Figure 332

Cascade of adaptive changes occurring at norepinephrine (NE) synapses following chronic TCA drug treatment.

function parallel the time delay associated with clinical efficacy of these drugs (2-3 weeks). These latter findings have added to the attractiveness of this theory. However, at noradrenergic synapses with multiple adrenoceptors (i.e., ar, a2-, and p-adrenoceptors), synaptic transmission through aj-adrenoceptors will likely be enhanced at the same time that synaptic transmission through a2-and p-adrenoceptors is reduced (Figure 33.3).

While much emphasis has been placed on alterations in noradrenergic neurotransmission, TCA drugs are not without effect on serotonin (5-HT) neurotransmission. Long-term studies with TCA drugs in animals have demonstrated postsynaptic supersensitivity to serotonin (5-HT1A) receptor agonists at serotonin synapses, with an associated enhancement of serotoner-gic neurotransmission. The sensitization to 5-HT1A agonists is mediated in part by an increase in the density of postsynaptic 5-HT1A receptors. Enhancement of trans mission through 5-HT1A receptors appears to be a common phenomenon after chronic administration of all clinically effective antidepressants and electroconvulsive treatment. The occurrence of this 5-HT1A supersen-sitivity parallels the delayed onset of the therapeutic actions of these agents (2-3 weeks). These observations lend strong support to the hypothesis that enhanced serotonergic neurotransmission is required for the therapeutic benefit from TCA drugs.

It is likely that TCA drugs produce their therapeutic benefits by acting at both serotonin and norepinephrine synapses. The literature also supports the notion of an interdependence of these two monoamine systems in the treatment of depression. The time-dependent changes in the flow of synaptic information through individual receptor subtypes within the norepinephrine and serotonin synapses following chronic TCA administration are summarized in Figure 33.3.

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