Increased brain dopamine D4-like binding after chronic ethanol is not associated with behavioral sensitization in mice

Abstract 

Dopaminergic D4 receptors have been hypothesized to be involved in neuropsychiatric disorders and substance abuse. In mice, repeated ethanol administration may induce behavioral sensitization, a phenomenon of increased sensitivity to the drug's stimulant properties. This study aimed to analyze brain D4 receptors binding in mice with different levels of behavioral sensitization to ethanol. Male Swiss mice received 2.2g/kg ethanol (n=64) or saline (n=16) intraperitoneally daily for 21 days and were weekly tested for locomotor activity and for blood ethanol levels. According to the locomotor scores presented across test days, ethanol-treated mice were classified as “sensitized” or “nonsensitized.” Twenty-four hours after the last administration, mice were sacrificed and brains were processed for autoradiography. Brain D4 binding was assessed by quantitative autoradiography using [³H]nemonapride+raclopride in three groups: saline-treated controls (n=10), ethanol-sensitized (n=11), and ethanol-nonsensitized (n=9) mice. Both sensitized and nonsensitized mice showed higher D4 binding densities than saline-treated controls in the posterior caudate–putamen and the olfactory tubercle (p<.02), but only sensitized mice presented higher D4 binding than controls at the lateral septal nucleus (p<.02). However, there were no differences between sensitized and nonsensitized mice in any of the brain regions analyzed. Furthermore, sensitized and nonsensitized mice presented similar blood ethanol levels during the treatment. The higher D4 binding levels observed in both ethanol-treated subgroups (sensitized and nonsensitized) suggest that chronic ethanol treatment may induce upregulation of D4 receptors in specific brain regions. However, this mechanism does not seem to be associated with the differential ability to develop behavioral sensitization to ethanol in mice.

Keywords: [³H]Nemonapride, Dopamine, Striatum, Lateral septal nucleus, Blood ethanol levels