Abstract
The development of pharmacotherapeutics that reduce relapse to alcohol drinking in patients with alcohol dependence is of considerable research interest. Preclinical data support a role for nucleus accumbens (NAc) κ opioid receptors (KOR) in chronic intermittent ethanol (CIE) exposure-induced increases in ethanol intake. Nalmefene, a high-affinity KOR partial agonist, reduces drinking in at-risk patients and relapse drinking in rodents, potentially due to its effects on NAc KORs. However, the effects of nalmefene on accumbal dopamine transmission and KOR function are poorly understood. We investigated the effects of nalmefene on dopamine transmission and KORs using fast scan cyclic voltammetry in NAc brain slices from male C57BL/6J mice following five weeks of CIE or air exposure. Nalmefene concentration-dependently reduced dopamine release similarly in air and CIE groups, suggesting that dynorphin tone may not be present in brain slices. Further, nalmefene attenuated dopamine uptake rates to a greater extent in brain slices from CIE-exposed mice, suggesting that dopamine transporter-KOR interactions may be fundamentally altered following CIE. Additionally, nalmefene reversed the dopamine-decreasing effects of a maximal concentration of a KOR agonist selectively in brain slices of CIE-exposed mice. It is possible that nalmefene may attenuate withdrawal-induced increases in ethanol consumption by modulation of dopamine transmission through KORs.
Highlights
Chronic alcohol use disorders are an enormous economic and financial burden in the United States [1]
We investigated the effects of nalmefene on dopamine transmission and kappa receptors (KOR) using fast scan cyclic voltammetry in nucleus accumbens (NAc) brain slices from male C57BL/6J mice following five weeks of chronic intermittent ethanol (CIE) or air exposure
A Repeated measures (RM) two-way analysis of variance (ANOVA) revealed a main effect of KOR activation on dopamine release that was dose-dependent (Figure 3C, F3,10 = 31.69, p < 0.001), which was greater in brain slices from mice exposed to CIE (F1,10 = 6.26, p < 0.05)
Summary
Chronic alcohol use disorders are an enormous economic and financial burden in the United States [1]. KOR reductions extended in dopamine terminal function andwithdrawal increased ethanol following extended blockade reducesand relapse-like behavior in intra-NAc rodents [16]. KORs [16,18] Despite this behavioral evidence, evidence, the the effects of nalmefene on dopamine terminal and NAc KOR function following chronic ethanol ethanol exposure exposure are poorly understood, understood, and and elucidation elucidation of of its its effects may aid in understanding thebasis basisofofitsits clinical efficacy. Evidence, the the effects of nalmefene on dopamine terminal and NAc KOR function following chronic ethanol ethanol exposure exposure are poorly understood, understood, and and elucidation elucidation of of its its effects may aid in understanding thebasis basisofofitsits clinical efficacy To this ex fast vivoscan fastcyclic scan voltammetry cyclic voltammetry understanding the clinical efficacy.
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