Effect neuroreceptors

Liechti, M.E. and Vollenweider, F.X., Which neuroreceptors mediate the subjective effects of MDMA in humans A summary of mechanistic studies, Hum. Psychopharmacol. 16(8), 589-598, 2001. 

Because of its sequential, concentration-dependent effects on 5-HT and NE uptake pumps, venlafaxine may offer a wider spectrum of efficacy than SSRIs. Because of its absence of effects on other neuroreceptors and fast Na channels, venlafaxine has a better safety and tolerability profile than do TCAs. 

Several neurochemical hypotheses have been set forth to explain the mechanisms leading to the clinical manifestations of anxiety disorders. Although a detailed account goes beyond the scope of this book, it is enough to state that norepinephrine, serotonin, and GABA (gamma-aminobutyric acid) are three of the neurotransmitters most often implicated. The medications found to be most useful for the treatment of anxiety disorders—SSRIs, TCAs, MAOIs, and benzodiazepines—have profound effects on these neurotransmitters and their respective neuroreceptors. 

Table 16. Examples of the Effects of Agonists or Antagonists at Higher Dosage on Neuroreceptors, Transmitter-related Enzymes, and Ion Channels (After f 17, 89, 323] "Normal" Agonistic Activities of Neurotransmitters...

Low affinity for the multiple neuroreceptors known to be responsible for many of the adverse effects of the TCAs (e.g., acetylcholine, histamine, and adrenergic receptors). 

Citalopram, primarily through its S-enantiomer, blocks 5-FIT reuptake, leading to potentiation of serotonergic activity in the CNS. Citalopram exhibits the greatest in vitro selectivity for 5-HT reuptake inhibition compared with the other SSRIs (Fig. 21.6). The drug essentially has no effect on NE or dopamine reuptake, nor does it show affinity for other neuroreceptors. 

Sertraline is a potent and selective inhibitor of the neuronai reuptake 5-HT transporter, in vitro binding studies suggest that sertraiine has a substantiaiiy higher seiectivity for inhibiting 5-HT reuptake than other SSRis or TCAs, inciuding ciomipramine (Fig. 21.6). it has oniy weak effects on neuronai uptake of NE and dopamine, its mechanism of action is common to the SSRis. Sertraiine is very seiective, iacking affinity for other neuroreceptors at therapeutic concentrations. 

Fluvoxamine is a highly selective inhibitor of 5-HT reuptake at the presynaptic membrane. Potency data from in vitro affinity studies suggest that fluvoxamine is less potent than the other SSRIs (e.g., paroxetine, sertraline, and citalopram). Its mechanism of action is similar to that of the other SSRIs. Fluvoxamine appears to have little or no effect on the reuptake of NE or dopamine. In vitro studies have demonstrated that fluvoxamine possesses virtually no affinity for other neuroreceptors. Its onset of action is similar to the other SSRIs (2-4 weeks). 

The imaging of a neuroreceptor in the human brain (DA receptors) by PET in 1983 was stimulated by the work of Creese, Burt, and Snyder (Science 192 481-483, 1976), who showed that the antipsychotic effect of drugs in schizophrenic patients was directly related to the degree of blocking of Dj DA receptors. In 1978, Kuhar and associates at Johns Hopkins showed that DA receptors in the basal gangha could be visualized by autoradiography after administration of drugs that were bound by DA receptors. 

Venlafaxine a racemate has no appreciable affinity for muscarinic, alpha-adrenergic, beta-adrenergic, histamine-1, 5-HT-lA, 5-HT-2, dopamine-2, benzodiazepine, or opiate receptors [45] and thus is not expected to induce side-effects caused by interaction of venlafaxine itself with these receptors. However, the possibility remained that metabolites of venlafaxine could have affinity for the above mentioned neuroreceptors and thereby cause unwanted side-effects. 

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