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. 1990 Feb;99(2):227–232. doi: 10.1111/j.1476-5381.1990.tb14685.x

Effect of 5-HT3 receptor antagonists on responses to selective activation of mesolimbic dopaminergic pathways in the rat.

R M Hagan 1, B J Jones 1, C C Jordan 1, M B Tyers 1
PMCID: PMC1917401  PMID: 1691672

Abstract

1. The effects of 5-hydroxytryptamine3 (5-HT3) receptor antagonists on the behavioural hyperactivity response which results from injection of the neurokinin receptor agonist [pGlu5, MePhe8, Sar9]-substance P (5-11) (DiMe-C7) into the ventral tegmental area (VTA) of the rat midbrain have been determined. 2. Subcutaneous administration of ondansetron (GR38032) (0.001-0.3 mg kg-1), GR65630 (0.01 mg kg-1), ICS 205-930 (0.1 mg kg-1) and MDL 72222 (0.1 mg kg-1), inhibited the DiMe-C7-induced hyperactivity response. 3. The effects of ondansetron on DiMe-C7-induced changes in dopamine and 5-HT metabolism in discrete areas of rat forebrain were studied in order to investigate further the possible mechanism of action of 5-HT3 antagonists in modifying mesolimbic dopaminergic systems. 4. Intra-VTA administration of DiMe-C7 increased levels of dihydroxyphenylacetic acid (DOPAC) in the nucleus accumbens, olfactory tubercules and right amygdala, indicating increased mesolimbic dopamine metabolism. DOPAC levels were not significantly increased in the frontal cortex, left amygdala or striatum. Dopamine levels were not altered in any of these brain areas. DiMe-C7 also increased 5-hydroxyindoleacetic acid (5-HIAA) levels in the amygdala but this was only statistically significant in the right amygdala. 5-HT levels were not changed significantly by DiMe-C7 treatment. 5. In control rats, pretreatment with ondansetron (0.1 mg kg-1) had no effect on the levels of dopamine, 5-HT or their metabolites, but in rats given DiMe-C7, ondansetron significantly inhibited the increase in DOPAC levels in the nucleus accumbens.(ABSTRACT TRUNCATED AT 250 WORDS)

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Selected References

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  1. Blandina P., Goldfarb J., Green J. P. Activation of a 5-HT3 receptor releases dopamine from rat striatal slice. Eur J Pharmacol. 1988 Oct 18;155(3):349–350. doi: 10.1016/0014-2999(88)90528-6. [DOI] [PubMed] [Google Scholar]
  2. Bozarth M. A., Wise R. A. Involvement of the ventral tegmental dopamine system in opioid and psychomotor stimulant reinforcement. NIDA Res Monogr. 1986;67:190–196. [PubMed] [Google Scholar]
  3. Butler A., Hill J. M., Ireland S. J., Jordan C. C., Tyers M. B. Pharmacological properties of GR38032F, a novel antagonist at 5-HT3 receptors. Br J Pharmacol. 1988 Jun;94(2):397–412. doi: 10.1111/j.1476-5381.1988.tb11542.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Carboni E., Acquas E., Leone P., Di Chiara G. 5HT3 receptor antagonists block morphine- and nicotine- but not amphetamine-induced reward. Psychopharmacology (Berl) 1989;97(2):175–178. doi: 10.1007/BF00442245. [DOI] [PubMed] [Google Scholar]
  5. Costall B., Domeney A. M., Naylor R. J. Behavioural and biochemical consequences of persistent overstimulation of mesolimbic dopamine systems in the rat. Neuropharmacology. 1982 Apr;21(4):327–335. doi: 10.1016/0028-3908(82)90096-x. [DOI] [PubMed] [Google Scholar]
  6. Costall B., Domeney A. M., Naylor R. J., Tyers M. B. Effects of the 5-HT3 receptor antagonist, GR38032F, on raised dopaminergic activity in the mesolimbic system of the rat and marmoset brain. Br J Pharmacol. 1987 Dec;92(4):881–894. doi: 10.1111/j.1476-5381.1987.tb11394.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Eison A. S., Eison M. S., Iversen S. D. The behavioural effects of a novel substance P analogue following infusion into the ventral tegmental area or substantia nigra of rat brain. Brain Res. 1982 Apr 22;238(1):137–152. doi: 10.1016/0006-8993(82)90777-6. [DOI] [PubMed] [Google Scholar]
  8. Eison A. S., Iversen S. D., Sandberg B. E., Watson S. P., Hanley M. R., Iversen L. L. Substance P analog, DiMe-C7: evidence for stability in rat brain and prolonged central actions. Science. 1982 Jan 8;215(4529):188–190. doi: 10.1126/science.6171884. [DOI] [PubMed] [Google Scholar]
  9. Elliott P. J., Alpert J. E., Bannon M. J., Iversen S. D. Selective activation of mesolimbic and mesocortical dopamine metabolism in rat brain by infusion of a stable substance P analogue into the ventral tegmental area. Brain Res. 1986 Jan 15;363(1):145–147. doi: 10.1016/0006-8993(86)90667-0. [DOI] [PubMed] [Google Scholar]
  10. Elliott P. J., Iversen S. D. Behavioural effects of tachykinins and related peptides. Brain Res. 1986 Aug 27;381(1):68–76. doi: 10.1016/0006-8993(86)90691-8. [DOI] [PubMed] [Google Scholar]
  11. Fallon J. H., Moore R. Y. Catecholamine innervation of the basal forebrain. IV. Topography of the dopamine projection to the basal forebrain and neostriatum. J Comp Neurol. 1978 Aug 1;180(3):545–580. doi: 10.1002/cne.901800310. [DOI] [PubMed] [Google Scholar]
  12. Fozard J. R. MDL 72222: a potent and highly selective antagonist at neuronal 5-hydroxytryptamine receptors. Naunyn Schmiedebergs Arch Pharmacol. 1984 May;326(1):36–44. doi: 10.1007/BF00518776. [DOI] [PubMed] [Google Scholar]
  13. Hagan R. M., Butler A., Hill J. M., Jordan C. C., Ireland S. J., Tyers M. B. Effect of the 5-HT3 receptor antagonist, GR38032F, on responses to injection of a neurokinin agonist into the ventral tegmental area of the rat brain. Eur J Pharmacol. 1987 Jun 19;138(2):303–305. doi: 10.1016/0014-2999(87)90450-x. [DOI] [PubMed] [Google Scholar]
  14. Higgins G. A., Kilpatrick G. J., Bunce K. T., Jones B. J., Tyers M. B. 5-HT3 receptor antagonists injected into the area postrema inhibit cisplatin-induced emesis in the ferret. Br J Pharmacol. 1989 May;97(1):247–255. doi: 10.1111/j.1476-5381.1989.tb11948.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kilpatrick G. J., Jones B. J., Tyers M. B. Identification and distribution of 5-HT3 receptors in rat brain using radioligand binding. Nature. 1987 Dec 24;330(6150):746–748. doi: 10.1038/330746a0. [DOI] [PubMed] [Google Scholar]
  16. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  17. Ohizumi Y., Kobayashi M., Muroyama A., Nakamura H., Kobayashi J. The mechanism of the inotropic action of striatoxin, a novel polypeptide toxin from a marine snail, in isolated cardiac muscle. Br J Pharmacol. 1988 Nov;95(3):867–875. doi: 10.1111/j.1476-5381.1988.tb11716.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Richardson B. P., Engel G., Donatsch P., Stadler P. A. Identification of serotonin M-receptor subtypes and their specific blockade by a new class of drugs. Nature. 1985 Jul 11;316(6024):126–131. doi: 10.1038/316126a0. [DOI] [PubMed] [Google Scholar]
  19. Shearman G. T., Tolcsvai L. Effect of the selective 5-HT3 receptor antagonists ICS 205-930 and MDL 72222 on 5-HTP-induced head shaking and behavioral symptoms induced by 5-methoxy-N,N,dimethyltryptamine in rats: comparison with some other 5-HT receptor antagonists. Psychopharmacology (Berl) 1987;92(4):520–523. doi: 10.1007/BF00176488. [DOI] [PubMed] [Google Scholar]
  20. Smith W. W., Sancilio L. F., Owera-Atepo J. B., Naylor R. J., Lambert L. Zacopride, a potent 5-HT3 antagonist. J Pharm Pharmacol. 1988 Apr;40(4):301–302. doi: 10.1111/j.2042-7158.1988.tb05253.x. [DOI] [PubMed] [Google Scholar]
  21. Stinus L., Kelley A. E., Iversen S. D. Increased spontaneous activity following substance P infusion into A10 dopaminergic area. Nature. 1978 Dec 7;276(5688):616–618. doi: 10.1038/276616a0. [DOI] [PubMed] [Google Scholar]
  22. Stoessl A. J., Dourish C. T., Iversen S. D. The NK-3 tachykinin receptor agonist senktide elicits 5-HT-mediated behaviour following central or peripheral administration in mice and rats. Br J Pharmacol. 1988 Jun;94(2):285–287. doi: 10.1111/j.1476-5381.1988.tb11527.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Wise R. A., Bozarth M. A. Brain reward circuitry: four circuit elements "wired" in apparent series. Brain Res Bull. 1984 Feb;12(2):203–208. doi: 10.1016/0361-9230(84)90190-4. [DOI] [PubMed] [Google Scholar]

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