Nicotinic mechanisms involved in the dopamine activating and reinforcing properties of ethanol

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Abstract

Ethanol shares with all major dependence producing drugs the ability to activate brain mesocorticolimbic dopamine neurons, an important part of the brain reward systems. This dopamine activation may be involved in mediating the positive reinforcing effects of ethanol. The mechanisms of action of ethanol in its activation of this dopamine system remain, however, to be elucidated. A selective pharmacological interference with these mechanisms may offer a possibility to reduce the reinforcing properties of ethanol without simultaneously interfering with the reinforcing properties of natural rewards. Ethanol has been shown to directly influence the function of various ligand-gated ion-channels. Several of these are located on or nearby mesocorticolimbic dopamine neurons. One such receptor is the nicotinic acetylcholine receptor (nAChR). The present article reviews a series of investigations aimed at investigating whether nAChRs are involved in the dopamine activating and reinforcing properties of ethanol. To this end acute and chronic behavioral and neurochemical experiments were performed in mice and rats. The results obtained indicate that central nAChRs in the ventral tegmental area are involved in mediating the mesolimbic dopamine activating and reinforcing effects of ethanol. Furthermore, the ethanol-induced activation of these receptors is probably indirect, subsequent to a primary interference of ethanol in the nucleus accumbens. Moreover, subchronic nicotine treatment enhances the reinforcing and dopamine activating properties of ethanol. This long-term effect may, however, derive from autonomic adaptations in response to intermittent blockade of peripheral nAChRs (rather than from intermittent stimulation of central receptors), and appears to be associated with development of a disinhibitory behavior that could involve also other neurotransmittors, e.g. serotonin. Taken together, these findings could provide a neurobiological explanation to the often observed co-abuse of nicotine and ethanol in man. Furthermore, since the behavioral models applied previously have predicted therapeutic drug effects in the clinic, the results suggest that selective blockade of the ventral tegmental nAChRs that are involved in the above effects may provide a new pharmacological alternative in the treatment of alcoholism.

Section snippets

Alcohol abuse and the community

Alcohol abuse is common and alcohol dependence may afflict as many as 10% of the adult population. This abuse is associated with a multitude of medical, social and legal complications to the alcoholic as well as to the family, relatives and friends of the alcoholic. These complications interact in a complex manner and result in a considerably shortened life-span of the alcoholic. The annual total cost to the Swedish community associated with alcohol abuse was recently estimated to about 100

Brain reward systems

The original discovery by Olds and Milner [73] that experimental animals will engage in self-stimulatory behavior if provided with electrodes in discrete brain regions made clear that there are specific regions in the brain that, if activated, will promote a repetitive approach behavior also at the expense of other important or necessary behaviors, such as food or water intake or sexual behavior. The brain regions along which electrical self-stimulatory behavior can be established have

Drugs of abuse and the mesocorticolimbic dopamine system

Another line of research has, since the discovery of the monoamines in the central nervous system, investigated whether different psychoactive drugs, among them dependence producing compounds such as opiates and psychostimulants (amphetamine and cocaine), interfere with these neurotransmitters. In the late 1970s it was suggested that two common denominators for dependence producing drugs (opiates, psychostimulants and ethanol) are that they at least in some doses increase locomotor activity in

Ethanol and ligand-gated ion-channels

While the primary mechanism(s) of action of, e.g. the psychostimulants, opiates and nicotine in their mesolimbic dopamine activating properties are fairly well-established that of ethanol remains to be elucidated. Identification of this mechanism(s) of action of ethanol could theoretically allow a selective blockade of ethanol’s mesolimbic dopamine activating and reinforcing properties without simultaneously interfering with mechanisms involved in mediating motivation and positive reinforcement

Ethanol and nicotine, clinical findings

Apart from the general common sense observation that there is a linkage between the intake of ethanol and nicotine, several clinical studies have demonstrated that this is indeed the case. For example, alcoholism is ten times more common among smokers than non-smokers, and there appears to be a strong correlation between early smoking debut and subsequent alcohol dependence [24], or dependence to other drugs of abuse [57]. Moreover, more than 90% of alcoholics are also smokers [10], [22], [92].

Ethanol, nicotinic receptors and the mesolimbic dopamine system

Given the above circumstances it was hypothesized that ethanol produces its mesolimbic dopamine activating effects via a primary interference with central nAChRs located on the cell-bodies and/or the neuronal terminals of the mesolimbic dopamine neurons and experiments were designed to challenge this hypothesis.

First the interaction between various doses of ethanol and nicotine was studied with respect to effects on locomotor activity in mice. Ethanol-induced locomotor stimulation in the mouse

Ethanol and nicotine, animal findings related to reinforcement

The functional, behavioral correlate to the dialysis findings was tested by means of a free-choice two-bottle test. In this model Wistar rats are screened with regard to their ethanol preference in a free-choice situation between ethanol 6% v/v and water. For the initial studies both ethanol high-preferring animals (over 60% of their daily fluid intake taken as ethanol 6% v/v) and low-preferring animals were selected (less than 20% of their daily fluid intake taken as ethanol 6% v/v). These

Ethanol and central nAChRs

Based on early studies performed on peripheral nAChRs and on the fact that central nAChRs are structurally similar to other ligand-gated ion-channels we originally hypothesized (see above), that ethanol would ‘directly’ interact also with central nAChRs.

Indeed, one of us had previously reported that chronic ethanol treatment alters the Bmax of ex vivo 3H-nicotine binding in some rat brain areas [102]. Also Booker and Collins [11] have observed enhancements of 3H-nicotine binding after chronic

Nicotine and ethanol, chronic effects

As mentioned above some studies indicate that an early smoking debut predisposes to future alcoholism (for references, see above). It could be argued that this is an association that is due merely to a general vulnerability to develop dependence and/or to, e.g. socioeconomic, demographic or psychological factors. However, the possibility remains that nicotine, being a powerful neurospsychoactive agent, when taken on a chronic basis produces neuronal alterations that will increase the propensity

Concluding remarks

The present series of investigations suggest that the dopamine-activating and reinforcing effects of ethanol involve activation of ventral tegmental nAChRs and that subchronic exposure to nicotine may enhance both these effects of ethanol. Surprisingly, this latter enhancement may, however, derive from an intermittent blockade of peripheral nAChRs and subsequent autonomic adaptations in response to this, rather than from an intermittent stimulation of central nAChRs. Moreover, this latter

Acknowledgements

These studies were financially supported by grants from the Swedish Medical Research Council (no 11583 and no 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 (104)

  • P.W. Kalivas et al.

    Dopamine transmission in the initiation and expression of drug- and stress-induced sensitization of motor activity

    Brain Res. Rev.

    (1991)
  • G.F. Koob

    Drugs of abuse: anatomy, pharmacology and function of reward pathways

    TiPS

    (1992)
  • C. Ksir et al.

    Nicotine exposure enhances behavioral stimulant effect and increases [3H]acetylcholine binding to nicotinic receptors

    Neuropharmacology

    (1985)
  • D. LeMarquand et al.

    Serotonin and alcohol intake, abuse, and dependence: clinical evidence

    Biol. Psychiatry

    (1994)
  • R. Nadal et al.

    Operant self-administration after nicotine treatment and withdrawal

    Alcohol

    (1999)
  • A. Nordberg et al.

    Relations between muscimol, quinuclidinyl benzilate and nicotine binding sites in brain after very long treatment with ethanol in rats

    Eur. J. Pharmacol.

    (1985)
  • A.D. Potthoff et al.

    Ethanol intake increases during continuous administration of amphetamine and nicotine, but not several other drugs

    Pharmacol. Biochem. Behav.

    (1983)
  • M.S. Reid et al.

    A nicotine antagonist, mecamylamine, reduces cue-induced cocaine craving in cocaine-dependent subjects

    Neuropsychopharmacology

    (1999)
  • T.E. Robinson et al.

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

    Brain Res. Rev.

    (1993)
  • G.J. Schaefer et al.

    Interactions between alcohol and nicotine on intracranial self-stimulation and locomotor activity in rats

    Drug Alcohol Depend.

    (1992)
  • M.K. Ticku et al.

    Ethanol enhances GABA-induced 36Cl-influx in primary spinal cord cultured neurons

    Brain Res. Bull.

    (1986)
  • W.P. Watson et al.

    Prolonged effects of chronic ethanol treatment on reponses to repeated nicotine administration: interactions with environmental cues

    Neuropharmacology

    (1999)
  • X. Yang et al.

    Action of ethanol on responses to nicotine from cerebellar Purkinje neurons: relationship to methyllycaconitine (MLA) inhibition of nicotine responses

    Neurochem. Int.

    (1999)
  • A.M. Allan et al.

    Ethanol and barbiturates enhance GABA-stimulated influx of 36Cl in isolated brain membranes

    Pharmacologist

    (1985)
  • M.E.M. Benwell et al.

    Evidence that smoking increases the density of nicotine binding sites in human brain

    J. Neurochem.

    (1988)
  • Berglund M. Neuroleptikabehandling av missbrukare. In: The Swedish Council on Technology Assessment in Health Care...
  • Blomqvist O. Ethanol and central nicotine acetylcholine receptors: a behavioral and neurochemical study in rodents....
  • J.B. Burch et al.

    Chronic ethanol or nicotine treatment results in partial cross-tolerance between these agents

    Psychopharmacology (Berl.)

    (1988)
  • R.A. Cardoso et al.

    Effects of ethanol on recombinant human neuronal nicotinic acetylcholine receptors expressed in Xenopus oocytes

    J. Pharmacol. Exp. Ther.

    (1999)
  • A. Carlsson et al.

    Inhibition of ethanol-induced excitation in mice and rats by α-methyl-p-tyrosine

    Psychopharmacologia (Berl.)

    (1972)
  • A.C. Collins et al.

    Modulation of nicotine receptors by chronic exposure to nicotinic agonists and antagonists

  • J. Cott et al.

    Suppression of ethanol-induced locomotor stimulation by GABA-like drugs

    Naunyn-Schmied Arch. Pharmacol.

    (1976)
  • T.J. Craig et al.

    The association of smoking and drinking habits in a community sample

    J. Stud. Alcohol

    (1977)
  • H.E. Criswell et al.

    Molecular basis for regionally specific action of ethanol on γ-aminobutyric acidA receptores: generalization to other ligan-gated ion channels

    J. Pharmacol. Exp. Ther.

    (1993)
  • A. Dahlström et al.

    Evidence for the existence of monoamine-containing neurons in the central nervous system. I. Demonstration of monoamines in the cell bodies of brain stem neurons

    Acta Physiol. Scand.

    (1964)
  • C.M. de Fiebre et al.

    Effects of ethanol on neuronal nicotinic receptors expressed in Xenopus oocytes

    Soc. Neurosci. Abstr.

    (1995)
  • K.F. Dreher et al.

    Smoking habits of alcohol outpatients

    Int. J. Addict.

    (1967)
  • G. Di Chiara et al.

    Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats

    Proc. Natl. Acad. Sci. USA

    (1988)
  • J.R. DiFranza et al.

    Alcoholism and smoking

    J. Stud. Alcohol

    (1990)
  • J.P. Dilger et al.

    Effects of ethanol on ACh receptor channels

    Biophys. J.

    (1994)
  • W. Dyr et al.

    Involvement of nicotinic acetylcholine receptors in the regulation of alcohol drinking in Wistar rats

    Alcohol Alcohol.

    (1999)
  • E.F. El-Fakahany et al.

    Alcohol modulation of drug binding to the channel sites of the nicotinic acetylcholine receptor

    J. Pharm. Exp. Ther.

    (1983)
  • A.C. Engblom et al.

    Effect of ethanol on gamma-aminobutyric acid and glycine receptor-coupled Cl fluxes in rat brain synaptoneurosomes

    J. Neurochem.

    (1991)
  • Engel JA. Neurochemical aspects of the euphoria induced by dependence-producing drugs. In: Excerpta Medica...
  • J.A. Engel et al.

    Catecholamines and behaviour

  • J.A. Engel et al.

    Serotonergic and dopaminergic involvement in ethanol intake

  • J.A. Engel et al.

    Biochemical and behavioural evidence for an interaction between ethanol and calcium channel antagonists

    J. Neural. Transm.

    (1988)
  • J.A. Engel et al.

    The involvement of different central neurotransmitters in mediating stimulatory and sedative effects of ethanol

  • J. Engel et al.

    Suppression by α-methyl-p-tyrosine of ethanol-induced locomotor stimulation: partial reversal by l-DOPA

    Psychopharmacologia (Berl.)

    (1974)
  • M. Ericson et al.

    Ethanol increases accumbal dopamine levels via indirect activation of ventral tegmental nicotinic acetylcholine receptors

    Nord. J. Psychiatry

    (1999)
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