Ethanol normalizes glutamate-induced elevation of intracellular sodium in olfactory neuroepithelial progenitors from subjects with bipolar illness but not nonbipolar controls: Biologic evidence for the self-medication hypothesis.

Abstract

Alcohol use disorders are quite common in bipolar patients with a prevalence of comorbidity that exceeds all other primary psychiatric diagnoses other than other substance use disorders1; over 60% of people with bipolar disorder type I (BD I) have comorbid alcohol dependence at some point in their lives.1 This intimate relationship has served as the basis of the proposed idea of “self-medication.”2 However, biological confirmation of “self-medication,” specifically, the correction of an abnormal biologic marker with alcohol, has never been demonstrated. Recently, we have succeeded in utilizing olfactory neuroepithelium biopsy to produce permanent cell lines of olfactory neuroepithelial progenitors (ONPs) from patients with BD and matched nonbipolar controls.3 These cells possess the genetic heritage of BD I and can be used for investigation of differential biological responses to ethanol. Ionic regulatory abnormalities have repeatedly been documented in patients with BD I.4 Most notably, intracellular sodium and calcium are elevated during both mania and depression, this distribution of cations alters transmembrane potential of lymphocytes—a phenomenon which may be a useful diagnostic marker (reviewed in references 4). Both pharmacologic and genetic animal models which inhibit the sodium pump to elevate intracellular sodium and calcium concentrations create mania-like behaviors (reviewed in 4). Similarly, altered-glutamate metabolism is a consistent finding in BD (reviewed in 4). Importantly, brain glutamate and glutamine are elevated in most brain areas in patients with bipolar illness during mania, depression, and euthymia. By extension, treating ONP cells with glutamate to increase both intracellular sodium and calcium may be a cellular model of bipolar illness, mania, and/or bipolar depression.