Abstract
In mice there are clear individual differences in the development of behavioral sensitization to ethanol, a progressive potentiation of its psychomotor stimulant effect. Variability in the behavioral responses to ethanol has been associated with alcohol preference. Here we investigated if the functional hyperresponsiveness of D1 receptors observed in ethanol sensitized mice leads to an increased activation of DARPP-32, a central regulatory protein in medium spiny neurons, in the nucleus accumbens - a brain region known to play a role in drug reinforcement. Swiss Webster mice received ethanol (2.2 g/kg/day) or saline i.p. administrations for 21 days and were weekly evaluated regarding their locomotor activity. From those treated with ethanol, the 33% with the highest levels of locomotor activity were classified as “sensitized” and the 33% with the lowest levels as "non-sensitized”. The latter presented similar locomotor levels to those of saline-treated mice. Different subgroups of mice received intra-accumbens administrations of saline and, 48 h later, SKF-38393, D1 receptor agonist 0.1 or 1 µg/side. Indeed, sensitized mice presented functional hyperresponsiveness of D1 receptors in the accumbens. Two weeks following the ethanol treatment, other subgroups received systemic saline or SKF 10 mg/kg, 20 min before the euthanasia. The nucleus accumbens were dissected for the Western Blot analyses of total DARPP-32 and phospho-Thr34-DARPP-32 expression. D1 receptor activation induced higher phospho-Thr34-DARPP-32 expression in sensitized mice than in non-sensitized or saline. The functionally hyperresponsiveness of D1 receptors in the nucleus accumbens is associated with an increased phospho-Thr34-DARPP-32 expression after D1 receptor activation. These data suggest that an enduring increase in the sensitivity of the dopamine D1 receptor intracellular pathway sensitivity represents a neurobiological correlate associated with the development of locomotor sensitization to ethanol.
Highlights
Alcoholism is a worldwide problem resulting in millions of deaths_ENREF_1, only a small percentage of alcohol users become addicted [1]
We demonstrated an important association between the variability in behavioral sensitization to the stimulant effect of ethanol and the functionality of dopamine D1 receptors and its intra-cellular cascade pathway
It is important to note that these effects were not observed in all mice submitted to the 21-day ethanol treatment
Summary
Alcoholism is a worldwide problem resulting in millions of deaths_ENREF_1, only a small percentage of alcohol users become addicted [1]. Psychomotor sensitization to ethanol, a form of drugdependent behavioral adaptation (defined as a progressive increase in psychomotor stimulant response with repeated drug exposure), has been suggested as a behavioral marker for alcohol preference and/or abuse liability in both animals [5,6] and humans [7]. Our previous studies identified significant individual differences in the development of behavioral sensitization to ethanol in outbred Swiss Albino Webster mice. While a subgroup of ethanol-treated mice showed a robust sensitization (sensitized group), others, in spite of receiving identical ethanol treatment, failed to show this drug-induced behavioral plasticity (non-sensitized group) and presented similar levels of activity to a saline-treated control group [8,9]. Variations in the development of ethanol sensitization probably reflect individual differences in addiction vulnerability, since sensitized mice voluntarily drink more ethanol than nonsensitized or saline-treated control mice [10]
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