A possible common mechanism of action of antidepressant treatments

Abstract

The response of the noNEpinephrine (NE) sensitive cyclic AMP generating system in slices of the rat limbic forebrain after both the acute and chronic administration of the tricyclic antidepressants desipramine (DMI) and iprindole as well as electro-convulsive treatment (ECT) was investigated. Neither the basal level of cyclic AMP nor the hormonal response to NE were altered after administration of a single dose of short term treatment with DMI and iprindole. However, the administration of the antidepressants on a clinically more relevant time basis markedly reduced the sensitivity of the cyclic AMP generating system to NE. This change in sensitivity was not related to the levels of the drugs in brain. The response of cyclic AMP to NE was also reduced by ECT, but the onset of this action was shorter than that observed with the antidepressants. ECT also antagonized the enhanced response of cyclic AMP to NE following destruction of central adrenergic nerve terminals with 6-hydroxydopamine. It thus appears that the therapeutic action of tricyclic antidepressants could be related to postsynaptic adaptive changes in the sensitivity of the noradrenergic adenylate cyclase receptor system rather than to acute presynaptic events.

Effect of Antidepressant Drugs in Mice Lacking the Norepinephrine Transporter

“…These adaptive changes at the level of central adrenergic receptors might be interpreted as a response to sustained elevated levels of extracellular NE in the NET À/À mice, which has indeed been shown by Wang et al (1999) and Xu et al (2000). In many studies, it has been reported that repeated treatment with tricyclic ADs or electroconvulsive shock increases either the density or agonist affinity of brain a 1 -adrenergic receptors (Menkes and Aghajanian, 1981;Menkes et al, 1980;Nalepa et al, 2002;Vetulani et al, 1984). However, not all investigators have been able to confirm the above findings (Heal, 1984;Stockmeier et al, 1987;Hayakawa et al, 1992), indicating that variables involved have not been completely isolated.…”

Chronic treatment with lithium or desipramine alters discharge frequency and norepinephrine responsiveness of cerebellar Purkinje cells.

“…The first group ("chronic DMI, high") received, by gavage, DMI-HCl at 50 mg/kg in 2 ml of tap water once daily for 3 days, and then 30 mg/kg per day thereafter for [7][8][9][10][11] days. The second group ("chronic DMI, low") received DMI at 30 mg/kg per day for [8][9][10][11][12][13][14][15][16][17][18] days.…”

“…The second group ("chronic DMI, low") received DMI at 30 mg/kg per day for [8][9][10][11][12][13][14][15][16][17][18] days. These two "chronic groups" were tested electrophysiologically [24][25][26][27][28][29][30][31][32][33][34][35][36] hr after the last dose, when cerebellar DMI is roughly one-half the level during treatment (unpublished data). The third group ("controls") received 2 ml of tap water by gavage daily for [6][7][8][9][10] days.…”

Some anticonvulsant drugs alter monoamine‐mediated behaviour in mice in ways similar to electroconvulsive shock; implications for antidepressant therapy

“…Firstly, in common with many other antidepressant treatments, repeated ECS administration decreases P-adrenoceptor number (Bergstrom & Kellar, 1979;Deakin et al, 1981) and noradrenaline-sensitive adenylate cyclase activity (Vetulani et al, 1976). Secondly, it attenuates both the sedation response of rodents to the M2-adrenoceptor agonist clonidine and the decrease in brain 3-methoxy-4-hydroxyphenylglycol sulphate (MOPEG-SO4) concentration produced by this drug (Heal et al, 1981), suggesting a decrease in the function of the, possibly, presynaptic a2-adrenoceptors in the brain.…”