The effect of the fenofibrate on the acquisition and reinstatement of ethanol-induced conditioned place preference in mice

Introduction: Alcohol is a psychoactive substance with dependence-producing properties that has been widely used in many cultures for centuries. In the present study, we examined the effect of the fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARα) agonist on the acquisition and reinstatement of ethanol-induced conditioned place preference (CPP) in mice. Methods: Before the CPP I procedure, animals received a single injection of ethanol (2g/kg, 20% v/v, intraperitoneally [i.p.]) for 8 days. The ethanol-induced CPP was developed by four injections of ethanol (2 g/kg, 20% v/v, i.p.) every other day. Control rats received saline instead of ethanol. Fenofibrate (100 or 150 mg/kg, i.p.) were administered before ethanol during conditioning or before the reinstatement of ethanol-induced CPP. In the extinction phase, all animals received normal saline (i.p.) to wash out the effect of ethanol in I CPP I phase. In final experiment, animals received ethanol or ethanol + Fenofibrate (100 or 150 mg/kg, i.p.) similar to CPP I phase. Then effect of Fenofibrate on reinstatement of ethanol-induced CPP was evaluated. Result: Fenofibrate (100 or 150 mg/kg, i.p.) significantly reversed the establishment of ethanol-induced CPPs and effectively attenuated reinstatement of conditioned rewarding effects of ethanol. Discussion: It is known that fenofibrate can enhance the catalase activity three times, and consequently increase the level of acetaldehyde by 10%. This effect of fenofibrate is similar to that of disulfiram, which increases the level of acetaldehyde with an unpleasant effect on the consumer which leads to a 60-70% inhibition of voluntary alcohol intake. In another study, Mascia et al. found that the administration of PPARα agonists (WY14643 and methOEA) inhibited the self-administration of nicotine in mice and monkeys, and when the treatment was discontinued animals return to their highest level of consumption. The administration of these drugs also inhibited the reinstatement of nicotine in animals recurring with nicotine. Mechanistic studies showed that PPARα agonists inhibited the release of dopamine in the ventral tegmental area and increased it in the nucleus acumens. Given that these effects were reversed in the co-administration of the PPARα antagonist (MK886), they concluded that these effects are due to the activation of the PPARα receptor. Since PPARα agonists have been identified as anti-inflammatory agents because of their ability to inhibit transcription factors such as NF-κB which led to reducing alcohol consumption and tendency in mice, it was hypothesized that the effect of fenofibrate in reducing consumption and the desire for ethanol may be related to its anti-inflammatory effects. Fenofibrate can modulate the expression of various genes in the prefrontal and amygdala cortex, which has previously been proven to be involved in alcoholism. The other alternate supportive hypothesis suggesting the possibility of involvement of GABA, a primary inhibitory neurotransmitter in the brain, which plays a vital role in many of ethanol pharmacological and behavioral effects. It was proved that chronic alcohol consumption results in significant downregulation of GABAergic and increased alcohol consumption. Fenofibrate reverses the attenuation of GABAergic neurotransmission induced by alcohol consumption in the amygdala which leads to reduced ethanol drinking. It has been well established that the mesolimbic dopamine system dysregulation plays an important role in alcoholism. It seems the activation of the PPARα receptor by fenofibrate regulates the activity of dopaminergic neurons by the negative regulation of β2-nAChRs which reduces the activity of dopamine neurons. Integrating the facts altogether, the attenuated ethanol preference in fenofibrate -treated mice could be reasonably linked to PPARα-associated mechanisms, anti-inflammatory effects, and modulation of mesolimbic dopamine transmission.

کلیدواژه ها:

Addition ، Alcohol ، Fenofibrate ، Conditioned place preference