The role of alpha-2A-adrenergic receptor antagonism in therapeutic efficacy and onset of action of antidepressant drugs in a rat model of depression

Abstract

While delayed onset of antidepressant action remains a shortcoming of current antidepressants, preliminary clinical data with newer antidepressants, including mirtazapine, show promise for a hastened onset. Several potential mechanisms have been postulated and investigated. Mirtazapine displays serotonin 5-HT2 and 5-HT3, receptor blocking properties, while its putative earlier onset of action is thought to be related to its 2-adrenoceptor lytic action (at 2-adrenergic autoreceptors and heteroreceptors), thereby modulating central serotonergic and noradrenergic neurotransmission. The current study investigated the role of 2-adrenoceptor antagonism for earlier onset of action in a rat model of depression. First of all, the treatment period necessary to produce antidepressant-like responses with fluoxetine (an antidepressant with a delayed onset of action) was established. Rats were treated for 3, 7, and 11 days with fluoxetine, whereafter the forced swim test (FST) was employed and cortical β-adrenoceptor density was measured. The results showed that fluoxetine elicits antidepressant-like behavioural and neuroreceptor effects after 7 and 11, but not 3 days of treatment. Therefore, antidepressant-like effects in this study would be recognised as early effects if they were visible after 3 days of treatment. To investigate the role of 2-adrenoceptor antagonism for earlier onset of action, rats were treated for 3 and 7 days with fluoxetine, mirtazapine (2-lytic mode unknown), yohimbine (2- adrenoceptor inverse agonist), idazoxan (2-adrenoceptor neutral antagonist), or combinations with fluoxetine, where after the FST was employed and cortical β-adrenoceptor and hippocampal 5-HT1A receptor densities were measured. Results with the FST support an earlier onset of action by mirtazapine, but do not support an important role for a,-lytic action in this regard. β-Adrenoceptor density generally decreased with antidepressant action, but is not a good marker of hastened onset. Furthermore, 5-HT1A receptor density is not a good marker for antidepressant action. It was concluded that a property different from its 2-adrenoceptor-lytic action may be important for the earlier onset of action by mirtazapine.