Isobolographic analysis of clonidine and clozapine's antidepressant- and anxiogenic-like effects

Clozapine, a second-line treatment for psychiatric disorders, exhibits high affinity for various neurotransmitter receptors. This study investigated the interaction between clozapine and α₂-adrenoceptor (α₂-AR) agents in modulating anxiety- and depression-like behaviors.

Adult male NMRI mice were implanted with a guide cannula in the lateral ventricle and tested using the elevated plus maze (EPM) for anxiety-like behaviors and the forced swimming test (FST) for depression-like behaviors.

Microinjection of the α₂-AR agonist clonidine (0.5 µg/mouse, icv) or the α₂-AR antagonist yohimbine (0.5 and 1 µg/mouse) reduced time spent and entries into the open arms of the EPM, suggesting anxiogenic-like effects. Subthreshold doses of clonidine (0.125 µg/mouse) or yohimbine (0.25 µg/mouse) induced an anxiogenic-like behavior in clozapine-treated mice. Meanwhile, clozapine/clonidine combinations decreased locomotor activity. All drugs alone reduced immobility time in the FST, indicating antidepressant-like properties. A subthreshold dose of clonidine decreased the immobility time of the lowest dose of clozapine in the FST. Isobologram analysis revealed additive or synergistic interactions between clonidine and clozapine in the EPM and FST, respectively.

The dual interaction profile between clonidine and clozapine highlights both the therapeutic potential and limitations of targeting the noradrenergic system for mood disorder treatment.