Modulation of behavioral and neurochemical measures of forebrain dopamine function in mice by species-specific interleukin-2

Abstract

Interleukin-2 (IL-2) has recently been implicated as a modulator of brain neuronal function and in the pathogenesis of several major neuropsychiatric disorders involving the dopamine system (e.g. schizophrenia and Parkinson's disease). Little is known, however, about the effects of IL-2 on dopamine-mediated behaviors. A series of behavioral experiments were performed in mice to examine the hypothesis that species-specific IL-2 could modify behaviors known to be mediated by forebrain dopamine pathways. IL-2 administered subcutaneously produced a robust increase in locomotor activity in an elevated plus-maze. No effects of the cytokine were evident on measures of acoustic startle, prepulse inhibition of the startle response (PPI), or fearfulness. In complementary in vitro neurochemical experiments, to most closely assess physiologically relevant effects of the cytokine on dopamine release from striatal neurons, species-specific IL-2 as well as high performance liquid chromatography (HPLC) were used to measure endogenous dopamine release from striatal slices. IL-2 dose-dependently modulated veratrine-evoked release of endogenous dopamine in a biphasic pattern, increasing release at lower concentrations and inhibiting release at a high concentration of the cytokine. In radioligand competition binding experiments, IL-2 was not active at striatal binding sites for [3H]spiroperidol (D2-like receptors), [3H]mazindol binding (dopamine uptake sites) and [3H]SCH23390 (D1-like receptors), indicating that the neuromodulatory actions of IL-2 are not the result of direct or allosteric effects on dopamine receptors. Knowledge of the mechanisms by which IL-2 influences brain dopamine function could provide new insight into the pathophysiology of forebrain dopamine neurons seen in disorders such as Parkinson's disease and schizophrenia.