Neurotransmitter receptors sensitivity

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,... 

Age-related variations in central nervous system (CNS) neurotransmitter production and receptor sensitivity are the most likely explanations for the pharmacodynamic differences observed between children and adults following administration of psychotropic medications [39a], Children have lower phenobarbital ratios than adults, and the ratio increases with gestational age [40,41]. Conversely, a lower therapeutic range for children has been identified for cyclosporine, phenytoin, and digoxin [42]. 

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. 

Pharmacology Lithium alters sodium transport in nerve and muscle cells, and effects a shift toward intraneuronal catecholamine metabolism. The specific mechanism in mania is unknown, but it affects neurotransmitters associated with affective disorders. Its antimanic effects may be the result of increases in norepinephrine reuptake and increased serotonin receptor sensitivity. Pharmacokinetics ... 

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... 

Mechanism of Action A mood stabilizer that affects the storage, release, and reuptake of neurotransmitters. Antimanic effect may result from increased norepinephrine re-uptake and serotonin receptor sensitivity. Therapeutic Effect Produces antimanicand antidepressant effects. 

None of the TCAs seem to have an effect on dopaminergic neurotransmission in the central nervous system (CNS). This has been supported by the lack of alterations in dopamine receptor sensitivity in chronically treated patients who have shown response to treatment (Sugrue, 1983). More recent investigations have also shown that administration of DMI to depressed subjects had no effect on levels of homovanillic acid, the principal metabolite of dopamine, in a measure of brain neurotransmitter production. In this investigation, DMI administration did increase norepinephrine production and overall cerebral metabolism (Lambert, 2000). 

Since many toxins act on ion channels, they provide a wealth of chemical tools for studying the function of these channels. In fact, much of our current understanding of the properties of ion channels comes from studies utilizing only a small percentage of the highly potent and selective toxins that are now available. The toxins typically target voltage-sensitive ion channels, but a number of very useful toxins block ionotropic neurotransmitter receptors. Table 21-1 lists some of the toxins most commonly used in research, their mode of action, and their source. 

Studies of sudden death in novice as well as experienced drug abusers found that cocaine causes vasoconstriction of the coronary arteries which seems to result from an enhancement of Ca2+ influx across myocardial membranes. However, remember that this class of drug affects other neurotransmitter systems. Cocaine inhbiits reuptake of NE and 5-HT as well as binds to the DA transporter. It increases catecholamine receptor sensitivity but does not seem to directly influence enkephalinergic receptors. In addition it also affects neurotransmission the H, Ach and phenylethylamine pathways. Activation of DA, NE or 5-HT neurons independently does not produce the euphoria associated with cocaine misuse. Euphoria seems to be related to simultaneous inteeraction between catecholamine and serotoninergic systems. 

A prolonged decrease in the stimulation of the postsy-naptic receptors can result in a functional increase in receptor sensitivity. The best example of this is the denervation supersensitivity seen when a peripheral nerve is severed.7 In this situation, the lack of presynaptic neurotransmitter release results in a compensatory increase in postsynaptic receptor numbers on the muscle cell. Similarly, the loss of the endogenous neurotransmitter dopamine in neurodegenerative conditions such as Parkinson disease can result in supersensitivity of receptors for that neurotransmitter.14 This increased receptor sensitivity becomes problematic because administration of dopaminelike drugs can cause excessive or untoward responses (see Chapter 10).14... 

The idea that depression is associated with changes in amine receptor sensitivity is summarized in Figure 7-1. For reasons that are still unclear, depression might occur because of an increase in postsynaptic receptor sensitivity to amine neurotransmitters, particularly norepinephrine and serotonin.4 Antidepressant drugs increase amine transmission by a variety of methods, thereby bringing about overstimulation of the postsynaptic receptor. (The exact method by which these drugs increase amine stimulation is discussed later in this chapter.) Overstimulation... 

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