The Relationship between Duration of Initial Alcohol Exposure and Persistence of Molecular Tolerance Is Markedly Nonlinear

Abstract

The neuronal calcium-and voltage-activated BK potassium channel is modulated by ethanol, and plays a role in behavioral tolerance in vertebrates and invertebrates. We examine the influence of temporal parameters of alcohol exposure on the characteristics of BK molecular tolerance in the ventral striatum, an important component of brain reward circuitry. BK channels in striatal neurons of C57BL/6J mice exhibited molecular tolerance whose duration was a function of exposure time. After 6 h exposure to 20 mM (0.09 mg%) ethanol, alcohol sensitivity was suppressed beyond 24 h after withdrawal, while after a 1 or 3 h exposure, sensitivity had significantly recovered after 4 h. This temporally controlled transition to persistent molecular tolerance parallels changes in BK channel isoform profile. After withdrawal from 6 h, but not 3 h alcohol exposure, mRNA levels of the alcohol-insensitive STREX (stress axis-regulated exon) splice variant were increased. Moreover, the biophysical properties of BK channels during withdrawal from 6 h exposure were altered, and match the properties of STREX channels exogenously expressed in HEK 293 cells. Our results suggest a temporally triggered shift in BK isoform identity. Once activated, the transition does not require the continued presence of alcohol. We next determined whether the results obtained using cultured striatal neurons could be observed in acutely dissociated striatal neurons, after alcohol administration in the living mouse. The results were in remarkable agreement with the striatal culture data, showing persistent molecular tolerance after injections producing 6 h of intoxication, but not after injections producing only 3 h of intoxication.

BK Channels in the Central Nervous System

“…An miRNA-mediated BK α isoform switch contributes to this rapid desensitization in supraoptic nucleus and striatal neurons, with miR-9 targeting ALCOREX-containing splice variants to degradation, thereby favoring the expression of alcohol-insensitive STREX-containing isoforms (Pietrzykowski et al, 2008; Velazquez-Marrero et al, 2011). Whether miR-9-driven regulation of BK α splice variants also occurs following in vivo alcohol exposure, possibly in a brain region- or cell type-specific manner, awaits further investigation.…”

Assessing ethanol's actions in the suprachiasmatic circadian clock using in vivo and in vitro approaches

“…Ethanol tolerance has been subdivided into three categories based on the duration of ethanol exposure (Radcliffe et al, 2006;Vieira et al, 2008;Pohorecky and Roberts, 1992;Velazquez-Marrero et al, 2011). Acute tolerance is a form of desensitization that occurs within 5-30 min of initial ethanol exposure, and has been seen to last approximately 24 h. Rapid tolerance is seen approximately 8-24 h after initial ethanol exposure, and the amount of time it lasts has not been routinely assessed.…”

Fear conditioning suppresses large-conductance calcium-activated potassium channels in lateral amygdala neurons

“…Participation of BK channels in neuronal processes underlying fear conditioning, which we showed here, is not particularly surprising, given that BK channel activity is known to support neuronal survival and proliferation [21][22][23][24][25], and to be associated with a number of neurological and psychiatric disorders [26][27][28][29][30]. A particular type of epilepsy combined with paroxysmal dyskinesia is recognized as the first example of BK channel channelopathy caused by a single mutation [26].…”