Blockade of Nicotine Reward and Reinstatement by Activation of Alpha-Type Peroxisome Proliferator-Activated Receptors

Mascia, Paola; Pistis, Marco; Justinová, Zuzana; Panlilio, Leigh V.; Luchicchi, Antonio; Lecca, Salvatore; Scherma, María; Fratta, Walter; Fadda, Paola; Barnes, Chanel; Redhi, Godfrey H.; Yaşar, Sevil; Foll, Bernard Le; Tanda, Gianluigi; Piomelli, Daniele; Goldberg, Steven R.

doi:10.1016/j.biopsych.2010.07.009

Cited by 109 publications

(119 citation statements)

References 41 publications

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“…Although OEA has no significant activity in the CB 1 receptors, it strongly activates peroxisome proliferator-activated receptor a (PPAR a ) signaling in vivo (Fu et al, 2003). 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).…”

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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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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“…We have shown that experimental drugs that activate PPARa block nicotine-induced firing of dopamine neurons in the VTA and nicotine-induced elevations of extracellular dopamine levels in the nucleus accumbens shell of rats, and that they decrease nicotine-seeking behavior in rats and monkeys (Melis et al, 2008Scherma et al, 2008;Forget et al, 2009;Luchicchi et al, 2010;Mascia et al, 2011). These preclinical findings suggest that PPARa could be an effective target for anti-smoking medications.…”

Section: Introductionmentioning

confidence: 90%

“…Completion of each five-response fixed ratio was treated by the computer as a virtual injection of nicotine, and the rat's virtual nicotine level was calculated continuously based on a clearance half-life of 55 min. The light was only presented when the virtual nicotine level was below 202 mg/kg, the mean level (calculated using the procedure of Panlilio et al, 2003) at which rats self-administered nicotine in a previous study (Mascia et al, 2011). To assess potential interactions between nicotine and clofibrate, half the rats were treated with nicotine (0.4 mg/kg, subcutaneous, 10 min before session) and half with saline before every food self-administration session.…”

Section: Food Self-administration In Ratsmentioning

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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“…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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Blockade of Nicotine Reward and Reinstatement by Activation of Alpha-Type Peroxisome Proliferator-Activated Receptors

Cited by 109 publications

References 41 publications

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

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

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

Hub and switches: endocannabinoid signalling in midbrain dopamine neurons

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