Neuronal signaling systems and ethanol dependence |
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Authors: | Subhash C Pandey |
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Institution: | (1) The Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago and Psychiatry Research Service, VA Chicago Health Care System (West Side Division), 60612 Chicago, IL |
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Abstract: | In recent years there have been remarkable developments toward the understanding of the molecular and/or cellular changes
in the neuronal second-messenger pathways during ethanol dependence. In general, it is believed that the cyclic adenosine
3′, 5′-monophosphate (cAMP) and the phosphoinositide (PI) signal-transduction pathways may be the intracellular targets that
mediate the action of ethanol and ultimately contribute to the molecular events involved in the development of ethanol tolerance
and dependence. Several laboratories have demonstrated that acute ethanol exposure increases, whereas protracted ethanol exposure
decreases, agonist-stimulated adenylate cyclase activity in a variety of cell systems, including the rodent brain. Recent
studies indicate that various postreceptor events of the cAMP signal transduction cascade (i.e., Gs protein, protein kinase A PKA], and cAMP-responsive element binding protein CREB]) in the rodent brain are also modulated
by chronic ethanol exposure. The PI signal-transduction cascade represents another important second-messenger system that
is modulated by both acute and chronic ethanol exposure in a variety of cell systems. It has been shown that protracted ethanol
exposure significantly decreases phospholipase C (PLC) activity in the cerebral cortex of mice and rats. The decreased PLC
activity during chronic ethanol exposure may be caused by a decrease in the protein levels of the PLC-Β1 isozyme but not of PLC-δ1 or PLC-γ1 isozymes in the rat cerebral cortex. Protein kinase C (PKC), which is a key step in the Pi-signaling cascade, has been shown
to be altered in a variety of cell systems by acute or chronic ethanol exposure. It appears from the literature that PKC plays
an important role in the modulation of the function of various neurotransmitter receptors (e.g., γ-aminobutyrate type A GABAa],
N-methyl-D-aspartate NMDA], serotonin2A 5-HT2a], and 5-HT2C, and muscarinic m1] receptors) resulting from ethanol exposure.
The findings described in this review article indicate that neuronal-signaling proteins represent a molecular locus for the
action of ethanol and are possibly involved in the neuroadaptational mechanisms to protracted ethanol exposure. These findings
support the notion that alterations in the cAMP and the PI-signaling cascades during chronic ethanol exposure could be the
critical molecular events associated with the development of ethanol dependence. |
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Keywords: | cAMP-dependent protein kinase A adenylate cyclase cAMP-responsive-ele-ment binding protein neurotransmitter receptor protein kinase C phospholipase C second mes-sengers phosphoinositide signaling ethanol dependence ethanol tolerance |
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