UFR2709, a Nicotinic Acetylcholine Receptor Antagonist, Decreases Ethanol Intake in Alcohol-Preferring Rats

Abstract

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.

Nicotinic Antagonist UFR2709 Inhibits Nicotine Reward and Decreases Anxiety in Zebrafish

“…Thus, our results indicate that UFR2709 produces a blockade of the effects of nicotine. In addition, we have recently reported the ability of UFR2709 to decrease ethanol intake in alcohol-preferring rats [40]. Therefore, our current and previous results indicate that this compound might serve to counteract the effects of a relatively wide spectra of addictive compounds and give further support to the notion that nAChR play a pivotal role in drug abuse [44].…”

“…Here, we report that both UFR2709 ( Figure 1), a nAChR antagonist that reduces ethanol intake in rats [40], and nicotine exert anxiolytic effects on zebrafish subjected to the novel tank diving test. Furthermore, we show that UFR2709 blocks the effect evoked by nicotine on the CPP paradigm and that both treatments differentially affect the levels of mRNA expression of α4 and α7 nACh receptor subunits in the brain of adult zebrafish.…”

“…The drugs were administered by submerging the fish in either a beaker or a test tank, depending on the experiment, with the dissolved drug at the corresponding concentration. Drug concentrations (50-100 mg/L) were chosen on the basis of literature data for nicotine or UFR2709 in behavioural [4,24], functional [47], or LogP assessments [40].…”

UFR2709, an Antagonist of Nicotinic Acetylcholine Receptors, Delays the Acquisition and Reduces Long-Term Ethanol Intake in Alcohol-Preferring UChB Bibulous Rats

“…It was demonstrated that different nicotinic ligands can reduce ethanol ingestion in animal models and humans. [ 16 , 17 , 18 , 19 , 20 , 21 ]. The reward system or mesocorticolimbic system projects dopamine neurons from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) and prefrontal cortex (PFC) [ 22 , 23 ].…”

“…Moreover, we recently demonstrated, using UChB rats, that UFR2709, a competitive nicotinic antagonist [ 59 ], reduces voluntary ethanol intake in a dose-dependent manner without affecting body weight or locomotor activity, and does not produce a DA release from the striatum under i.p. injection [ 20 ]. In this work, we studied the effect of UFR2709 administration in the acquisition and the maintenance of ethanol intake in UChB rats that were chronically exposed to ethanol consumption.…”