Central alpha-adrenoceptors and the mechanisms of action of antidepressant drugs.
In conclusion, central alpha-receptors have been shown to be involved in the actions of antidepressants on noradrenergic systems in the brain in several ways. The alpha-2-autoreceptors seem to mediate the so-called feedback inhibition of central NE systems produced indirectly especially by the secondary tricyclics, an effect that is probably reflected in the reduced MHPG levels in CSF of patients treated with these agents (4). During chronic drug treatment, some attenuation of this mechanism seems to occur, mainly because of developing subsensitivity of the alpha-2-receptors. In other cases, such as for mianserin, an alpha-2-receptor blocking action probably explains its direct activating effect on brain NE systems as observed both in acute and chronic studies. Thus, the overall result of these effects appears facilitatory for the efficiency of central noradrenergic neurotransmission, at least when repeated drug treatment schedules are taken into account. Postsynaptic, central alpha-1-receptors (which, inter alia, appear to mediate psychomotor activation) are also implicated in the actions of antidepressants. Experimental data indicate that the sedative action of some of the drugs may be related to their alpha-1-antagonistic properties, although other effects, such as antihistaminic properties, also may be significant in this regard. Clinical studies have shown that thyroid hormone may affect some critical mechanism for obtaining antidepressant activity by tricyclics. Our experimental data suggest that one such mechanism may be sensitization at or beyond postsynaptic alpha-1-receptors in the central nervous system since this effect appears to be produced somewhat specifically, not only by thyroid hormone but also by chronic administration of a variety of antidepressants alone.
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D001921:Brain / Q000187:drug effects*; D003000:Clonidine / Q000494:pharmacology; D006801:Humans; D008125:Locus Coeruleus / Q000187:drug effects; D008803:Mianserin / Q000494:pharmacology; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009638:Norepinephrine / Q000378:metabolism; D010643:Phenoxybenzamine / Q000494:pharmacology; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects*; D013963:Thyroid Hormones / Q000494:pharmacology
D000928:Antidepressive Agents; D000929:Antidepressive Agents, Tricyclic; D011942:Receptors, Adrenergic, alpha; D013963:Thyroid Hormones; D010643:Phenoxybenzamine; D008803:Mianserin; D003000:Clonidine; D009638:Norepinephrine