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

Abstract

Alcoholism is a worldwide public health problem with high economic cost and which affects health and social behavior. It is estimated that alcoholism kills 3 million people globally, while in Chile it is responsible for around 9 thousand deaths per year. Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels expressed in the central nervous system, and they were suggested to modulate the ethanol mechanism involved in abuse and dependence. Previous work demonstrated a short-term treatment with UFR2709, a nAChRs antagonist, which reduced ethanol intake using a two-bottle free-choice paradigm in University of Chile bibulous (UChB) rats. Here, we present evidence of the UFR2709 efficacy in reducing the acquisition and long-term ethanol consumption. Our results show that UFR2709 (2.5 mg/kg i.p.) reduces the seek behavior and ethanol intake, even when the drug administration was stopped, and induced a reduction in the overall ethanol intake by around 55%. Using naïve UChB bibulous rats, we demonstrate that UFR2709 could delay and reduce the genetically adaptive impulse to seek and drink ethanol and prevent its excessive intake.

Synthesis of Novel Neonicotinoids Derivatives

“…On the other hand, when an antagonistic ligand such as mecamylamine (Figure 2) binds to these receptors, the ion channel does not open, preventing the flow of ions across the membrane [17]. The action of these ligands on the nAChRs is associated to different functions and disorders in the CNS, such as memory, learning, anxiety [17], ethanol consumption [18], depression and addiction to drugs of abuse such as nicotine (Figure 2). In previous works, guided by the available information and the combination of the chemical structure of nicotine and acetylcholine, we designed and synthesized new NEOs derivatives with potential bioactivity on α4β2 nAChRs.…”