Regional Differences in the Effects of Chronic Ethanol Administration on [³H]Zolpidem Binding in Rat Brain

Abstract

A strong association has been observed between [3H]zolpidem binding and the presence of gamma-aminobutyric acid (GABAA) receptor mRNA for alpha 1-, beta 2-, and gamma 2-subunits in specific brain regions. This correlates with observed sensitivity of individual neurons to zolpidem and ethanol in these same regions. Previous studies using homogenate binding approaches showed small alterations in [3H]zolpidem binding levels after chronic ethanol exposure. This study was undertaken to ascertain if there is regional specificity of the effects of chronic ethanol administration on [3H]zolpidem binding levels. Chronic ethanol administration induced small, but significant alterations in [3H]zolpidem (5 nM) binding in the inferior colliculus, substantia nigra, and the medial septum. [3H]Zolpidem binding was increased in the inferior colliculus and substantia nigra, and decreased in the medial septum. No significant differences in [3H]zolpidem binding were noted in any other brain area analyzed, including the cortex and cerebellum. These findings show that chronic ethanol administration has small effects on [3H]zolpidem binding, although they occur in a site-specific and bidirectional manner. Moreover, there is no correlation between changes in [3H]zolpidem binding and alterations in GABAA receptor subunit expression.

Neuropeptide modulation of central amygdala neuroplasticity is a key mediator of alcohol dependence

“…Slices from alcohol-dependent rats also exhibit increased mIPSC amplitude relative to naïve rats, indicative of a post-synaptic effect of chronic alcohol. Substantial evidence suggests that alcohol-induced behavioral and neural adaptations are attributable to marked changes in GABA A R subunit assembly rather than decreases in the number of GABA A Rs (Devaud et al, 1995; Eckardt et al, 1998; Grobin et al, 1998; Kumar et al, 2004; Kumar et al, 2009; Morrow et al, 1992). That said, there is considerable ambiguity in the literature (both within and across species) regarding which GABA A R subunits are most critical for mediating alcohol actions (e.g., Borghese & Harris, 2007; Hemby et al, 2006; Korpi et al, 2007), and the critical subunits are likely to vary across brain regions (Grobin et al, 2000).…”

Corticotropin-releasing factor (CRF) and neuropeptide Y (NPY): Effects on inhibitory transmission in central amygdala, and anxiety- & alcohol-related behaviors

“…Substantial evidence suggests that alcohol-induced behavioral and neural adaptations are attributable to changes in GABA A R subunit assembly rather than decreases in the number of GABA A Rs (Devaud et al, 1995; Eckardt et al, 1998; Grobin et al, 1998;Kumar et al, 2004, 2009;Morrow et al, 1992). For example, α 1 and α 4 subunit expression is significantly decreased after two weeks of chronic alcohol consumption, suggesting that chronic alcohol may increase GABA A receptor function in the amygdala by altering GABA A R subunit expression in that region (Papadeas et al, 2001).…”

Neurosteroid Influences on Sensitivity to Ethanol

“…This treatment also resulted in greater sensitivity to the anticonvulsant effects of alphaxalone. Likewise, the anticonvulsant efficacy and potency of allopregnanolone (Devaud et al, 1995) and THDOC (Devaud et al, 1996) was increased by chronic ethanol treatment in rats (liquid diet, 10–12 g/kg/day for 14 days) and mice (72 h ethanol vapor inhalation, Finn et al, 2000). These data indicate that chronic ethanol and withdrawal are associated with increased sensitivity, rather than cross-tolerance, to the anticonvulsant and possibly the anxiolytic effects of GABAergic neuroactive steroids.…”