Time of Administration of Acute or Chronic Doses of Imipramine Affects its Antidepressant Action in Rats

The pathogenesis and therapeutics of depression are linked to the operation of the circadian system. Here, we studied the chronopharmacological action of a tricyclic antidepressant, imipramine. Male adult Wistar–Hannover rats were administered imipramine acutely or chronically in the morning or in the evening. The antidepressant action of imipramine was analyzed using the forced swim test (FST). A single dose of imipramine (30 mg/kg) in the morning, but not in the evening, reduced immobility and increased climbing in the FST. The plasma concentrations of imipramine and its metabolite, desipramine, were slightly higher in the morning than in the evening, which might explain the dosing time-dependent action of imipramine. Next, we analyzed the effect of chronic imipramine treatment. Rats received imipramine in the morning or in the evening for 2 weeks. The morning treatment resulted in larger effects in the FST than the evening treatment, and was effective at a dose that was ineffective when administered acutely. The levels of brain α-adrenergic receptors tended to decrease after chronic imipramine treatment. Imipramine might interact with noradrenergic neurons, and this interaction might chronically alter receptor expression. This alteration seemed greater in the morning than in the evening, which might explain the dosing time-dependent action of imipramine.