Voluntary ethanol intake in the rat and the associated accumbal dopamine overflow are blocked by ventral tegmental mecamylamine

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Abstract

The mesocorticolimbic dopamine system is believed to be involved in mediating the positive reinforcing effects of drugs of abuse, including ethanol. The nicotinic acetylcholine receptor antagonist mecamylamine perfused via reversed microdialysis in the ventral tegmental area antagonizes the increase of accumbal extracellular dopamine levels after systemic ethanol, and, after systemic injection, lowers ethanol intake in the rat. In the present study the effect of ventral tegmental mecamylamine on ethanol intake and preference, as well as on extracellular accumbal dopamine levels, was investigated in the same animal. To this end, in vivo microdialysis using a double probe approach (one in the nucleus accumbens and one in the ventral tegmental area) was combined with an ethanol preference model invoking a free choice between a bottle of water and a bottle of ethanol 6% (v/v) solution. Wistar rats drinking more than 60% of their total daily fluid intake from the ethanol solution (ethanol high-preferring animals) were selected during a screening period and used for the experiments. The animals received vehicle or mecamylamine (100 μM) in the ventral tegmental area and were then presented with a choice between water and ethanol in a limited access paradigm to which they previously had been adapted. On the next day the rats that received vehicle day 1 now received mecamylamine, and vice versa. When treated with vehicle, ethanol intake and preference were unaltered, as compared to baseline behavior, and accumbal dopamine levels increased significantly to approximately 130% of the pre-drug baseline level. When receiving mecamylamine, ethanol intake and preference were reduced markedly and dopamine levels were unaltered, as compared to pre-drug baseline levels. The present results further indicate that nicotinic acetylcholine receptors in the ventral tegmental area are involved in the positive reinforcing effects of ethanol. Thus, mecamylamine or other antagonists specifically aimed at ventral tegmental nicotinic acetylcholine receptors could represent a new pharmacological treatment principle against alcohol abuse, the efficacy of which should be explored in high-scale alcohol consumers or alcoholics.

Introduction

Ethanol, like other drugs of abuse, has repeatedly been demonstrated to activate the mesocorticolimbic dopamine system after systemic injections (Engel and Carlsson, 1977; Imperato and Di Chiara, 1986; Mereu et al., 1987; Koob, 1992; Blomqvist et al., 1993, Blomqvist et al., 1997). This dopamine pathway appears to be a crucial component of the so-called brain reward system, and its activation has been suggested to be important for the development of addictive behavior towards various drugs of abuse (Wise and Bozarth, 1987; Koob and Bloom, 1988; Robinson and Berridge, 1993).

Whereas several studies are available demonstrating activation of the mesocorticolimbic dopamine system in association with self-administration of psychostimulants in experimental animals, to our knowledge only one study has been presented addressing this issue in animals self-administering ethanol (Weiss et al., 1993). The first aim of the present study was therefore to examine whether voluntary oral ethanol intake in ethanol high-preferring Wistar rats choosing between ethanol and water consumption in a limited access free-choice paradigm is associated with increased accumbal dopamine levels, concomitantly measured by in vivo microdialysis.

The mechanisms of action for psychostimulants, opiates and nicotine in their activation of the mesocorticolimbic dopamine system are fairly well-established, whereas for ethanol it remains unknown. However, based on a series of investigations in mice and rats we have recently suggested that ethanol-induced activation of the mesocorticolimbic dopamine system involves central nicotinic acetylcholine receptors (Blomqvist et al., 1992, Blomqvist et al., 1993; Söderpalm et al., 1993; Johnson et al., 1995; Blomqvist et al., 1996, Blomqvist et al., 1997). The most important evidence for such an involvement is that ethanol-induced dopamine overflow in the rat nucleus accumbens is counteracted by systemic administration of mecamylamine, a blood brain barrier penetrating nicotinic acetylcholine receptor antagonist, but not by the peripheral nicotinic antagonist hexamethonium (Blomqvist et al., 1993, Blomqvist et al., 1997). Moreover, since local application of mecamylamine or hexamethonium into the ventral tegmental area, but not into the nucleus accumbens, prevents ethanol-induced dopamine overflow after systemic administration, ventral tegmental nicotinic acetylcholine receptors appear to be the most important in this respect (Blomqvist et al., 1997). That this interaction may be important also for ethanol reinforcement is illustrated by the finding that systemic mecamylamine, but not hexamethonium, reduces ethanol intake in ethanol high-preferring Wistar rats (Blomqvist et al., 1996).

The second part of the present study was aimed at determining in the same animal whether nicotinic receptor blockade in the ventral tegmental area by means of mecamylamine is associated with reduced voluntary ethanol intake and preference as well as a reduction of ethanol-induced accumbal dopamine overflow. This part of the study represents the first attempt to monitor neurochemical events believed to be associated with ethanol reward concomitantly with measuring the reinforced behavior and applying a treatment that is hypothesized to prevent it.

Section snippets

Animals

Male Wistar rats, about 100 days old, were supplied by Beekay (Stockholm, Sweden). Upon arrival in the laboratory, the animals were housed in groups of 5 per cage (55×35×20 cm3) at a constant cage temperature (25°C) and humidity (65%) for 2 weeks to adapt to the novel environment. The animals were kept under artificial light–dark conditions (light on at 0900 a.m. and off at 0900 p.m.) and had free access to `rat and mouse standard feed' (Beekay Feeds) and tap water.

Screening for ethanol preference

Rats had continuous access to

Methodological considerations

Approximately one third of the high-preferring animals was excluded from the study due to technical malfunctions (malfunctioning probes or misimplanted probes), or due to an inability to maintain ethanol high-preference (according to the above definition) after surgery. Thus, in order to collect the results from the number of animals reported in this study 150 animals were initially screened for ethanol preference.

Ethanol intake and preference

When subjected to a free-choice between ethanol and water in a limited access

Discussion

The present study demonstrates that ethanol intake in ethanol high-preferring Wistar rats in a limited access paradigm invoking a free choice between ethanol and water is associated with increased extracellular dopamine levels in the nucleus accumbens. This finding confirms that of Weiss et al. (1993), who reported that ethanol-reinforced lever-pressing behavior in the rat is associated with elevated accumbal dopamine levels. Furthermore, the present results extend these findings by showing

Acknowledgements

This study was financially supported by grants from the Swedish Medical Research Council (nos. 11583 and 4247), the Swedish Alcohol Monopoly Foundation for Alcohol Research, Swedish Society for Medical Research, Swedish Match, Orion Pharma neurology, Lundbecks Fond för Psykofarmakologisk Forskning, Wilhelm och Martina Lundgrens vetenskapsfond, Fredrik och Ingrid Thurings Stiftelse, Stiftelsen Sigurd och Elsa Goljes minne and National Institute on Drug Abuse Grant (IR 01 DA 10765-01A1).

References (37)

  • I. Panocka et al.

    Suppression of alcohol preference in rats induced by risperidone, a serotonin 5-HT2 and dopamine D2 receptor antagonist

    Brain Res. Bull.

    (1993)
  • T.S. Rao et al.

    Selective activation of dopaminergic pathways in the mesocortex by compounds that act at the phencyclidine (PCP) binding site: a tentative evidence for PCP recognition sites not coupled to N-methyl-d-aspartate (NMDA) receptors

    Neuropharmacology

    (1990)
  • S. Rassnick et al.

    The effects of 6-hydroxydopamine lesions of the nucleus accumbens and the mesolimbic dopamine system on oral self-administration of ethanol in the rat

    Brain Res.

    (1993)
  • T.E. Robinson et al.

    The neural basis of drug craving: an incentive-sensitization theory of addiction

    Brain Res. Rev.

    (1993)
  • N. Waters et al.

    The dopamine D3 receptor and autoreceptor preferring antagonists (+)-AJ76 and (+)-UH232; a microdialysis study

    Eur. J. Pharmacol.

    (1993)
  • W. Danysz et al.

    The involvement of NMDA receptors in acute and chronic effects of ethanol

    Alcohol. Clin. Exp. Res.

    (1992)
  • J.R. DiFranza et al.

    Alcoholism and smoking

    J. Stud. Alcohol

    (1990)
  • Engel, J.A., Carlsson, A., 1977. Catecholamines and behaviour. In: Valzelli, L., Essman, W.B. (Eds.), Current...
  • Cited by (0)

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