Distinct Effects of Nalmefene on Dopamine Uptake Rates and Kappa Opioid Receptor Activity in the Nucleus Accumbens Following Chronic Intermittent Ethanol Exposure

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.

Simultaneous wireless and high-resolution detection of nucleus accumbens shell ethanol concentrations and free motion of rats upon voluntary ethanol intake

“…Moreover, these devices appear particularly promising for implantation in other brain areas for the real-time managing of tissue ethanol concentrations and behavior that could be of great interest, particularly in studies devoted to characterizing the relationship between ethanol-induced motor activity (S anchez-Catal an et al, 2009), reward (Ikemoto, 2010), and motivation (Camarini et al, 2010). In addition, given the critical role of dopamine transmission in the AcbSh in motivated behaviors, the application of this technology might also be combined with the real-time detection of ethanol-induced dopamine release (Imperato & Di Chiara, 1986) by means of ultra microsensors and fast-scan cyclic voltammetry (Rose, Karkhanis, Steiniger-Brach, & Jones, 2016).…”

Chronic intermittent ethanol exposure selectively increases synaptic excitability in the ventral domain of the rat hippocampus

“…Moreover, similar CIE effects on anxiety measures have been shown with other behavioral tests. For example, following CIE, C57 mice exhibit an escalation in marble burying, a behavior indicative of an anxiogenic state (Pleil et al, 2015;J. Rose et al, 2016).…”

Crosstalk Between Kappa Opioid and Dopamine Systems in Compulsive Behaviors

“…Nevertheless, the effect of KOR activation on dopamine uptake has yet not been not fully elucidated. The systemic administration of the KOR partial agonist nalmefene decreased striatal dopamine uptake dose dependently, quantified by fast scan cyclic voltammetry (FSCV) (Rose et al, 2016). Using a nonet flux microdialysis in adult male rats, blocking of KOR was accompanied by an increase in extraction fraction (Ed), which is an indirect measure of dopamine uptake Azocar et al, 2019), suggesting that tonic activation of KOR exerts an inhibitory control on DAT activity (dopamine uptake).…”