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,... 

A. M. Davis and S. J. Teague, Hydrogen bonding, hydrophobic interactions, and failure of the rigid receptor hypothesis, Angew. Chem. Int. Ed. 38 736 (1999). 

Holsboer F (2000) The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology 23 477-501... 

Holsboer F (1999) The rationale for corticotropin-releasing hormone receptor (CRH-R) antagonists to treat depression and anxiety. J Psychiatr Res 33 181-214 Holsboer F (2000) The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology 23 477-501... 

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... 

The general steroid-receptor hypothesis is based mainly on estrogen and progesterone receptors. The currently accepted mechanism is unique and consists of several steps at different subcellular structures ... 

Results from sensory evaluation of mixed solution are seen in Table IV. The data list the theoretical response for both the independent and competitive receptor hypothesis as well as the actual sensory score. The actual sensory scores were found to agree fairly well with the competitive model. The minor dissimilarity between the actual and theoretical is due to the inability of individual to taste bitterness in solutions that are extremely sweet, i.e., there is some masking of overall sensory perception which is concentration dependent. The data, therefore, clearly indicate that sweetness and bitterness act in a competitive manner and should be considered to compete for the binding sites at the same receptor. 

Hemmings, W.A., and E.W. Williams, The attachment of IgG to cell components a reconsideration of BrambelTs receptor hypothesis of protein transmission. Proc R Soc Lond B Biol Sci, 1974. 187(1087) 209-19. 

Lithium has several effects on the endocrine system. For example, it can interfere with the synthesis and the release of testosterone, leading to an increase in luteinizing hormone levels. The thyroid system has been most implicated in neuroendocrine theories of lithium s antimanic effects. In particular, thyroid hormones can potentiate b-NE activity, and lithium s ability to block their release may subserve its mood-stabilizing properties (i.e., the thyroid-catecholamine receptor hypothesis)... 

FIGURE 5—60. The monoamine receptor hypothesis of depression posits that something is wrong with the receptors for the key monoamine neurotransmitters. Thus, according to this theory, an abnormality in the receptors for monoamine neurotransmitters leads to depression. Such a disturbance in neurotransmitter receptors may be caused by depletion of monoamine neurotransmitters, by abnormalities in the receptors themselves, or by some problem with signal transduction of the neurotransmitter s message from the receptor to other downstream events. Depicted here is the normal monoamine neuron with the normal amount of monoamine neurottansmitter and the normal amount of correctly functioning monoamine receptors. 

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. 

The monoamine receptor hypothesis of depression suggests that depression is caused predominantly by an absence of key monoamine receptors in the brain. 

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