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Researchers at the Ernest Gallo Clinic and Research Center, University
of California-San Francisco, reported in the Journal ‘Cell’ in
June that the brain chemical messenger dopamine and ethanol act
through independent mechanisms to synergistically produce a common
cellular response that sustains voluntary alcohol consumption.
The work may provide an additional target for pharmacologic treatment
of alcoholism.
Considerable previous research indicates that dopamine release
within the brain’s natural reward centre, either in anticipation
of drinking or during exposure to alcohol, contributes to incentive
processes and alcohol consumption. In Beta Gamma Dimers Mediate
Synergy of Dopamine D2 and Adenosine A2 Receptor-Stimulated PKA
Signaling and Regulate Ethanol Consumption, Ivan Diamond, M.D.,
Ph.D., and his colleagues demonstrate a biological mechanism for
this response.
The researchers showed in rat cell cultures that dopamine binding
to one of its receptors (D2 subtype) generates signaling proteins
known as beta gamma dimers that, through a series of events, cause
the activation of protein kinase A (PKA), another protein involved
in intracellular communication, gene expression, and animal behavioural
responses to alcohol. Although acting through a different receptor
(adenosine type 2, or A2), ethanol generates the same signaling
protein and subsequent activation of PKA. Further,dopamine and
ethanol applied together to the cells at concentrations that individually
would not activate PKA signaling produced a synergistic response
between the A2 and D2 receptors that increased beta gamma dimer
formation and, in turn, generated PKA signaling. To explore whether
the cellular effects produced a behavioural response, the researchers
examined alcohol-drinking behaviour in rats injected with a scavenger
molecule designed to reduce the level of beta gamma dimers. The
injection reduced both alcohol consumption and alcohol preference
in the animals, lending further support to a significant role
of beta gamma dimers in voluntary drinking."Our experiments suggest
that synergy of dopamine D2 and adenosine A2 receptors creates
hypersensitivity to ethanol and that beta gamma dimers are required
to sustain voluntary drinking," commented Dr. Diamond.
Source: Yao L et al. Beta-Gamma Dimers Mediate Synergy of Dopamine
D2 andAdenosine A2 Receptor-Stimulated PKA Signaling and Regulate
Ethanol Consumption. Cell 2002;109:733-43. |
