In alcohol-treated rats, naloxone decreases extracellular dopamine and increases acetylcholine in the nucleus accumbens: evidence of opioid withdrawal

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Abstract

Withdrawal from ethanol is aversive. The question is why. As with the withdrawal from morphine, nicotine, diazepam and sugar, the ethanol withdrawal state may involve an increase in nucleus accumbens (NAc) acetylcholine (ACh) causing an alteration of the dopamine (DA)–ACh balance in favor of ACh. Therefore the effects of acute and chronic alcohol (1 gm/kg/day i.p.) treatment on extracellular concentrations of NAc ACh and DA were determined before and after naloxone-precipitated withdrawal. Ethanol initially increased DA to 119% of baseline as measured by microdialysis. This was still the case on the 21st day of ethanol injection when DA increased to 126%. There was no effect of ethanol on ACh. However, naloxone (3 mg/kg s.c.) injected the next day decreased extracellular DA to 83% of baseline and caused a significant rise in ACh to 119%. This state of high ACh combined with low DA may contribute to the aversive aspects of alcohol 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.

References (58)

  • A. Imperato et al.

    Rapid increase in basal acetylcholine release in the hippocampus of freely moving rats induced by withdrawal from long-term ethanol intoxication

    Brain Res.

    (1998)
  • K. Kiianmaa et al.

    Effect of ethanol on extracellular dopamine in the nucleus accumbens of alcohol-preferring AA and alcohol-avoiding ANA rats

    Pharmacol. Biochem. Behav.

    (1995)
  • G.F. Koob et al.

    Drug addiction, dysregulation of reward, and allostasis

    Neuropsychopharmacology

    (2001)
  • N. Lindefors et al.

    Amphetamine regulation of acetylcholine and gamma-aminobutyric acid in nucleus accumbens

    Neuroscience

    (1992)
  • G.P. Mark et al.

    Cholinergic activity in the nucleus-accumbens may be inversely related to food-intake

    Appetite

    (1992)
  • G.P. Mark et al.

    Extracellular acetylcholine is increased in the nucleus accumbens following the presentation of an aversively conditioned taste stimulus

    Brain Res.

    (1995)
  • C.P. O'Brien et al.

    Naltrexone in the treatment of alcoholism: a clinical review

    Alcohol

    (1996)
  • T.P. Piepponen et al.

    Effects of ethanol on the accumbal output of dopamine, GABA and glutamate in alcohol-tolerant and alcohol-nontolerant rats

    Pharmacol. Biochem. Behav.

    (2002)
  • P.V. Rada et al.

    Aversive hypothalamic stimulation releases acetylcholine in the nucleus accumbens, and stimulation-escape decreases it

    Brain Res.

    (2001)
  • P. Rada et al.

    Microdialysis evidence that acetylcholine in the nucleus accumbens is involved in morphine withdrawal and its treatment with clonidine

    Brain Res.

    (1991)
  • P.V. Rada et al.

    Morphine and naloxone, IP or locally, affect extracellular acetylcholine in the nucleus accumbens and prefrontal cortex

    Pharmacol. Biochem. Behav.

    (1996)
  • H.H. Samson et al.

    Effects of d-amphetamine injected into the nucleus accumbens on ethanol reinforced behavior

    Brain Res. Bull.

    (1991)
  • H.H. Samson et al.

    Effects of dopamine agonists and antagonists on ethanol-reinforced behavior

    Brain Res. Bull.

    (1993)
  • K.M. Wozniak et al.

    Focal application of alcohols elevates extracellular dopamine in rat brain: a microdialysis study

    Brain Res.

    (1991)
  • H.J. Yim et al.

    Ethanol-induced increase in dopamine extracellular concentration in rat nucleus accumbens are accounted for by increased release and not uptake inhibition

    Alcohol

    (2000)
  • V. Bassareo et al.

    Non psychostimulant drugs of abuse and anxiogenic drugs activate with differential selectivity dopamine transmission in the nucleus accumbens and in the medial prefrontal cortex of the rat

    Psychopharmacology

    (1996)
  • R.E. Blackburn et al.

    Acute effects of alcohol on ingestive behavior in rats

    Alcohol., Clin. Exp. Res.

    (1994)
  • M.S. Brodie et al.

    Ethanol directly excites dopaminergic ventral tegmental area reward neurons

    Alcohol., Clin. Exp. Res.

    (1999)
  • C. Colantuoni et al.

    Evidence that intermittent, excessive sugar intake causes endogenous opioid dependence

    Obes. Res.

    (2002)
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