Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ritanserin is a potent and selective serotonin-S2 antagonist which slowly dissociates from the receptor sites, while setoperone has potent serotonin and moderate dopamine antagonistic properties and dissociates rapidly from the receptor sites. Acute administration of ritanserin (1-10 mg/kg) produced a non-competitive inhibition of 3H-ketanserin binding, measured ex vivo in washed frontal cortex membranes, which lasted for 12 h. This is in accordance with the slow dissociation of the drug from the receptor sites. Setoperone (1-10 mg/kg orally) also produced a partially non-competitive inhibition of 3H-ketanserin binding in washed membranes, which is unlike its rapid dissociation. In contrast, there was no inhibition of dopamine receptor binding in washed striatal membranes. Chronic oral administration of 10 mg/kg X day of the drugs significantly reduced the Bmax values of 3H-ketanserin, without changing the KD value when drug-free periods were longer than 1 day. The maximum reduction following 25 days' treatment with 14 mg/kg ritanserin was 50% at 1 day drug-free; the Bmax values gradually returned to the control value in about 12 days. The receptor half-life was calculated to be 3.5 days and the receptor synthesis rate 4 fmoles/mg tissue X day. Ritanserin treatment did not alter radioligand binding to serotonin-S1, alpha 1-, alpha 2- and beta-adrenergic, dopamine-D2, benzodiazepine and substance P sites. Chronic treatment with setoperone at 10 mg/kg X day, orally, significantly reduced the Bmax value of 3H-ketanserin binding in frontal cortex but treatment with 1 mg/kg X day did not. In contrast, a dose-dependent increase in the number of striatal dopamine-D2 sites was observed, in accordance with the moderate dopamine-antagonistic properties of setoperone. Dopamine-D2 receptor up regulation up to 150% of control values, was maintained at the same level for 9 days, it started to decline 12 days after stopping drug treatment. Following chronic treatment and drug withdrawal for more than 1 day, ritanserin and setoperone levels in whole brain homogenates were below detection level (less than 1 ng/g). The similar reduction in the Bmax values of 3H-ketanserin binding following chronic treatment with the rapidly dissociating setoperone and the slowly dissociating ritanserin, the absence of effect on the KD value, the slow reappearance of the receptor sites and the opposite effect on serotonin-S2 and dopamine-D2 receptors with setoperone suggest that real serotonin-S2 receptor down regulation occurs following antagonist treatment. The findings illustrate the difference in receptor regulation between the serotonergic and the dopaminergic system.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Down regulation of serotonin-S2 receptor sites in rat brain by chronic treatment with the serotonin-S2 antagonists: ritanserin and setoperone. 301 Mar 61

The possibility that serotonin (5-HT) modulates dopamine (DA) synthesis by acting at 5-HT2 receptor sites during methamphetamine (METH) treatment was investigated. The neostriatal accumulation of 3,4-dihydroxyphenylalanine was not altered by ritanserin (1 mg/kg i.p.), a 5-HT2/1c receptor antagonist, or by METH (15 or 25 mg/kg s.c.), which indicates that METH-induced DA and 5-HT release did not invoke increased DA synthesis. Interestingly, the combined treatment of METH with ritanserin reduced 3,4-dihydroxyphenylalanine formation. We also examined the possibility that 5-HT2 receptors participate in the mechanism by which METH alters central tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH) activities as well as the concentration of neurotensin-like and substance P-like immunoreactivity. Five administrations of METH given at 6-hr intervals reduced neostriatal TH and TPH activity to 27 and 13% of control, respectively, 18 to 20 hr after the last drug administration; ritanserin failed to alter these decreases significantly. Ritanserin also failed to alter the METH-induced increase in neostriatal neurotensin-like immunoreactivity or in nigral neurotensin-like immunoreactivity and substance P-like immunoreactivity. Finally, the administration of ICS 205-930, a 5-HT3/4 receptor antagonist, also failed to prevent the METH-induced decrease in TH and TPH activities at doses below 200 micrograms/kg, whereas a dose of 500 micrograms/kg potentiated the effect of METH. These results suggest that 5-HT2 does not modulate DA synthesis nor does it mediate the changes in central TH and TPH activity, or neurotensin-like immunoreactivity and substance P-like immunoreactivity content induced by METH. Because 3,4-methylenedioxymethamphetamine is reported to stimulate DA synthesis by a 5-HT2 receptor-dependent mechanism, these observations suggest that METH and 3,4-methylenedioxymethamphetamine regulate the central dopaminergic system in a different manner.
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PMID:Role of the 5-HT2 receptor in the methamphetamine-induced neurochemical alterations. 791