α2-adrenoceptor blockade prevents the effect of desipramine in the forced swimming test

The influence of α₂-adrenoceptor blockade on the activity of desipramine in an experimental model of depression was studied by using idazoxan and 1-(pyrimidinyl)piperazine (1-PP). The two drugs antagonists at these receptors, were studied for their ability to modify the effect of repeated treatment with the antidepressant, desipramine in the forced swimming test. Idazoxan (0.03, 0.3 and 3 mg/kg s.c.) and 1-PP (0.3 and 3 mg/kg p.o.) given with the last dose of a 7-day schedule of 10 mg/kg i.p. desipramine significantly reduced the effect of the latter on immobility. On its own neither drug modified the immobility time of rats at any dose. Infusion of various concentrations of idazoxan (1.6, 8 and 40 ng/μl) in the rat locus coeruleus (LC), dose dependently antagonized the effect of desipramine without causing any appreciable change in motor behavior or immobility. The effect of idazoxan (8 ng/μl) infusion in the LC was completely prevented by administering 6 μg 6-hydroxydopamine in the same region 12 days earlier. It thus appears that α₂-adrenoceptor blockade prevents the effect of desipramine in the forced swimming test, presumably by an effect on noradrenaline-containing cells in the LC. The question of how blockade or activation of α₂-adrenoceptors, both in the LC and in other sites, could influence antidepressant activity is discussed.