Norepinephrine receptor sites

Surprisingly, amitriptyline shows antidepressant activity rather than antipsychotic activity. It is now known that amitriptyline inhibits the reuptake of norepinephrine and serotonin from the synaptic cleft. Because the reuptake of these neurotransmitters is inhibited, their effects are potentiated. That is, the two neurotransmitters remain available to interact with serotonin and norepinephrine receptor sites... 

The original monoamine hypothesis of depression states that depressions are associated with a deficiency of catecholamines, particularly norepinephrine, at functionally important adrenergic receptor sites in the brain. Elation conversely may be associated with an excess of such amines. The hypothesis was articulated in 1966 only after the mechanism of action of the tricyclic antidepressant desipramine and of the psychostimulants... 

Serotonin uptake sites Norepinephrine uptake sites D-1 dopamine receptors Cholme uptake... 

The neurochemical effects of the tricyclic antidepressants are blockade of the re-uptake of norepinephrine and for some drugs also serotonin by nerve terminals in the CNS and peripherally. This reuptake inhibition results in higher concentrations of the neurotransmitters at their receptors sites. There is little or no effect on DA neurotransmission. The tricyclic antidepressants have varying affinities for U2... 

Mechanism of Action A tricyclic antidepressant that blocks the reuptake of neu-retransmitters, including norepinephrine and serotonin, at presynaptic membranes, thus increasing their availability at postsynaptic receptor sites. Also has strong anticholinergic activity. Therapeutic Effect Relieves depression. 

Mechanism of Action A sympathomimetic amine that produces CNS and respiratory stimulation, mydriasis, bronchodilation, a pressor response, and contraction of the urinary sphincter Directly effects alpha and beta receptor sites in peripheral system. Enhancesreleaseof norepinephrine by blocking reuptake, inhibiting monoamine oxidase. Therapeutic Effect Increases motor activity, mental alertness decreases drowsiness, fatigue. 

MecfianismofAction An antidepressant that inhibits the MAO enzyme system at central nervous system (CNS) storage sites. The reduced MAO activity causes an increased concentration in epinephrine, norepinephrine, serotonin, and dopamine at neuron receptor sites. Therapeutic Effect Produces antidepressant effect. 

Mechanism of Action An MAOI that inhibits the activity of the enzyme monoamine oxidase at CNS storage sites, leading to increased levels of the neurotransmitters epinephrine, norepinephrine, serotonin, and dopamine at neuronal receptor sites. Therapeutic Effect Relieves depression. 

Mechanism of Action A tricyclic antidepressant that blocks the reuptake of neu-rotransmitters, such as norepinephrine and serotonin, at presynaptic membranes, in-creasing their concentration at postsynaptic receptor sites. Therapeutic Effect Results in antidepressant effect. Anticholinergic effect controls nocturnal enuresis, Pharmacohinetics Rapidly, completely absorbed after PO administration, and not affected by food. Protein binding 95%, Metabolized in liver (significant first-pass effect), Primarily excreted in urine. Not removed by hemodialysis. Half-life 16-40 hr. 

The tertiary amine tricyclics have similar effects on norepinephrine and serotonin transmission, while the two secondary amines have more specific effects on norepinephrine, with much smaller effects on serotonin. This can be seen in the fCj (inhibitory constant) values for the TCAs, as listed in Table 23.1. is the concentration of drug required to block transport of the neurotransmitter (in this case, norepinephrine or serotonin). Lower fCj equals greater relative ability to block transport. Desipramine and NT have the greatest inhibitory effects at the receptor site, while CMI has... 

Thus, studies of clonidine and methyldopa suggest that normal regulation of blood pressure involves central adrenergic neurons that modulate baroreceptor reflexes. Clonidine and a-methylnorepinephrine bind more tightly to a2 than to adrenoceptors. As noted in Chapter 6, a2 receptors are located on presynaptic adrenergic neurons as well as some postsynaptic sites. It is possible that clonidine and -methylnorepinephrine act in the brain to reduce norepinephrine release onto relevant receptor sites. Alternatively, these drugs may act on postsynaptic a2 adrenoceptors to inhibit activity of appropriate neurons. Finally, clonidine also binds to a nonadrenoceptor site, the imidazoline receptor, which may also mediate antihypertensive effects. 

Amphetamines not only mimic the action of norepinephrine and dopamine they also boost the levels of these neurotransmitters in a synaptic cleft by blocking their removal. Normally, neurotransmitters are reabsorbed by presynaptic neurons after they have exerted their effect on postsynaptic receptor sites. This process, commonly called neurotransmitter reuptake and illustrated in Figure 14.24, is the body s way of recycling neurotransmitters, molecules that are difficult to synthesize. Special membrane-embedded proteins are required to pull once-used neurotransmitter molecules back into a presynaptic neuron. Amphetamines inactivate norepinephrine and dopamine reuptake proteins by binding to them. As a consequence, the concentration of these stimulating neurotransmitters in the synaptic cleft is maintained at a higher-than-normal level. 

Long-term cocaine or amphetamine abuse leads to a deterioration of the nervous system. The body recognizes the excessive stimulatory actions produced by these drugs. To deal with the overstimulation, the body creates more depressant receptor sites for neurotransmitters that inhibit nerve transmission. A tolerance for the drugs therefore develops. Then, to receive the same stimulatory effect, the abuser is forced to increase the dose, which induces the body to create even more depressant receptor sites. The end result over the long term is that the abusers natural levels of dopamine and norepinephrine are insufficient to compensate for the excessive number of depressant sites. Lasting personality changes are thus often observed. 

An example of negative allosteric modulation is the case of the antidepressants, which act as neurotransmitter reuptake blockers for the neurotransmitters norepinephrine and serotonin. This has already been discussed in Chapter 2. When the neurotransmitters norepinephrine and serotonin bind to their own selective receptor sites, they are normally transported back into the presynaptic neuron, as shown in Figure 2-23- Thus the empty reuptake carrier (Fig. 2—20) binds to the neurotransmitter (Fig. 2—21) to begin the transport process (Fig. 2—23). However, when certain antidepressants bind to an allosteric site close to the neurotransmitter transporter (represented as an icon in Figs. 2—22 and 2—24), this causes the neurotransmitter to no longer be able to bind there, thereby blocking synaptic re-... 

Hallucinogens have rather complex interactions at neurotransmitter systems, but one of the most prominent is a common action as agonists at serotonin 2A (5HT2A) receptor sites (Fig. 13—10). Hallucinogens certainly have additional effects at other 5HT receptors (especially 3HT1A somatodendritic autoreceptors) and also at other neurotransmitter systems, especially norepinephrine and dopamine, but the relative importance of these other actions are less well known. Also, MDMA appears to be a powerful releaser of serotonin and it and several drugs structurally related to it... 

Lithium is thought to exert its effect by interfering with the calcium-mediated release of norepinephrine, increasing the uptake of norepinephrine, and decreasing the sensitivity of postsynaptic receptor sites to norepinephrine. 

In addition to releasing norepinephrine (through exocytosis), the stimulation of sympathetic neurons also releases ATP, storage protein, and dopamine P-hydroxylase. The released norepinephrine interacts with receptor sites located postsynaptically (a,) to produce the desired effects. 

---