The effect of combined treatment with imipramine and amantadine on the behavioral reactivity of central alpha1-adrenergic system in rats.

The problem of drug-resistant depression implies a strong need for alternative antidepressant therapies. Recently, it has been shown that joint administration of a tricyclic antidepressant, imipramine (IMI), with amantadine (AMA), a drug already approved for clinical use in the treatment of other diseases, induces a stronger 'antidepressant' effect in the forced swimming test in rats than treatment with either drug given separately. Combined treatment with IMI and AMA also induces up-regulation of dopamine D2 and D3 receptors in the rat brain, and appears to be effective in the treatment of patients with drug-resistant unipolar depression. In the present study, we examined the effect of IMI (5 or 10 mg/kg p.o.) and AMA (10 mg/kg p.o.) given separately or jointly, either as a single dose or repeatedly (twice daily for 14 days) on the development of adaptive changes in the behavioral reactivity of the central alpha1-adrenergic system. Following repeated administration of the higher dose of IMI together with AMA, we observed an increase in clonidine-induced aggression in mice, and significant enhancement of D-amphetamine-induced locomotor hyperactivity, as well as phenylephrine-induced exploratory behavior, in rats. In binding studies using [3H]prazosin, no changes in the density (Bmax) or affinity (Kd) of alpha1-adrenergic receptors were observed in rat brain cortex. However, competition analysis allowed us to observe an increase in the affinity of alpha1-adrenergic receptors (Ki) for an agonist (phenylephrine) upon repeated treatment with IMI, given alone or in combination with AMA. AMA appears to act through several pharmacological mechanisms, none of which has been identified as the chief mode of action. In the light of data obtained in the present study, one can supplement the postulated mechanisms of antidepressant action of AMA by adaptive changes in the reactivity of alpha1-adrenergic receptors, which develop upon repeated combined treatment with IMI.