Department of Psychiatry, Brudnick Neuropsychiatric Research Institute
Medical Subject Headings
8-Bromo Cyclic Adenosine Monophosphate; Animals; Animals, Newborn; Calcium; Cell Survival; Cells, Cultured; Central Nervous System Depressants; Corpus Striatum; DNA, Recombinant; Ethanol; Exons; Humans; Ion Channel Gating; Large-Conductance Calcium-Activated Potassium; Channels; Male; Membrane Potentials; Mice; Mice, Inbred C57BL; Neurons; *Nonlinear Dynamics; RNA Splicing; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome; Time Factors; Up-Regulation
Life Sciences | Medicine and Health Sciences | Neuroscience and Neurobiology
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.
Rights and Permissions
Citation: J Neurosci. 2011 Feb 16;31(7):2436-46. Link to article on publisher's site