Neurotransmitter receptors antidepressant specificity

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. 

In my admittedly biased view, the most coherent approach is that of a profoundly disturbed stress system that under specific conditions paves the way to development of mood disorders. These stress-system alterations can be genetic or acquired through trauma in early life or even in utero. Consistent with this neuroendocrine hypothesis are findings that centrally released neuropeptides that drive the HPA system also have behavioral effects that are similar to affective symptoms. This view is further supported by the documented ability of various antidepressants to enhance corticosteroid receptor synthesis and efficacy. Moreover, the stress system, particularly the corticosteroids and their receptors, interferes with all of the neurotransmitter receptor systems, including intracellular signaling, that have been considered in the context of mood disorders. New drugs targeted directly to various elements of the stress system will constitute a major step forward. 

In terms of the therapeutic actions of tricyclic antidepressants, they essentially work as allosteric modulators of the neurotransmitter reuptake process. Specifically, they are negative allosteric modulators. After the neurotransmitter norepinephrine or serotonin binds to its own selective receptor site, it is normally transported back into the presynaptic neuron as discussed in Chapter 5 (Fig. 5-16). However, when certain antidepressants bind to an allosteric site close to the neurotransmitter transporter, this causes the neurotransmitter to no longer be able to bind there, thus blocking synaptic reuptake of the neurotransmitter (Figs. 6-28 and 6—29). Therefore, norepinephrine and serotonin cannot be shuttled back into the presynaptic neuron. 

There is another reason why medications exert multiple effects. For example, an antidepressant that very specifically promotes serotonin neurotransmission and has little or no interaction with other receptor types will still produce multiple effects. How can this be Remember that in different areas of the brain, a single neurotransmitter can assume very distinct roles. When an individual takes a medication that alters the activity of a particular neurotransmitter, it generally does so throughout the brain. Consequently, the dopamine receptor blocking effect of haloperidol (Haldol) reduces hallucinations and paranoia in one brain region but causes upper extremity stiffness through its action in another brain region. 

Because many have suggested that the beneficial effect of antidepressants is based on their ability to block the uptake of NE and 5-HT, pharmaceutical companies screen potential antidepressants for their ability to block neurotransmitter uptake. Partially as a result of this paradigm (i.e., reuptake blockade), the industry has developed agents that can specifically block NE uptake, 5-HT uptake, or both. More recently, drugs that also affect specific receptors or receptor subtypes have been... 

Norepinephrine Mostly excitatory, but inhibitory in some areas. Secreted by neurons in the locus ceruleus (subcortical area) to widespread areas of the brain, controlling wakefulness, overall activity, and mood. Also diffusely secreted in the sympathetic nervous system. Diffuse and widespread symptoms, including depression, changes in blood pressure, heart rate, and diffuse physiological responses, among many others. An important transmitter in the sympathetic branch of the autonomic nervous system. Diffusely affected by many medications. Several antidepressants work specifically on this neurotransmitter and its receptor sites. Many medications for general medical conditions affect this neurotransmitter as well. 

Serotonin Usually inhibitory helps control mood, influences sleep, and inhibits pain pathways in the spinal cord. Secreted by subcortical structures into hypothalamus, brain, and spinal cord. There are many subtypes of serotonin receptors. Diffuse and widespread symptoms depression, headache, diarrhea, constipation, sexual dysfunction, and other medical symptoms. The selective serotonin reuptake inhibitors (SSRIs), the most commonly used antidepressants, work specifically on this neurotransmitter system. 

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