5-HT, agonists

Table 4 Modulation of pKa and oral exposure of 5-HT agonists following fluorine substitution...

Finally, treatments that directly stimulate 5-HT receptors also produce the 5-HT syndrome. First, intraventricular administration of 5-HT, although ineffective in control rats, produces a pronounced syndrome in 5,7-DHT-pretreated subjects (157,188). Systemic administration of 5-HT was ineffective (163), indicating that this effect was centrally mediated. Second, with the exception of one report in mice (94), the direct-acting 5-HT agonist quipazine has been reported to produce the syndrome also (39,108,161,185). 

Evoked potential studies showed that LSD facilitated a PSR this effect was blocked by cyproheptadine (18). The 5-HT agonist quipazine augmented a PSR this effect was blocked by cinanserin but (curiously) not by metergoline (80). Finally, tryptamine (183) and L-tryptophan (19) have been reported to increase PSRs in a cyproheptadine-reversible manner. 

Pharmacology Naratriptan, rizatriptan, sumatriptan, frovatriptan, almotriptan, eletriptan, and zolmitriptan are selective agonists for a vascular 5-hydroxytryptamine-i(serotonin) receptor subtype. Use of 5-HT- agonists results in... 

Other vasospasm-related events Peripheral vascular ischemia and colonic ischemia with abdominal pain and bloody diarrhea have been reported with 5-HT- agonists. 

Chest, jaw, or neck tightness Chest, jaw, or neck tightness is relatively common after 5-HT- agonist administration, and atypical sensations over the precordium... 

Do not use dihydroergotamine, 5-HT- agonists (eg, sumatriptan), ergotamine-containing or ergot-type medications, or methysergide within 24 hours of each other. 

Finally, while on the subject of possible clinical effects of (%2 antagonism, it should be noted that many of the 5-HT, agonists (e.g., buspirone, gepirone, and ipsapirone] that were developed or tested for antianxiety and antidepressant effects are extensively metabolized to l-(2-pyrimidyl]-piperazine, itself an active 0(2-adrenoceptor antagonist (G. Bianchi et al. 1988). Whether this is relevant in vivo in humans remains to be seen. 

Quartermain D, Clement J, Schemer A 5-HT, agonists disrupt memory of fear conditioning in mice. Biol Psychiatry 33 247-254, 1993 Quartermain D, Clement J, Schemer A The 5-HT, agonist tandospirone disrupts retention but not acquisition of active avoidance learning. Pharmacol Biochem Behav 48 805-807, 1994... 

It is a selective 5-HT agonist. It restores and increases motility throughout gastrointestinal tract. It appears to increase the release of acetylcholine from myenteric plexus of the gut. 

There is also evidence of low levels of 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF) of impulsive individuals. We might hypothesize that, in a nonresponsive, impulsive patient, diminished serotonin plays a role in the pathophysiology. This hypothesis could now be tested and simultaneously serve as the foundation for a pathophysiologically based treatment by choosing therapies specific for various components of this system. For example, the 5-HT agonist buspirone might be tried, because there is limited evidence from open trials that it has antiaggressive properties. 

Lithium may facilitate the release of 5-HT, perhaps by increasing tryptophan uptake, enhancing 5-HT release through presynaptic autoreceptors, and/or by increasing activity at postsynaptic 5-HT receptors (i.e., act as a 5-HT agonist). Some data, however, question the long-term effect of lithium on 5-HT enhancement when studied in patients, as opposed to healthy control subjects ( 27). Similar to lithium, clonazepam can increase 5-HT synthesis and cerebrospinal fluid (CSF) levels of its major metabolite, 5-hydroxyindoleacetic acid. Other agents known to enhance 5-HT activity by different mechanisms have also shown initial promise as potential antimanic treatments (e.g., L-tryptophan, a 5-HT precursor). 

Buspirone is an azapirone anxiolytic that acts as a partial 5-HT agonist. In contrast to the BZDs, this agent has no immediate effect on the anxiety seen in patients undergoing medical procedures (e.g., endoscopy, cardioversion). Further, it cannot be given parenterally, because the drug is not available in an i.v. or i.m. formulation. Buspirone does not produce disinhibition euphoria and even in high doses has not been found to have antipsychotic activity. 

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