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