In vivo interactions between α7 nicotinic acetylcholine receptor and nuclear peroxisome proliferator-activated receptor-α: Implication for nicotine dependence

Abstract

Chronic tobacco use dramatically increases health burdens and financial costs. Limitations of current smoking cessation therapies indicate the need for improved molecular targets. The main addictive component of tobacco, nicotine, exerts its dependency effects via nicotinic acetylcholine receptors (nAChRs). Activation of the homomeric α7 nAChR reduces nicotine's rewarding properties in conditioned place preference (CPP) test and i.v. self-administration models, but the mechanism underlying these effects is unknown. Recently, the nuclear receptor peroxisome proliferator-activated receptor type-α (PPARα) has been implicated as a downstream signaling target of the α7 nAChR in ventral tegmental area dopamine cells. The present study investigated PPARα as a possible mediator of the effect of α7 nAChR activation in nicotine dependence. Our results demonstrate the PPARα antagonist GW6471 blocks actions of the α7 nAChR agonist PNU282987 on nicotine reward in an unbiased CPP test in male ICR adult mice. These findings suggests that α7 nAChR activation attenuates nicotine CPP in a PPARα-dependent manner. To evaluate PPARα activation in nicotine dependence we used the selective and potent PPARα agonist, WY-14643 and the clinically used PPARα activator, fenofibrate, in nicotine CPP and we observed attenuation of nicotine preference, but fenofibrate was less potent. We also studied PPARα in nicotine dependence by evaluating its activation in nicotine withdrawal. WY-14643 reversed nicotine withdrawal signs whereas fenofibrate had modest efficacy. This suggests that PPARα plays a role in nicotine reward and withdrawal and that further studies are warranted to elucidate its function in mediating the effects of α7 nAChRs in nicotine dependence.

A Systems Biology Approach to Investigating Sex Differences in Cardiac Hypertrophy

“…In some studies, GW6471, a potent inhibitor of PPARα, was also given at 4 mg/kg per day. GW6471 has an IC 50 of 240 nmol/L and has been shown to function as an antagonist in mice within the range of 2 to 10 mg/kg per day . Following treatment, echocardiography was performed on the mice.…”

“…GW6471 has an IC 50 of 240 nmol/L and has been shown to function as an antagonist in mice within the range of 2 to 10 mg/kg per day. 21,22 Following treatment, echocardiography was performed on the mice. Mice were then anesthetized and euthanized.…”

Validation of Brain Angiotensin System Blockade as a Novel Drug Target in Pharmacological Treatment of Neuropsychiatric Disorders

“…It has recently been shown that full PPAR-γ agonists suppress alcohol drinking and relapse to alcohol seeking [198], while PPAR-α agonists dose-dependently decreased nicotine self-administration and nicotine-induced reinstatement in rats and monkeys [199]. This clearly indicates the involvement in nicotine reward and withdrawal [200]. Finally, several studies indicate that negative effects of stress-related neuropsychologic conditions, which are followed by accumulation of oxidative/nitrosative species and subsequent brain damage, are effectively reduced by anti-inflammatory PPAR-γ pathway stimulation [201,202].…”

Testing the PPAR hypothesis of tobacco use disorder in humans: A randomized trial of the impact of gemfibrozil (a partial PPARα agonist) in smokers

“…In humans, the dose of PPARα agonists that reach the brain is not yet known, which could explain the negative results of studies using the dose of medication indicated for lipid control. Recently, Jackson et al 2017 showed that the selective experimental PPAR α agonist WY14643 had better results than fenofibrate for nicotine seeking behavior in a conditioned place preference and nicotine self-administration tests in mice [ 48 ]. It is known that fibrates as ligands have low affinity to PPAR α receptors [ 49 ] and that the clinical available fibrates show moderate selectivity on PPAR receptors [ 50 ].…”