In alcohol-treated rats, naloxone decreases extracellular dopamine and increases acetylcholine in the nucleus accumbens: evidence of opioid withdrawal
Introduction
Dopamine (DA) agonists given locally in the nucleus accumbens (NAc) can increase ethanol (ETOH) intake (Samson et al., 1991, Hodge et al., 1992, Samson et al., 1993), suggesting that DA plays a role in alcohol consumption. Conversely, local injection of a dopamine antagonist into the NAc decreases ethanol-seeking behavior (Samson and Chappell, 2004). Ethanol, like most drugs of abuse, increases extracellular DA in the NAc of rats (Di Chiara and Imperato, 1988a, Di Chiara and Imperato, 1988b, Weiss et al., 1993, Bassareo et al., 1996, Lewis, 1996, Yim and Gonzales, 2000). Activation of the dopaminergic system by ETOH seems to be mediated in part by an endogenous opioid system. An opiate antagonist blocks the ethanol-induced increase in accumbens DA release (Acquas et al., 1993, Gonzales and Weiss, 1998), and naltrexone is used in the treatment of alcohol dependence (O'Brien et al., 1996). These findings suggest a major role of endogenous opioid systems in ETOH intake, due in part to interactions with the mesolimbic DA system.
Acetylcholine (ACh) in the NAc works in opposition to DA and can cause an aversive state (Rada and Hoebel, 2001). Extracellular accumbens ACh decreases following systemic or local NAc morphine and is released during naloxone-induced morphine withdrawal. This occurs in both morphine-dependent rats (Rada et al., 1991, Rada et al., 1996) and sugar-dependent rats (Colantuoni et al., 2002). Accumbens ACh is also released during flumazenil-induced withdrawal in diazepam dependence (Rada and Hoebel, 2003) and mecamylamine-induced withdrawal in nicotine dependence (Rada et al., 2001). This led to the hypothesis that ethanol withdrawal might also involve the DA/ACh imbalance. Even though withdrawal behavior is minimal in ethanol-treated rats, the neurochemical signs of the aversive state may be present. If naloxone induces opioid withdrawal in ethanol-treated rats, we hypothesize that a decrease in extracellular DA accompanied by release of ACh in the NAc should occur. An abstract of this study has been published (Rada and Hoebel, 2003).
Section snippets
Subjects and surgery
Male Sprague–Dawley rats (Taconic Farms, Germantown, NY) weighing 300–350 g were housed individually on a reversed 12:12-h light/dark schedule with rodent chow pellets and water available ad libitum. For surgeries, subjects were anesthetized with a combination of ketamine (100 mg/kg i.p.) and xylazine (10 mg/kg i.p.). Bilateral 21-gauge stainless-steel guide shafts were stereotaxically implanted for the posterior medial accumbens (shell) as follows: AP +1.2 mm, L 0.8 mm and V 4.0 mm, with
Basal extracellular levels do not change
Basal levels of DA, DOPAC, HVA and ACh are presented in Table 1. The values are not normalized and not corrected for probe recovery. Values did not differ significantly between groups or following chronic injection of ETOH.
Experiment 1: acute ETOH significantly increases accumbens DA without affecting ACh
An injection of ETOH significantly increased DA levels to 119±6.5% compared to 100±2% in saline-injected rats (F(6,48)=4.03, p<0.02, Fig. 1). This increase in DA was accompanied by a significant increase in both metabolites DOPAC and HVA (F(6,48)=5.509, p<0.01 and F
Discussion
Ethanol produced an increase in DA release on both the 1st day and 21st day of injection, confirming previous findings by others. The lack of tolerance to this important neurochemical effect of ETOH is in agreement with research involving different routes of alcohol administration (Di Chiara and Imperato, 1985, Imperato and Di Chiara, 1986, Fadda et al., 1989, Weiss et al., 1993, Bassareo et al., 1996, Yim and Gonzales, 2000) and in several different lines of alcohol-preferring rats (Kiianmaa
Acknowledgements
Supported by USPHS grants AA-12882, DA-10608 and the Minnie and Bernard Lane Foundation.
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