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

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Distinct Effects of Nalmefene on Dopamine Uptake Rates and Kappa Opioid Receptor Activity in the Nucleus Accumbens Following Chronic Intermittent Ethanol Exposure International Journal of Molecular Sciences Article Distinct Effects of Nalmefene on Dopamine Uptake Rates and Kappa Opioid Receptor Activity in the Nucleus Accumbens Following Chronic Intermittent Ethanol Exposure Jamie H. Rose 1, Anushree N. Karkhanis 1, Björn Steiniger-Brach 2 and Sara R. Jones 1,* 1 Department of Physiology and Pharmacology Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; [email protected] (J.H.R.); [email protected] (A.N.K.) 2 H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark; [email protected] * Correspondence: [email protected]; Tel.: +1-336-716-8533; Fax: +1-336-716-8501 Academic Editor: Ashok K. Singh Received: 31 May 2016; Accepted: 22 July 2016; Published: 27 July 2016 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. Keywords: C57BL/6; mouse; voltammetry; release; partial agonist; dynorphin; dopamine; alcohol 1. Introduction Chronic alcohol use disorders are an enormous economic and financial burden in the United States [1]. A large body of literature has shown that chronic alcohol exposure down-regulates dopamine transmission in the nucleus accumbens (NAc) mice: [2]; rats: [3,4]; humans: [5,6], potentially leading to the negative affective states experienced during withdrawal [7,8]. It is plausible that attenuated dopamine neurotransmission following chronic ethanol exposure and withdrawal may be driven, at least in part, by increased function of inhibitory receptors on dopamine terminals in the NAc [2,9–11]. The dynorphin/Kappa opioid receptor (KOR) system is of particular interest due to its involvement in modulating ethanol drinking behaviors. For example, prodynorphin knockout mice showed lower preference for ethanol and consumed lower amounts of ethanol compared to wild-type mice [12]. Furthermore, multiple studies have shown increases in NAc KOR function following chronic ethanol exposure [9,10,13,14]. In fact, augmented NAc KOR function may mediate CIE-induced Int. J. Mol. Sci. 2016, 17, 1216; doi:10.3390/ijms17081216 www.mdpi.com/journal/ijms Int. J. J. Mol. Mol. Sci. Sci. 20162016,, 1717,, 1216 1216 2 of 13 CIE-induced reductions in dopamine terminal function and increased ethanol consumption followingreductions extended in dopamine ethanol terminal exposure function and and withdr increasedawal ethanol [15,16]. consumption Furthermore, following intra-NAc extended KOR blockadeethanol exposure reduces and relapse-like withdrawal drinking [15,16]. Furthermore,behavior in intra-NAcrodents [16]. KOR These blockade data reduces suggest relapse-like that the dynorphin/KORdrinking behavior system in rodents may be [16 a]. promising These data pharmaco suggesttherapeutic that the dynorphin/KOR target to reduce systemrelapse maydrinking be a inpromising patients pharmacotherapeuticwith alcohol dependence. target to reduce relapse drinking in patients with alcohol dependence. Nalmefene (6-methylene naltrexone) is a pharma pharmacotherapeuticcotherapeutic agent approved in the European Union to to combat combat heavy heavy alcohol alcohol drinking drinking in at-risk in at-risk patients patients [17] [(2517] February (25 February 2013). 2013). Preclinical Preclinical work workshowed showed that intra-NAc that intra-NAc infusions infusions of nalmefene of nalmefene reduced reduced ethanol ethanol intake intake at atlower lower doses doses in ethanol-dependent ethanol ethanol self-adminis self-administeringtering rats rats than than in innon-dependen non-dependentt animals animals [16], [ 16an], effect an effect that wasthat wascredited credited to the to thepartial partial agonist agonist activity activity and and high high affinity affinity of of nalmefene nalmefene at at KORs KORs [16,18]. [16,18]. Despite Despite this behavioral evidence, the the effects of nalmefenenalmefene on dopamine terminal and NAc KOR function following chronic ethanol exposure exposure are are poorly understood, and and elucidation of of its its effects may aid in understanding thethe basisbasis of of its its clinical clinic efficacy.al efficacy. To thisTo this end, end, ex vivo ex fastvivo scan fast cyclic scan voltammetrycyclic voltammetry (FSCV) was(FSCV) used was to used evaluate to evaluate the effects the ofeffects nalmefene of nalmef onene dopamine on dopamine transmission transmission and KOR and function KOR function in the inNAc the core, NAc 72 core, h following 72 h following five weeks fiveof weeks chronic of intermittentchronic intermittent ethanol (CIE)ethanol exposure, (CIE) exposure, in male C57BL/6 in male C57BL/6(C57) mice. (C57) mice. 2. Results Results 2.1. CIE Exposure Reduced Dopamine Transmission inin thethe NAcNAc CoreCore We maintained BECsBECs atat behaviorallybehaviorally andand physiologicallyphysiologically relevantrelevant levelslevels (219.50(219.50˘ ± 39.31 mg/dL), as per [[19].19]. Representative Representative FSCV FSCV traces traces are are overlaid overlaid in in Figure Figure 11AA (Air:(Air: blueblue trace;trace; CIE: redred trace).trace). Consistent with previous work from from our laborato laboratoryry [2,9] [2,9] CIE CIE reduced reduced dopamine dopamine release release (Figure (Figure 11B,B, t = 2.38 p < 0.05; Air: 1.06 ˘ 0.26 µM; CIE: 0.71 ˘ 0.40 µM) and increased rates of dopamine t18 = 2.38 p < 0.05; Air: 1.06 ± 0.26 µM; CIE: 0.71 ± 0.40 µM) and increased rates of dopamine uptake uptake (Figure1C, t = 3.80, p < 0.05; Air: 1.52 ˘ 0.32 µM/s; CIE: 2.46 ˘ 0.68 µM/s) compared to (Figure 1C, t17 = 3.80,17 p < 0.05; Air: 1.52 ± 0.32 µM/s; CIE: 2.46 ± 0.68 µM/s) compared to air-exposed controls.air-exposed controls. Figure 1. Chronic intermittent ethanol (CIE) exposure reduced dopamine release and increased Figure 1. Chronic intermittent ethanol (CIE) exposure reduced dopamine release and increased dopamine uptake in the nucleus accumbens (NAc) core. Representative FSCV traces are overlaid in dopamine uptake in the nucleus accumbens (NAc) core. Representative FSCV traces are overlaid (inA) ( A(Air:) (Air: blue blue trace; trace; CIE: CIE: red redtrace); trace); (B) CIE (B) CIEreduced reduced dopamine dopamine release release in brain in brain slices slices of the of NAc the from NAc CIE-exposedfrom CIE-exposed mice compared mice compared to air-exposed to air-exposed controls; controls; (C) CIE (C increased) CIE increased dopamine dopamine uptake uptake rates (V ratesmax) in brain slices from CIE-exposed mice compared to controls. * p < 0.05, ** p < 0.05 (CIE: chronic (Vmax) in brain slices from CIE-exposed mice compared to controls. * p < 0.05, ** p < 0.05 (CIE: chronic intermittent ethanol). 2.2. Nalmefene Slowed Dopamine Uptake Rates More in Brain Slices from CIE-Exposed Mice Than Controls To examineexamine thethe effectseffects of of nalmefene nalmefene on on dopamine dopamine release release and and uptake uptake following following ethanol ethanol vapor vapor and andair exposure, air exposure, increasing increasing concentrations concentrations of this of compound this compound were were bath-applied bath-applied to accumbal to accumbal brain slices.brain slices.A comparison A comparison of percent of change percent in dopaminechange in uptake dopamine rate showed uptake that rate nalmefene showed dose-dependently that nalmefene dose-dependently reduced uptake rates in both groups (Figure 2A, F4,8 = 5.29, p < 0.01), although this reduced uptake rates in both groups (Figure2A, F4,8 = 5.29, p < 0.01), although this effect was greater effect was greater in CIE exposed animals (F1,8 = 7.94, p < 0.05). No interaction between these factors in CIE exposed animals (F1,8 = 7.94, p < 0.05). No interaction between these factors was detected was detected (F4,8 = 5.40, p > 0.05). When the absolute values of dopamine uptake rates after (F4,8 = 5.40, p > 0.05). When the absolute values of dopamine uptake rates after application of nalmefene wereapplication compared of nalmefene across the were two co groups,mpared there across were the no two differences groups, there (Figure were2B). no Moreover, differences two-way (Figure 2B). Moreover, two-way RM ANOVA revealed a main effect of nalmefene concentration on Int. J. Mol. Sci. 2016, 17, 1216 3 of 13 dopamine release (Figure
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