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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 simplified representation of the sites of action for alcohol and alcohol metabolites on posterior ventral tegmental area dopamine neurons.
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Figure 2: A simplified representation of the sites of action for alcohol and alcohol metabolites on posterior ventral tegmental area dopamine neurons.

Mentions: Several studies have focused on the role of the projection from the VTA to the Acb in the neurobiological actions of EtOH as well as the metabolites of EtOH (see Figure 2). Specifically within the VTA, EtOH and ACD have been shown to activate DA neurons by significantly increasing their firing rate (Gessa et al., 1985; Brodie et al., 1990; Foddai et al., 2004), albeit through differing mechanisms (for review see: Deehan et al., 2013). Sequestering ACD formation through the direct infusion of D-penicillamine into the VTA inhibits DA neuronal activation by the intra-gastric administration of both EtOH and ACD (Enrico et al., 2009). Local application of an ADH (Foddai et al., 2004) or catalase inhibitor (Melis et al., 2007; Diana et al., 2008) in the VTA prevents EtOH stimulated increases in DA neuronal activity. These findings coupled with data from in vitro studies showing that ACD stimulates VTA DA neuronal activity at concentrations 1200–2000 fold lower than that required for EtOH suggest that ACD is critical component required for EtOH stimulated DA activity within the VTA (Brodie and Appel, 1998; Brodie et al., 1999; Diana et al., 2008). A recent paper has reported that SAL is also capable of stimulating VTA DA neuronal activity at concentrations 10-1,000 fold lower than the lowest effective concentration of ACD (Xie et al., 2012a).


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 simplified representation of the sites of action for alcohol and alcohol metabolites on posterior ventral tegmental area dopamine neurons.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: A simplified representation of the sites of action for alcohol and alcohol metabolites on posterior ventral tegmental area dopamine neurons.
Mentions: Several studies have focused on the role of the projection from the VTA to the Acb in the neurobiological actions of EtOH as well as the metabolites of EtOH (see Figure 2). Specifically within the VTA, EtOH and ACD have been shown to activate DA neurons by significantly increasing their firing rate (Gessa et al., 1985; Brodie et al., 1990; Foddai et al., 2004), albeit through differing mechanisms (for review see: Deehan et al., 2013). Sequestering ACD formation through the direct infusion of D-penicillamine into the VTA inhibits DA neuronal activation by the intra-gastric administration of both EtOH and ACD (Enrico et al., 2009). Local application of an ADH (Foddai et al., 2004) or catalase inhibitor (Melis et al., 2007; Diana et al., 2008) in the VTA prevents EtOH stimulated increases in DA neuronal activity. These findings coupled with data from in vitro studies showing that ACD stimulates VTA DA neuronal activity at concentrations 1200–2000 fold lower than that required for EtOH suggest that ACD is critical component required for EtOH stimulated DA activity within the VTA (Brodie and Appel, 1998; Brodie et al., 1999; Diana et al., 2008). A recent paper has reported that SAL is also capable of stimulating VTA DA neuronal activity at concentrations 10-1,000 fold lower than the lowest effective concentration of ACD (Xie et al., 2012a).

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