Locus coeruleus neuronal activity and noradrenaline availability in the frontal cortex of rats chronically treated with imipramine effect of α2-adrenoceptor blockade

Background: previous studies indicate a reduced feed-back inhibition of brain noradrenaline (NA) neurons in the locus coeruleus (LC) during chronic administration 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 administration 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 these rats, basal activity of central noradrenergic function and the effect of IDA was assessed by means of extracellular single-cell recording from LC neurons and in vivo microdialysis of extracellular NA levels in the frontal cortex (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 output of NA in the FC of all IMI-treated animals was significantly increased compared with saline-treated rats. Moreover, the enhancing effect of IDA on 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 administration. Conclusions: Our results clearly support the nation of development of functional downregulation of alpha(2)-autoreceptors on LC neurons during chronic administration of NA reuptake inhibiting antidepressants. Moreover, the data suggest that addition of alpha(2)-adrenoceptor antagonists may augment the clinical effect of such drugs in major depression. (C) 1999 Society of Biological Psychiatry.