Thyrotropin releasing hormone: Neurochemical evidence for the potentiation of imipramine effects on the metabolism and uptake of brain catecholamines

The effects of chronic exposure to imipramine and thyrotropin-releasing hormone, alone and in combination, have been investigated on tyrosine hydroxylase activity as well as on the levels of norepinephrine, dopamine, and their respective metabolites in certain areas of rat brain. Repeated injections of thyrotropinreleasing hormone (20 mg/kg/24h, in two equally divided doses) for 10 days increased catecholamine synthesis and release, as shown by the increased activity of tyrosine hydroxylase and the enhanced levels of metabolites, homovanillic acid, and 4-hydroxy-3-methoxyphenylglycol. Chronic thyrotropin-releasing hormone treatment altered neither the steady state levels of norepinephrine in several brain areas, nor the uptake of 3H-norepinephrine in a crude synaptosomal (P2 pellet) fraction. By contrast, daily administration of imipramine (10 mg/kg) for 10 days significantly decreased the uptake of 3H-norepinephrine in P2 pellets by 27%. Whereas the levels of brain norepinephrine and dopamine were decreased, the concentrations of homovanillic acid and 4-hydroxy-3-methoxyphenylglycol were elevated after imipramine treatment. Furthermore, chronic imipramine treatment decreased the activity of striatal tyrosine hydroxylase, probably by receptor-mediated negative feedback mechanism. When thyrotropin-releasing hormone was injected concurrently with imipramine (10 mg/kg), this tripeptide significantly potentiated the effects of imipramine on the levels of homovanillic acid and 4-hydroxy-3-methoxyphenylglycol. These findings demonstrate that whereas thyrotropin-releasing hormone elicits its rapid mood-elevating effect probably by increasing the turnover of catecholamines, imipramine acts by blocking their neuronl re-uptake. In addition, our data provide a possible neurochemical basis for the reported potentiation of tricyclic antidepressant action by thyrotropin-releasing hormone in depressed patients.