Neurotransmitter receptor hypothesis

The neurotransmitter receptor hypothesis suggests that depression is related to abnormal functioning of neurotransmitter receptors. In this model, antidepressants presumably exert therapeutic effects by altering receptor sensitivity. In fact,... 

The problem with the tricyclic-based neurotransmitter-receptor hypothesis of antidepressant activity is that it was based on observations in normal rat brain. Unfortunately, there are few techniques suitable for in vivo work on human CNS receptors of depressed patients. In addition, compounds related to dopaminergic and serotonergic... 

Depletion of monoamine neurotransmitters (cf. Fig. 5—60 and Fig. 5—61) has already been discussed as the central theme of the monoamine hypothesis of depression (see Figs. 5—13 and 5—14). The neurotransmitter receptor hypothesis of depression takes this theme one step further—namely, that the depletion of neurotransmitter causes compensatory up regulation of postsynaptic neurotransmitter receptors (Fig. 5—62). 

One theory to explain the ultimate mechanism of delayed therapeutic action of antidepressants is the neurotransmitter receptor hypothesis of antidepressant action (Figs. 6—1 through 6—6). This is a hypothesis related to the neurotransmitter receptor hypothesis of depression discussed in Chapter 5 (Figs. 5—60 through 5—62). As previously discussed, this latter hypothesis proposes that depression itself is linked to abnormal functioning of neurotransmitter receptors. 

Whether or not neurotransmitter receptors are abnormal in depression, the neurotransmitter receptor hypothesis of antidepressant action proposes that antidepressants, no matter what their initial actions on receptors and enzymes, eventually cause a desensitization, or down regulation, of key neurotransmitter receptors in a time course consistent with the delayed onset of antidepressant action of these drugs (Figs. 6—1 through 6—6). 

FIGURE 6-2. The neurotransmitter receptor hypothesis of antidepressant action—part 1. Shown here is the monoaminergic neuron in the depressed state, with up regulation of receptors (indicated in the red circle). 

In this chapter, we have discussed the mechanisms of action of the major antidepressant drugs. The acute pharmacological actions of these agents on receptors and enzymes have been described, as well as the major hypothesis that attempts to explain how all current antidepressants ultimately work. That hypothesis is known as the neurotransmitter receptor hypothesis of antidepressant action. We have also introduced pharmacokinetic concepts relating to the metabolism of antidepressants and mood stabilizers by the cytochrome P450 enzyme system. 

To understand the biological basis of depression, including the monoamine hypothesis, the neurotransmitter receptor hypothesis and the hypothesis of reduced activation of brain neurotrophic factors. 

Stahl, S. M. 1984, Regulation of neurotransmitter receptors by desipramine and other antidepressant drugs the neurotransmitter receptor hypothesis of antidepressant action, J.Clin.Psychiatry, vol. 45, no. 10, Pt 2, pp. 37-45. 

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