Effects of BMY 33462, a selective and potent serotonin type-3 receptor antagonist, on mesolimbic dopamine-mediated behavior

Autor: Houston H. Davis, Marie A. Geissler, Arlene S. Eison, Lawrence G. Iben, Robert N. Wright, Jonas A. Gylys, Frank D. Yocca, John R. Torrente
Rok vydání: 1993
Předmět:
Zdroj: Drug Development Research. 29:18-24
ISSN: 1098-2299
0272-4391
DOI: 10.1002/ddr.430290103
Popis: The compound BMY 33462 (4-amino-N-(1-azabicyclo-[2,2,2]oct-3-yl)-2-(butan-2-one-3-yl)oxy-5-chlorobenzamine 1.25 fumerate hydrate) has been shown to be a selective and potent serotonin type-3 (5-HT3) receptor antagonist. Its receptor binding profile includes subnanomolar affinity for the 5-HT3 receptor (Ki, 0.22 ± 0.06 nM) and no affinity for other serotonergic, dopaminergic, and adrenergic receptors (Ki > 1,000 nM). BMY 33462 was also shown to be a potent inhibitor of the Bezold-Jarisch reflex in the anesthetized rat (ED50, 0.09 μg/kg, iv), a functional correlate of 5-HT3 receptor antagonism in vivo. It has been reported that ondansetron and other 5-HT3 antagonists have the ability to block hyperactivity in rats induced by DiMe-C7 ([pGlu5, Me-Phe8, Sar9]SP5–11), a metabolically stable analogue of substance P [Hagan et al. (1990): Br J Pharmacol 99:227–232]. DiMe-C7-induced hyperactivity is thought to occur through activation of mesolimbic dopamine (DA) neurons which project to the nucleus accumbens [West and Michael (1991): Brain Res Bull 26:229–233]. BMY 33462 was examined for its ability to block DiMe-C7-induced hyperactivity as was haloperiodol and ondansetron. The dopamine-2 (D2) antagonist haloperidol produced the greatest inhibition of DiMe-C7-induced hyperactivity at a dose of 0.025 mg/kg (53.7%). Ondansetron significantly inhibited the DiMe-C7-induced increase in locomotor activity at doses of 0.10 mg/kg and 0.50 mg/kg (42% and 30%, respectively). BMY 33462, at doses of 0.025 mg/kg and 0.05 mg/kg, significantly decreased DiMe-C7-induced hyperactivity by 41% and 37%, respectively. Haloperidol proved to be highly efficacious and potent in blocking increases in DiMe-C7-induced locomotor activity, a phenomenon which may correlate with its clinical effectiveness as a neuroleptic agent. BMY 33462 and ondansetron were equally efficacious, however, BMY 33462 was more potent. The ability of 5-HT3 antagonists to alter a mesolimbic DA-mediated behavior indicates a complex interaction between these two neurotransmitter systems and perhaps a role for central 5-HT3 receptors and 5-HT in the regulation of DA transmission. In addition, BMY 33462 and ondansetron were unable to inhibit stereotypy induced by apomorphine (inactive at 100 mg/kg, orally) suggesting a lack of interaction with the nigrostriatal DA pathway. These results support the notion that 5-HT3 antagonists may be potential therapeutic agents for the treatment of hyperdopaminergic disease states, such as schizophrenia, without the side effect liability generally associated with classical neuroleptics. © 1993 Wiley-Liss, Inc.
Databáze: OpenAIRE
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