Long-term treatment with antidepressant drugs reduces the sensitivity of cortical cholinergic neurons to the activating actions of stress and the anxiogenic drug FG 7142

Certain antidepressant drugs exert an anxiolytic action in both humans and rodents. The effects of long-term treatment with imipramine or mirtazapine, two antidepressant drugs with different mechanisms of action, on the respo nse of cortical cholinergic neurons to foot-shock stress or to the anxiogen ic drug FG 7142 were investigated in freely moving rats. Chronic treatment with imipramine or mirtazapine reduced the increase in cortical acetylcholi ne output induced by foot-shock stress by similar to 50%. The same treatmen t also reduced the sensitivity of cortical cholinergic neurons to the stimu latory effect of acute administration of FG 7142. In contrast, the administ ration of a single dose of either antidepressant 40 min before foot shock o r FG 7142 injection failed to increase the threshold of excitability of cor tical cholinergic neurons. These results demonstrate that long-term treatme nt with either imipramine or mirtazapine reduces the sensitivity of cortica l cholinergic neurons to stress or to an anxiogenic drug with an efficacy s imilar to that of acute administration of benzodiazepines. The neurochemica l mechanism responsible for regulation of cholinergic neuron sensitivity mi ght contribute to the modulation of cognitive function associated with emot ional and affective disorders. (C) 2001 Elsevier Science Ltd. All rights re served.