Locus coeruleus neuronal activity and noradrenaline availability in the frontal cortex of rats chronically treated with imipramine effect of alpha(2)-adrenoceptor blockade

Background: previous studies indicate a reduced feed-back inhibition of bra in noradrenaline (NA) neurons in the locus coeruleus (LC) during chronic ad ministration of antidepressants which inhibit the NA reuptake mechanism due to functional downregulation of somatodendritic alpha(2)-adrenoceptors in the LC. Therefore, we have here studied the LC neuronal responsiveness to a dministration of the alpha(2)-adpenoceptor antagonist idazoxan (IDA) after both short-term and long-term imipramine (IMI) administration. Methods: Rats were treated for different periods with systemic IMI. In thes e rats, basal activity of central noradrenergic function and the effect of IDA was assessed by means of extracellular single-cell recording from LC ne urons and in vivo microdialysis of extracellular NA levels in the frontal c ortex (FC), Results: The average firing rate of LC neurons was significantly reduced in rats by short-term IMI treatment compared with long-term treatment. The ou tput of NA in the FC of all IMI-treated animals was significantly increased compared with saline-treated rats. Moreover, the enhancing effect of IDA o n both the firing rate of LC neurons and the cortical NA output was larger in rats after long-term treatment with IMI than after shout-term administra tion. Conclusions: Our results clearly support the nation of development of funct ional downregulation of alpha(2)-autoreceptors on LC neurons during chronic administration of NA reuptake inhibiting antidepressants. Moreover, the da ta suggest that addition of alpha(2)-adrenoceptor antagonists may augment t he clinical effect of such drugs in major depression. (C) 1999 Society of B iological Psychiatry.