title: 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.
authors.affiliation: Institute of Neurobiology, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico 00901, USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Velázquez-Marrero
authors.forename: Patricia
authors.initials: P
authors.lastname: Wynne
authors.forename: Alexandra
authors.initials: A
authors.lastname: Bernardo
authors.forename: Stephanie
authors.initials: S
authors.lastname: Palacio
authors.forename: Gilles
authors.initials: G
authors.lastname: Martin
authors.forename: Steven N
authors.initials: SN
authors.lastname: Treistman
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D003342:Corpus Striatum / Q000166:cytology; D004274:DNA, Recombinant / Q000187:drug effects / Q000235:genetics; D000431:Ethanol / Q000494:pharmacology*; D005091:Exons / Q000187:drug effects / Q000235:genetics; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects* / Q000235:genetics; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects; D017711:Nonlinear Dynamics; D012326:RNA Splicing; D051381:Rats; D017207:Rats, Sprague-Dawley; D013375:Substance Withdrawal Syndrome / Q000235:genetics / Q000503:physiopathology; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D002492:Central Nervous System Depressants; D004274:DNA, Recombinant; D051036:Large-Conductance Calcium-Activated Potassium Channels; D015124:8-Bromo Cyclic Adenosine Monophosphate; D000431:Ethanol; D002118:Calcium