the prevention of relapse.

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Peroxisome Proliferator-Activated Receptors-Alpha Modulate Dopamine Cell Activity Through Nicotinic Receptors

Cited by 82 publications

References 54 publications

Novel Use of a Lipid-Lowering Fibrate Medication to Prevent Nicotine Reward and Relapse: Preclinical Findings

Novel Use of a Lipid-Lowering Fibrate Medication to Prevent Nicotine Reward and Relapse: Preclinical Findings

The Volitional Nature of Nicotine Exposure Alters Anandamide and Oleoylethanolamide Levels in the Ventral Tegmental Area

Hub and switches: endocannabinoid signalling in midbrain dopamine neurons

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