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 feedback 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 α2-adrenoceptors in the LC. Therefore, we have here studied the LC neuronal responsiveness to administration of the α2-adrenoceptor 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 short-term administration. Conclusions: Our results clearly support the notion of development of functional downregulation of α2-autoreceptors on LC neurons during chronic administration of NA reuptake inhibiting antidepressants. Moreover, the data suggest that addition of α2-adrenoceptor antagonists may augment the clinical effect of such drugs in major depression.