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Elucidating the biological basis for the reinforcing actions of alcohol in the mesolimbic dopamine system: the role of active metabolites of alcohol.

Deehan GA, Hauser SR, Wilden JA, Truitt WA, Rodd ZA - Front Behav Neurosci (2013)

Bottom Line: A limitation of the alcohol research field has been examining the effects of alcohol only and ignoring the multiple biological active metabolites of alcohol.The mesolimbic dopamine system originates in the ventral tegmental area (VTA) and projects to forebrain regions that include the nucleus accumbens (Acb) and the medial prefrontal cortex (mPFC) and is thought to be the neurocircuitry governing the rewarding properties of drugs of abuse.Within this neurocircuitry there is convincing evidence that; (1) biologically active metabolites of alcohol can directly or indirectly increase the activity of VTA dopamine neurons, (2) alcohol and alcohol metabolites are reinforcing within the mesolimbic dopamine system, (3) inhibiting the alcohol metabolic pathway inhibits the biological consequences of alcohol exposure, (4) alcohol consumption can be reduced by inhibiting/attenuating the alcohol metabolic pathway in the mesolimbic dopamine system, (5) alcohol metabolites can alter neurochemical levels within the mesolimbic dopamine system, and (6) alcohol interacts with alcohol metabolites to enhance the actions of both compounds.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, Institute of Psychiatric Research, Indiana University, School of Medicine Indianapolis, IN, USA.

ABSTRACT
The development of successful pharmacotherapeutics for the treatment of alcoholism is predicated upon understanding the biological action of alcohol. A limitation of the alcohol research field has been examining the effects of alcohol only and ignoring the multiple biological active metabolites of alcohol. The concept that alcohol is a "pro-drug" is not new. Alcohol is readily metabolized to acetaldehyde within the brain. Acetaldehyde is a highly reactive compound that forms a number of condensation products, including salsolinol and iso-salsolinol (acetaldehyde and dopamine). Recent experiments have established that numerous metabolites of alcohol have direct CNS action, and could, in part or whole, mediate the reinforcing actions of alcohol within the mesolimbic dopamine system. The mesolimbic dopamine system originates in the ventral tegmental area (VTA) and projects to forebrain regions that include the nucleus accumbens (Acb) and the medial prefrontal cortex (mPFC) and is thought to be the neurocircuitry governing the rewarding properties of drugs of abuse. Within this neurocircuitry there is convincing evidence that; (1) biologically active metabolites of alcohol can directly or indirectly increase the activity of VTA dopamine neurons, (2) alcohol and alcohol metabolites are reinforcing within the mesolimbic dopamine system, (3) inhibiting the alcohol metabolic pathway inhibits the biological consequences of alcohol exposure, (4) alcohol consumption can be reduced by inhibiting/attenuating the alcohol metabolic pathway in the mesolimbic dopamine system, (5) alcohol metabolites can alter neurochemical levels within the mesolimbic dopamine system, and (6) alcohol interacts with alcohol metabolites to enhance the actions of both compounds. The data indicate that there is a positive relationship between alcohol and alcohol metabolites in regulating the biological consequences of consuming alcohol and the potential of alcohol use escalating to alcoholism.

No MeSH data available.


Related in: MedlinePlus

A general schematic representation of the central (brain) and peripheral (body) metabolism pathways for alcohol and alcohol metabolites.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 1: A general schematic representation of the central (brain) and peripheral (body) metabolism pathways for alcohol and alcohol metabolites.

Mentions: Following consumption, EtOH undergoes a number of reactions as it is metabolized. The primary pathway through which EtOH is eliminated from the body involves the action of the alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) enzymes (for review see: Deehan et al., 2013). The action of ADH oxidizes EtOH which results in the formation of ACD which is subsequently eliminated/metabolized by ALDH into acetate and eliminated from the body (for schematic depiction of EtOH metabolism see Figure 1). Alterations in either class of enzyme have been shown to produce alterations in ACD levels. An increase in the formation of ACD has been found to lead to an increase in the aversive symptoms (i.e., flushing, nausea, etc.) associated with EtOH consumption thereby decreasing further motivation to consume EtOH (Peng and Yin, 2009). Genetic studies have identified genetic polymorphisms in both ADH and ALDH which have been linked to a decreased susceptibility to develop an EtOH-use disorder (Edenberg, 2011). For instance, a recent study reported that Mexican Americans expressing the ADH1B*2 genotype were protected against EtOH-dependence (Ehlers et al., 2012). Such protection, against EtOH-dependence, likely occurs through a more rapid oxidation of EtOH resulting in significantly higher levels of peripheral ACD (Hurley and Edenberg, 2012). Research has indicated that an alteration in the expression of the ALDH2 gene results in a slower oxidation of ACD to acetate thereby resulting in a “Disulfiram-like” experience due to greater ACD levels (Ball, 2008). Recent endeavors have identified a polygenic contribution of the ADH gene cluster suggesting a potential role for several of the ADH genes in the development of alcoholism (Frank et al., 2012).


Elucidating the biological basis for the reinforcing actions of alcohol in the mesolimbic dopamine system: the role of active metabolites of alcohol.

Deehan GA, Hauser SR, Wilden JA, Truitt WA, Rodd ZA - Front Behav Neurosci (2013)

A general schematic representation of the central (brain) and peripheral (body) metabolism pathways for alcohol and alcohol metabolites.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3750600&req=5

Figure 1: A general schematic representation of the central (brain) and peripheral (body) metabolism pathways for alcohol and alcohol metabolites.
Mentions: Following consumption, EtOH undergoes a number of reactions as it is metabolized. The primary pathway through which EtOH is eliminated from the body involves the action of the alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) enzymes (for review see: Deehan et al., 2013). The action of ADH oxidizes EtOH which results in the formation of ACD which is subsequently eliminated/metabolized by ALDH into acetate and eliminated from the body (for schematic depiction of EtOH metabolism see Figure 1). Alterations in either class of enzyme have been shown to produce alterations in ACD levels. An increase in the formation of ACD has been found to lead to an increase in the aversive symptoms (i.e., flushing, nausea, etc.) associated with EtOH consumption thereby decreasing further motivation to consume EtOH (Peng and Yin, 2009). Genetic studies have identified genetic polymorphisms in both ADH and ALDH which have been linked to a decreased susceptibility to develop an EtOH-use disorder (Edenberg, 2011). For instance, a recent study reported that Mexican Americans expressing the ADH1B*2 genotype were protected against EtOH-dependence (Ehlers et al., 2012). Such protection, against EtOH-dependence, likely occurs through a more rapid oxidation of EtOH resulting in significantly higher levels of peripheral ACD (Hurley and Edenberg, 2012). Research has indicated that an alteration in the expression of the ALDH2 gene results in a slower oxidation of ACD to acetate thereby resulting in a “Disulfiram-like” experience due to greater ACD levels (Ball, 2008). Recent endeavors have identified a polygenic contribution of the ADH gene cluster suggesting a potential role for several of the ADH genes in the development of alcoholism (Frank et al., 2012).

Bottom Line: A limitation of the alcohol research field has been examining the effects of alcohol only and ignoring the multiple biological active metabolites of alcohol.The mesolimbic dopamine system originates in the ventral tegmental area (VTA) and projects to forebrain regions that include the nucleus accumbens (Acb) and the medial prefrontal cortex (mPFC) and is thought to be the neurocircuitry governing the rewarding properties of drugs of abuse.Within this neurocircuitry there is convincing evidence that; (1) biologically active metabolites of alcohol can directly or indirectly increase the activity of VTA dopamine neurons, (2) alcohol and alcohol metabolites are reinforcing within the mesolimbic dopamine system, (3) inhibiting the alcohol metabolic pathway inhibits the biological consequences of alcohol exposure, (4) alcohol consumption can be reduced by inhibiting/attenuating the alcohol metabolic pathway in the mesolimbic dopamine system, (5) alcohol metabolites can alter neurochemical levels within the mesolimbic dopamine system, and (6) alcohol interacts with alcohol metabolites to enhance the actions of both compounds.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, Institute of Psychiatric Research, Indiana University, School of Medicine Indianapolis, IN, USA.

ABSTRACT
The development of successful pharmacotherapeutics for the treatment of alcoholism is predicated upon understanding the biological action of alcohol. A limitation of the alcohol research field has been examining the effects of alcohol only and ignoring the multiple biological active metabolites of alcohol. The concept that alcohol is a "pro-drug" is not new. Alcohol is readily metabolized to acetaldehyde within the brain. Acetaldehyde is a highly reactive compound that forms a number of condensation products, including salsolinol and iso-salsolinol (acetaldehyde and dopamine). Recent experiments have established that numerous metabolites of alcohol have direct CNS action, and could, in part or whole, mediate the reinforcing actions of alcohol within the mesolimbic dopamine system. The mesolimbic dopamine system originates in the ventral tegmental area (VTA) and projects to forebrain regions that include the nucleus accumbens (Acb) and the medial prefrontal cortex (mPFC) and is thought to be the neurocircuitry governing the rewarding properties of drugs of abuse. Within this neurocircuitry there is convincing evidence that; (1) biologically active metabolites of alcohol can directly or indirectly increase the activity of VTA dopamine neurons, (2) alcohol and alcohol metabolites are reinforcing within the mesolimbic dopamine system, (3) inhibiting the alcohol metabolic pathway inhibits the biological consequences of alcohol exposure, (4) alcohol consumption can be reduced by inhibiting/attenuating the alcohol metabolic pathway in the mesolimbic dopamine system, (5) alcohol metabolites can alter neurochemical levels within the mesolimbic dopamine system, and (6) alcohol interacts with alcohol metabolites to enhance the actions of both compounds. The data indicate that there is a positive relationship between alcohol and alcohol metabolites in regulating the biological consequences of consuming alcohol and the potential of alcohol use escalating to alcoholism.

No MeSH data available.


Related in: MedlinePlus