As part of an ongoing effort to understand the biochemical basis of alcohol abuse, scientists at the US Department of Energy’s Brookhaven National Laboratory have published two studies on how modulating receptors for dopamine, a chemical ‘signaler’ in the brain’s reward circuits affects drinking behaviour in mice and rats.
‘Stopping alcohol abuse will never be as simple as turning on or off a switch, but finding ways to modulate the brain’s reward circuits could play a role in developing successful treatments,’ said Panayotis Thanos, lead author of both studies.
In the first study, the scientists increased the number of dopamine ‘D2’ receptors in strains of mice with genetically varying levels of D2 receptors. Earlier Brookhaven studies have shown that ‘up-regulating’ D2 receptors by delivering the D2 gene directly to the brain’s reward center decreased drinking behavior in rats trained or genetically predisposed to drink large quantities of alcohol.
The Life Sciences study demonstrates this same ‘alcoholism-quenching’ effect of D2 ‘gene therapy’ in mice with normal to moderately low levels of D2s, supporting the idea that receptor up-regulation could play a role in the treatment of alcoholism.
Also in that study, however, so-called ‘knockout’ mice, which initially had no D2s, drank more in response to D2 up-regulation. ‘This suggests that there may be a threshold level of D2 receptors needed for animals to respond to the reinforcing effects of alcohol,’ Thanos said. ‘When we up-regulated D2 levels in the knockout mice, we may have approached or obtained D2 levels close to this threshold, thus producing the reinforcement and an increase in ethanol intake, but...we could speculate that further increases in D2, above this threshold, would result in a decrease in ethanol consumption in this group as well,’.
In the second study, Thanos’ group tested the idea that blocking the activity of another kind of dopamine receptor, known as D3, might reduce alcohol consumption. They tested their hypothesis in rats with a genetic predisposition to prefer alcohol when given a choice between a 10 percent ethanol solution and pure water, comparing them with rats that had no prior preference for alcohol. Both sets of animals were treated with varying doses of ‘SB-277011-A,’ a known D3 receptor ‘antagonist’ (a chemical that binds to the receptor thus blocking dopamine’s ability to bind and send its pleasure/reward signal).
The two higher doses of the antagonist (10 and 30 milligrams per kilogram body weight) reduced drinking behavior in the alcohol-preferring rats; the highest dose decreased drinking (though less dramatically) in the non-preferring group, which drank less to begin with. The lowest dose (3mg/kg) had no effect in either group. None of the doses caused any side effects.
‘Recent studies have demonstrated that SB-277011-A is a highly selective D3-blocker and also reduces cocaine-seeking behavior, as well as behavior involving other drugs of abuse, such as nicotine and heroin,’ Thanos said, ‘these two studies provide further insight into the complex roles of dopamine and may help us better understand the mechanism(s) of alcohol abuse and assist in the development of specific, molecular-based treatments.’
Source: Thanos PK et al. Dopamine D2R DNA transfer in dopamine D2 receptor-deficient mice: Effects on ethanol drinking. Life Sciences 2005;77:130-9; and The selective dopamine D3 receptor,antagonist SB-277011-A attenuates ethanol consumption in ethanol preferring (P) and non-preferring (NP) rats. Pharmacology Biochemistry and Behavior 2005.