Depression 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). 

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. 

In SUMMARY, irrespective of the specificity of the antidepressants following their acute administration, it can be speculated that a common feature of all these drugs is to correct the abnormality in neurotransmitter receptor function. Such an effect of chronic antidepressant treatment may parallel the time of onset of the therapeutic response and contribute to the receptor sensitivity hypothesis of depression and the common mode of action of antidepressants. 

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. 

Before discussing the cyclics and MAOIs in more detail, we need to present the postulated biochemical hypotheses for depression. It is believed that depression results from a deficiency in biogenic amines, specifically catecholamines and serotonin, which act as central nervous system neurotransmitters (see Chapter 3). According to the catecholamine hypothesis, depression results from a deficiency in catecholamines (particularly norepinephrine) at varied neuron receptor sites in the brain. The cyclics are believed to block the reuptake of norepinephrine from the synaptic cleft. Thus, the result is a greater concentration of norepinephrine in the synaptic cleft, alleviating the hypothesized neurotransmitter deficiency. This cyclic-mediated process is thought to occur in the amygdala and reticular formation areas of the brain. 

Several mechanisms exist to explain the etiology of affective disorders all based on the hypothesis that certain levels of amine neurotransmitters (e.g., norepinephrine - NE, serotonin - 5-HT) and receptor sensitivity are necessary for normal mood. There is ample evidence that depression occms if receptors are insensitive or if amine synthesis, storage or... 

On balance, these actions could support a decrease rather than an increase in the functional state of CNS NE transmission, because depression can be conceptualized as a state of supersensitive catecholamine receptors secondary to decreased NE availability. This reasoning is consistent with the original hypothesis of diminished NE functioning, with antidepressants returning receptors to a more normal state of sensitivity. Siever and Davis ( 41) further elaborated on this concept by suggesting the possibility of dysregulation in the homeostatic mechanisms of one or more neurotransmitter systems, culminating in an unstable or erratic output. 

It now seems probable that specific disturbances occur in the immune system in psychiatric illness that are not artefacts of non-specific stress factor, institutionalization or medication. The known effects of the neuroendocrine system on the immune response, and the recent evidence that receptor sites for neurotransmitters and neuroendocrine factors occur on lymphocytes and macrophages, support the hypothesis that immunological abnormalities may assist in precipitating the symptoms of anxiety and depression, commonly symptoms of major affective disorders. 

The amine hypothesis of mood postulates that brain amines, particularly norepinephrine (NE) and serotonin (5-HT), are neurotransmitters in pathways that function in the expression of mood. According to the amine hypothesis, a functional decrease in the activity of such amines would result in depression a functional increase of activity would result in mood elevation. Difficulties with this hypothesis include the facts that (1) antidepressant drugs cause changes in amine activity within hours, but weeks may be required for them to achieve clinical effects (2) most antidepressants ultimately cause a down-regulation of amine receptors and (3) at least one antidepressant, bupropion, has minimal effects on brain NE or 5-HT. 

Depression may be due to a relative decrease in monoaminergic neurotransmission. In animal studies, tricyclic antidepressants initially block re-uptake of monoamines, resulting in higher neurotransmitter concentrations in the synaptic cleft. Over a period of time, the postsynaptic neuron responds to the chronic elevation of monoamines by expressing fewer receptors on the postsynaptic membrane. If indeed clinical response is due to receptor downregulation, then the hypothesis that depression is due to inadequate monoaminergic transmission would be unsatisfactory. It is unclear whether these mechanisms are responsible for relief from depression in humans. 

The permissive hypothesis (10) emphasizes the importance of the balance between 5-HT and NE in regulating mood, not the absolute levels of these neurotransmitters or their receptors. If 5-HT levels are too low, the balanced control of the NE system is lost, permitting abnormal levels of NE to cause mania, as seen in bipolar disorders. If the NE levels fall, the balanced control of the 5-HT system is lost, allowing abnormal levels of 5-HT to cause the person to exhibit the symptoms of depression. 

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