BIOCHEMICAL ACTIONS OF CHRONIC ETHANOL EXPOSURE IN THE MESOLIMBIC DOPAMINE SYSTEM

In previous studies, we have demonstrated that chronic administration of morphine or cocaine produces some common biochemical adaptations in the ventral tegmental area (VTA) and nucleus accumbens (NAc), compone nts of the mesolimbic dopamine system implicated in the reinforcing ac tions of these and other drugs of abuse. Since this neural pathway is also implicated in the reinforcing actions of ethanol, it was of inter est to determine whether chronic ethanol exposure results in similar b iochemical adaptations. Indeed, as seen for chronic morphine and cocai ne treatments, we show here that chronic ethanol treatment increased l evels of tyrosine hydroxylase and glial fibrillary acidic protein immu noreactivity, and decreases levels of neurofilament protein immunoreac tivity, in the VTA. Also like morphine and cocaine, ethanol increases levels of cyclic AMP-dependent protein kinase activity in the NAc. The se actions of ethanol required long-term exposure to the drug, and wer e in most cases not seen in the substantia nigra or caudate-putamen, c omponents of the nigrostriatal dopamine system studied for comparison. Altered levels of tyrosine hydroxylase in catecholaminergic cells fre quently reflect altered states of activation of the cells. Moreover, i ncreasing evidence indicates that ethanol produces many of its acute e ffects on the brain by regulating NMDA glutamate and GABAA receptors. We therefore examined the influence of chronic ethanol treatment on le vels of expression of specific glutamate and GABA receptor subunits in the VTA. It was found that long-term, but not short-term, ethanol exp osure increased levels of immunoreactivity of the NMDAR1 subunit, an o bligatory component of NMDA glutamate receptors, and of the GluR1 subu nit, a component of many AMPA glutamate receptors; but at the same tim e, long-term ethanol exposure decreased immunoreactivity levels of the al subunit of the GABA(A) receptor complex. These changes are consist ent with an increased state of activation of VTA neurons inferred from the observed increase in tyrosine hydroxylase (TH) expression. These results demonstrate that chronic ethanol exposure results in several b iochemical adaptations in the mesolimbic dopamine system, which may un derlie prominent changes in the structural and functional properties o f this neural pathway related to alcohol abuse and alcoholism. (C) 199 5 Wiley-Liss, Inc.