Receptor sensitivity hypothesis

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. 

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,... 

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... 

The most obvious hypothesis is that in mania, as in dream psychosis with elation and grandiosity, it is possible to raise to very high levels the general activation of the brain and the specific activation of the positive emotion generator in the medial septum and other limbic regions. Because this effect can be artificially accomplished by taking amphetamines, it is reasonable to propose that excessive endogenous dopamine release (or increased receptor sensitivity) may be involved. 

The other end of the psychiatric spectrum (Fig. 12-19) is depression. A catecholamine hypothesis that evolved here during the mid-1960s essentially stated that most of depression is associated with a relative or absolute catecholamine deficiency, especially NE at functionally important adrenergic receptor sites in the brain (Schildkraut, 1965). It is presumed that the opposite situation, which is excess catecholamines, may produce mania. Even though overly simplistic, the hypothesis served as a useful initiation into the developing complexity that followed. The NE deficiency, of course, can arise in any of several ways (1) decreased synthesis, (2) impairment of receptor binding, (3) storage impairment, (4) increased intracellular release, (5) increased oxidative metabolism rate, and (6) decreased receptor sensitivity. It is possible that different depression subtypes relate to dif-... 

Early investigations of peptides in membrane model systems included studies of mel-letin 124,125 220 221 spectra and polarization properties. This water-soluble peptide is found to be structureless in solution at neutral pH but was sensitive to environmental change. The undecapeptide hormone, substance P, a member of the tackykinin family, was also found by Choo et a].1222 to be unstructured in solution at physiological pH and to aggregate at high pH or on interaction with charged lipids. These data were used as counter-evidence to a hypothesis that the membrane surface structured the peptide to facilitate interaction with the receptor. 

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. 

Early research at our institute found that treatment with lithium decreased the b-adrenergic receptor number, consistent with the noradrenergic down-regulation hypothesis but difficult to reconcile with a complementary theory of mania ( 25). Lithium can also block dopamine receptor supersensitivity, and this is consistent with the postulate that mania is associated with an increased sensitivity of catecholamine receptors. 

Leptin makes the cells of liver and muscle more sensitive to insulin. One hypothesis to explain this effect suggests cross-talk between the protein tyrosine kinases activated by leptin and those activated by insulin (Fig. 23-35) common second messengers in the two signaling pathways allow leptin to trigger some of the same downstream events that are triggered by insulin, through insulin receptor substrate-2 (IRS-2) and phos-phoinositide 3-kinase (PI-3K) (Chapter 12). 

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