Dopamine D2R DNA transfer in dopamine D2 receptor-deficient mice: effects on ethanol drinking.

Dopamine (DA) signals are transmitted via specific receptors including the D2 receptors (D2R). Previous studies have shown that D2R upregulation in the nucleus accumbens (NAc) attenuated alcohol consumption. We hypothesized that upregulation of D2R in the NAc would significantly influence alcohol drinking. We tested this hypothesis by determining the effect that D2R upregulation has on alcohol intake in genetically altered mice lacking D2Rs. After a steady baseline of drinking behavior was established for all mice, a null vector or a genetically modified adenoviral vector containing the rat D2R cDNA was infused into the NAc of wild-type (Drd2+/+), heterozygous (Drd2+/-), and receptor-deficient mice (Drd2-/-). Ethanol intake and preference were then determined using the two-bottle choice paradigm. Our results indicated that Drd2+/+ mice treated with the D2R vector significantly attenuated (58 %) their ethanol intake as well as reduced preference. Drd2+/- and mutant mice showed a similar attenuation, although the change was not as marked (12 %) and did not last as long. In contrast, Drd2-/- mice treated with the D2R vector displayed a temporary but significant increase (46 %) in ethanol intake and preference (consumption). These results supported the notion that the D2R plays an important role in alcohol consumption in mice and suggest that a key threshold range of D2R levels is associated with elevated alcohol consumption. Significant deviations in D2R levels from this range could impact alcohol consumption, and could help to explain possible individual variations in alcohol response, metabolism, sensitivity and consumption.

DRD2 gene transfer into the nucleus accumbens core of the alcohol preferring and nonpreferring rats attenuates alcohol drinking.

BACKGROUND: Transient overexpression of the dopamine D2 receptor (DRD2) gene in the nucleus accumbens (NAc) using an adenoviral vector has been associated with a significant decrease in alcohol intake in Sprague Dawley rats. This overexpression of DRD2 reduced alcohol consumption in a two-bottle-choice paradigm and supported the view that high levels of DRD2 may be protective against alcohol abuse. METHODS: Using a limited access (1 hr) two-bottle-choice (water versus 10% ethanol) drinking paradigm, we examined the effects of the DRD2 vector in alcohol intake in the genetically inbred alcohol-preferring (P) and -nonpreferring (NP) rats. In addition, micro-positron emission tomography imaging was used at the completion of the study to assess in vivo the chronic (7 weeks) effects of ethanol exposure on DRD2 levels between the two groups. RESULTS: P rats that were treated with the DRD2 vector (in the NAc) significantly attenuated their alcohol preference (37% decrease) and intake (48% decrease), and these measures returned to pretreatment levels by day 20. A similar pattern of behavior (attenuation of ethanol drinking) was observed in NP rats. Analysis of the [C]raclopride micro-positron emission tomography data after chronic (7 weeks) exposure to ethanol revealed clear DRD2 binding differences between the P and NP rats. P rats showed 16% lower [C]raclopride specific binding in striatum than the NP rats. CONCLUSIONS: These findings further support our hypothesis that high levels of DRD2 are causally associated with a reduction in alcohol consumption and may serve as a protective factor against alcoholism. That this effect was seen in P rats, which are predisposed to alcohol intake, suggests that they are protective even in those who are genetically predisposed to high alcohol intake. It is noteworthy that increasing DRD2 significantly decreased alcohol intake but did not abolish it, suggesting that high DRD2 levels may specifically interfere with the administration of large quantities of alcohol. The significantly higher DRD2 concentration in NP than P rats after 7 weeks of ethanol therefore could account for low alcohol intake.