Imipramine receptor specificity

After long-term administration, antidepressants may enhance dopaminergic neurotransmission, even if direct acute effects are absent (Serra et al. 1990b). For example, the stress-induced decrease in the binding of quinpirole, an agonist of Dj and Dj receptors, can be reversed by chronic imipramine treatment [Papp et al. 1994). These and related data, however, do not allow the formulation of a dopamine hypothesis of depression, but rather point to a role for decreased dopaminergic neurotransmission in specific neuronal circuits that are responsible for those depressive syndromes associated with motivational loss, psychomotor retardation, and anhedonia [Willner 1995). 

Although postsynaptic DA agonists and presynaptic Dj autoreceptor antagonists share a common property of enhancing DA transmission, Dj autoreceptor agonists have been developed specifically to block DA transmission as an alternative approach to antipsychotic therapy (Benkert et al. 1992). A variety of such compounds are available (Seyfried and Boettcher 1990), four of which—talipexole, pramipexole, roxindole, and OPC-4392 —have been evaluated as antipsychotics in schizophrenic patients (Benkert et al. 1992). Only roxindole has been tested in depression, and then only in two uncontrolled pilot studies over 4 weeks of treatment (Benkert et al. 1992 M. Kellner et al. 1994). Response rates similar to those of imipramine were observed, with a fast onset of action in some patients. Roxindole s antidepressant action may lie in its ability to selectively stimulate supersensitive postsynaptic Dj receptors, and thereby enhance DA function, or in its additional properties as an inhibitor of serotonin reuptake and as a 5-HT, receptor agonist (Benkert et al. 1992 Seyfried et al. 1989). 

Many inhibitors of the amine transporters for norepinephrine, dopamine, and serotonin are used clinically. Although specificity is not absolute, some are highly selective for one of the transporters. Many antidepressants, particularly the older tricyclic antidepressants can inhibit norepinephrine and serotonin reuptake to different degrees. This may lead to orthostatic tachycardia as a side effect. Some antidepressants of this class, particularly imipramine, can induce orthostatic hypotension presumably by their clonidine-like effect or by blocking 04 receptors, but the mechanism remains unclear. 

HT reuptake into the presynaptic neuron. Inhibiting reuptake of 5-HT makes more 5-HT available to postsynaptic receptors and reduces formation of the 5-HT metabolite 5-hydroxyindoleacetic acid. Although other antidepressants, such as imipramine and amitriptyline, inhibit 5-HT reuptake, they are less potent and selective than the SSRIs and clomipramine. Prolonged exposure to increased amounts of 5-HT after chronic antidepressant treatment (2 to 3 weeks) leads to altered responsiveness of postsynaptic 5-HT receptors or presynaptic autoregulatory receptors that govern 5-HT release in specific brain regions. ... 

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