Serotonin action mechanism

Ketanserin (Figure 16-2) blocks 5-HT2 receptors on smooth muscle and other tissues and has little or no reported antagonist activity at other 5-HT or Hi receptors. However, this drug potently blocks vascular adrenoceptors. The drug blocks 5-HT2 receptors on platelets and antagonizes platelet aggregation promoted by serotonin. The mechanism involved in ketanserin s hypotensive action probably involves Kj adrenoceptor blockade more than 5-HT2 receptor blockade. Ketanserin is available in Europe for the treatment of hypertension and vasospastic conditions but has not been approved in the USA. 

Selected for clinical trials as a compound to calm agitated patients, imipramine was relatively ineffective. However, it was observed to be effective in the treatment of certain depressed patients (38). Early studies on the mechanism of action showed that imipramine potentiates the effects of the catecholamines, primarily norepinephrine. This finding, along with other evidence, led to the hypothesis that the compound exerts its antidepressant effects by elevating norepinephrine levels at central adrenergic synapses. Subsequent studies have shown that the compound is a potent inhibitor of norepinephrine reuptake and, to a lesser extent, the uptake of serotonin, thus fitting the hypothesis that had been developed to explain the antidepressant actions ofMAOIs. 

Neuronal Norepinephrine Depleting Agents. Reserpine (Table 6) is the most active alkaloid derived from Rauwolfia serpentina. The principal antihypertensive mechanism of action primarily results from depletion of norepinephrine from peripheral sympathetic nerves and the brain adrenergic neurons. The result is a drastic decrease in the amount of norepinephrine released from these neurons, leading to decrease in vascular tone and lowering of blood pressure. Reserpine also depletes other transmitters including epinephrine, serotonin [50-67-9] dopamine [51-61-6] ... 

Anxiolytics are drugs used for the treatment of anxiety disorders. Apart from benzodiazpines, a frequently used anxiolytic is the 5HT1A (serotonin) receptor agonist buspiron, which has no sedative, amnestic or muscle-relaxant side effects, but whose action takes about a week to develop. Furthermore, it is less efficaceous than the benzodiazepines. Buspiron s mechanism of action is not fully understood. 

The pharmacology of amphetamine is considerably more complex. It does not only block monoamine reuptake, but also directly inhibits the vesicular monoamine transporter, causing an increase in cytosolic but not vesicular dopamine concentration. This may lead to reverse transport of the amines via the membrane-bound transporters. Further mechanisms of amphetamine action are direct MAO inhibition and indirect release of both dopamine and serotonin in the striatum. 

Davis, LL, Yonkers, KA, Trivedi, M, Kramwer, GL and Petty, F (1999) The mechanism of action of SSRIs, a new hypothesis. In Selective Serotonin Reuptake Inhibitors (SSRIs) Past, Present and Future (Ed. Stanford, SC), RG Landes Co., Austen, TX, pp. 171-185. 

In view of the apparent pleasurable effects of MDMA, it becomes of considerable interest to understand the mechanism of action of substances with a similar effect. Major efforts have been directed toward the study of agents that have an effect on serotonin pathways, since that is the neurotransmitter system that seems most implicated in the mechanism of action of MDMA. This hypothesis is further reinforced by the observation that MDMA substitutes for fenfluramine (Schechter 1986). and fenfluramine substitutes for MBDB (Oberlender and Nichols, unpublished). The substitution data for (+)-amphetamine and cocaine in (-t-)-MBDB-trained rats are also similar to the data for substitution of these agents in fenfluramine-trained rats (White and Appel 1981). 

The behavioural effects of two antidepressants with opposite molecular actions, ie. tianeptine (a serotonin reuptake enhancer) and fluoxetine (a serotonin reuptake blocker) have been assessed and it was concluded that, apart from the effects on serotonin reuptake, these dmgs have other mechanisms playing an important role in the anti-depressant action <00AF5>. 

The amino acid L-tryptophan is the precursor for the synthesis of 5-HT. The synthesis and primary metabolic pathways of 5-HT are shown in Figure 13-5. The initial step in the synthesis of serotonin is the facilitated transport of the amino acid L-tryptophan from blood into brain. The primary source of tryptophan is dietary protein. Other neutral amino acids, such as phenylalanine, leucine and methionine, are transported by the same carrier into the brain. Therefore, the entry of tryptophan into brain is not only related to its concentration in blood but is also a function of its concentration in relation to the concentrations of other neutral amino acids. Consequently, lowering the dietary intake of tryptophan while raising the intake of the amino acids with which it competes for transport into brain lowers the content of 5-HT in brain and changes certain behaviors associated with 5-HT function. This strategy for lowering the brain content of 5-HT has been used clinically to evaluate the importance of brain 5-HT in the mechanism of action of psychotherapeutic drugs. 

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