Adrenergic receptors antidepressant mechanisms

The original monoamine hypothesis of depression states that depressions are associated with a deficiency of catecholamines, particularly norepinephrine, at functionally important adrenergic receptor sites in the brain. Elation conversely may be associated with an excess of such amines. The hypothesis was articulated in 1966 only after the mechanism of action of the tricyclic antidepressant desipramine and of the psychostimulants... 

Other available antidepressants have unique mechanisms of action that may have an impact on norepinephrine, serotonin, or dopamine indirectly through other mechanisms. For example, mirtazapine s direct antagonism of presynaptic a2-adrenergic receptors results in an indirect increase in central noradrenergic and serotonergic activity. 

Mirtazapine has been on the market in the United States since August 1996, and it is available in several other countries. The putative mechanism of action mediating antidepressant activity is the blockade of several serotonin receptors (i.e., 5-HT 2a and 5-HT2c) and a2-adrenergic receptors (172). The latter effect increases NE... 

With tricyclic antidepressant therapy, postsynaptic adrenergic receptors may be inhibited initially, probably contributing to early hypotensive effects of many tricyclics. Over weeks of treatment, receptors remain available and may even become more sensitive to NE as clinical mood-elevating effects gradually emerge. Therefore, as antidepressant treatment gradually becomes chnically effective, inactivation of transmitter reuptake continues to be blocked, presynaptic production and release of NE returns to or may exceed baseline levels, and a postsynaptic adrenergic mechanism is operative. 

Svensson TH, Usdin T (1978) Feedback inhibition of brain noradrenaline neurons by tricyclic antidepressants a-receptor mediation. Science 202 1089-91 Svensson TH, Bunney BS, Aghajanian G (1975) Inhibition of both noradrenergic and serotonergic neurons in the brain by the a-adrenergic agonist clonidine. Brain Res 92 291-306 Szabo B (2002) Imidazoline antihypertensive drugs a critical review on their mechanism of action. Pharmacol Therapeut, 93 1-35... 

Milnacipran selectively inhibits the reuptake of 5-HT (selectivity ratio, 9) at the presynaptic membrane site, thus increasing the concentration of 5-HT in the synaptic cleft (69). Although milnacipran is not a TCA, its mechanism of action is similar to that of imipramine, and its binding and reuptake inhibition profile more closely resembles that of the TCAs. Milnacipran has weak affinity for adrenergic, muscarinic, and Hi receptors and, therefore, is expected to be devoid of the prominent side effects observed for the TCAs. In clinical studies, milnacipran showed antidepressant efficacy similar to that of TCAs and SSRIs. 

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