According to recent research published in the journal Proceedings of the National Academy of Sciences of the United States of America, "Tolerance, described as the loss of drug effectiveness over time, is an important component of addiction. The degree of acute behavioral tolerance to Alcohol exhibited by a naive subject can predict the likelihood of Alcohol abuse."

"Thus, the determinants of acute tolerance are important to understand. Calcium- and voltage-gated (BK) potassium channels, consisting of pore forming alpha and modulatory beta subunits, are targets of ethanol (EtOH) action. Here, we examine the role, at the molecular, cellular, and behavioral levels, of the BK beta 4 subunit in acute tolerance. Single channel recordings in HEK-293 cells show that, in the absence of beta 4, EtOH potentiation of activity exhibits acute tolerance, which is blocked by coexpressing the beta 4 subunit. BK channels in acutely isolated medium spiny neurons from WT mice (in which the beta 4 subunit is well-represented) exhibit little tolerance. In contrast, neuronal BK channels from beta 4 knockout (KO) mice do display acute tolerance. Brain slice recordings showed tolerance to EtOH's effects on spike patterning in KO but not in WT mice. in addition, beta 4 KO mice develop rapid tolerance to EtOH's locomotor effects, whereas WT mice do not. Finally, in a restricted access ethanol self-administration assay, beta 4 KO mice drink more than their WT counterparts," wrote G.E. Martin and colleagues, University of Massachusetts (see also Addiction Medicine).

The researchers concluded: "Taken together, these data indicate that the beta 4 subunit controls ethanol tolerance at the molecular, cellular, and behavioral levels, and could determine individual differences in Alcohol abuse and alcoholism, as well as represent a therapeutic target for alcoholism."

Martin and colleagues published their study in Proceedings of the National Academy of Sciences of the United States of America (Identification of a BK channel auxiliary protein controlling molecular and behavioral tolerance to alcohol. Proceedings of the National Academy of Sciences of the United States of America, 2008;105(45):17543-17548).

For additional information, contact G.E. Martin, University of Massachusetts, School Medical, Brudnick Neuropsychiatry Research Institute, Dept. of Psychiatry, 303 Belmont St., Worcester, MA 01604, USA.

The publisher's contact information for the journal Proceedings of the National Academy of Sciences of the United States of America is: National Acad Sciences, 2101 Constitution Avenue NW, Washington, DC 20418, USA.