Background. Several studies have shown that the ethanol-derived metabolite salsolinol can activate the mesolimbic system, suggesting that salsolinol is the active molecule mediating the rewarding effects of ethanol. In vitro and in vivo studies suggest that salsolinol exerts its action on neuron excitability through a mechanism involving opioid neurotransmission. However, there is not direct pharmacologic evidence showing that salsolinol activates opioid receptors. Methods. The ability of racemic (R/S)-salsolinol, and its stereoisomers (R)-salsolinol and (S)-salsolinol, to activate the µ-opioid receptor was tested in cell-based (light-emitting) receptor assays. To further characterizing the interaction of salsolinol stereoisomers with the µ-opioid receptor, a molecular docking study was performed using the crystal structure of the µ-opioid receptor. Results. This study shows that salsolinol activates the µ-opioid receptor by the classical G protein-adenylate cyclase pathway with an EC50 of 2 x 10-5 M. The agonist action of salsolinol was fully blocked by the µ-opioid antagonist naltrexone. The EC50 for the purified stereoisomers (R)-salsolinol and (S)-salsolinol were 6 x 10-4 M and 9 x 10-6 M respectively. It was found that the action of racemic salsolinol on the µ-opioid receptor did not promote the recruitment of β-arrestin. Molecular docking studies showed that the interaction of (R)- and (S)-salsolinol with the µ-opioid receptor is similar to that predicted for the agonist morphine. Conclusions. It is shown that (R)-salsolinol and (S)-salsolinol are agonists of the µ-opioid receptor. (S)-salsolinol is a more potent agonist than the (R)-salsolinol stereoisomer. In silico analysis predicts a morphine-like interaction between (R)- and (S)-salsolinol with the µ-opioid receptor. These results suggest that an opioid action of salsolinol or its enantiomers is involved in the rewarding effects of ethanol.

Brain nicotinic acetylcholine receptors (nAChRs), a heterogeneous family of pentameric acetylcholine-gated cation channels, have been suggested as molecular targets for the treatment of alcohol abuse and dependence. Here, we examined the effect of the competitive nAChR antagonist UFR2709 on the alcohol consumption of high-alcohol-drinking UChB rats. UChB rats were given free access to ethanol for 24-h periods in a two-bottle free choice paradigm and their ethanol and water intake were measured. The animals were i.p. injected daily for 17 days with a 10, 5, 2.5, or 1 mg/kg dose of UFR2709. Potential confounding motor effects of UFR2709 were assessed by examining the locomotor activity of animals administered the highest dose of UR2709 tested (10 mg/kg i.p.). UFR2709 reduced ethanol consumption and ethanol preference and increased water consumption in a dose-dependent manner. The most effective dose of UFR2709 was 2.5 mg/kg, which induced a 56% reduction in alcohol consumption. Administration of UFR2709 did not affect the weight or locomotor activity of the rats, suggesting that its effects on alcohol consumption and preference were mediated by specific nAChRs.

Alcohol use disorder (AUD) is associated with dysregulation of glutamatergic and dopaminergic signaling within the nucleus accumbens (NAc), contributing to withdrawal syndrome, craving, and relapse. Fenofibrate, an agonist of the peroxisome proliferator-activated receptor alpha (PPARα), reduces alcohol intake; however, its effects on NAc neurotransmission and the relative contributions of central versus peripheral mechanisms remain unclear. Here, we investigated whether fenofibrate administration initiated during alcohol withdrawal and continued throughout reaccess reduces relapse drinking, and whether this effect involves normalization of glutamate and dopamine in the NAc. Fenofibrate treatment during withdrawal produced a sustained reduction in alcohol consumption throughout a 14-day relapse period in high-drinker female rats. This effect was abolished by systemic co-administration of the PPARα antagonist GW6471. Fenofibrate increased hepatic catalase activity and upregulated the glutamate transporter GLT-1 in the NAc, while dopamine transporter (DAT) protein levels remained unchanged. When GW6471 was administered intracerebroventricularly to block central PPARα activation selectively, the reduction in alcohol intake was only partially attenuated, indicating that approximately one-third of fenofibrate’s effect is centrally mediated, whereas two-thirds result from peripheral mechanisms. No-net-flux microdialysis showed that fenofibrate enhanced uptake rates for both glutamate and dopamine in the NAc. Steady-state extracellular glutamate levels were unchanged, whereas extracellular dopamine levels were significantly reduced, consistent with increased functional DAT activity. These findings demonstrate that fenofibrate reduces relapse-like alcohol consumption through a combination of peripheral and CNS PPARα-dependent mechanisms, restoring key aspects of glutamatergic and dopaminergic homeostasis in the NAc, highlighting PPARα activation as a promising therapeutic strategy for AUD.

Hyperpolarization-Activated Cyclic Nucleotide-Gated (HCN) ionic channels are known to play a key role in the control of neuron excitability and have been proposed as a molecular target of ethanol. ...