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. 1996 Sep;119(2):223–228. doi: 10.1111/j.1476-5381.1996.tb15974.x

PK 11195 blockade of benzodiazepine-induced inhibition of forskolin-stimulated adenylate cyclase activity in the striatum.

C C Tenn 1, J M Neu 1, L P Niles 1
PMCID: PMC1915837  PMID: 8886401

Abstract

1. The effects of benzodiazepine receptor antagonists on the inhibition of forskolin-stimulated adenylate cyclase (AC) activity by various benzodiazepine (BZ) and indoleamine agonists in the rat striatum were investigated. 2. A biphasic inhibition of forskolin-stimulated AC activity by the peripheral-type agonist, Ro5-4864, and a multiphasic inhibition by the non-selective BZ, diazepam, was observed. One phase of AC inhibition is consistent with a Gi-coupled receptor-mediated action, whereas the other phases appear to involve a direct effect on the enzyme itself. 3. While the central-type antagonist, flumazenil, had no effect on the ability of Ro5-4864 to inhibit AC activity, the peripheral-type receptor ligand, PK 11195, abolished the first phase of inhibition. 4. PK 11195 and pertussis toxin were found to block the inhibitory effect of various BZs and the indoleamines, melatonin and 2-iodomelatonin, on induced AC activity. 5. Saturation binding studies, conducted at 30 degrees C with [3H]-diazepam revealed a single binding site in the rat striatum (KD = 19.3 +/- 0.80 nM) which significantly decreased in affinity in the presence of GTP (KD = 30.5 +/- 2.6 nM; P < 0.05). No significant change in Bmax was observed. 6. These findings indicate the presence of Gi-coupled BZ receptors in the rat striatum. Thus, suppression of cyclic AMP production may contribute to the diverse neuropharmacological effects of BZs, melatonin and related drugs.

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Selected References

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  1. Albertson T. E., Peterson S. L., Stark L. G., Lakin M. L., Winters W. D. The anticonvulsant properties of melatonin on kindled seizures in rats. Neuropharmacology. 1981 Jan;20(1):61–66. doi: 10.1016/0028-3908(81)90043-5. [DOI] [PubMed] [Google Scholar]
  2. Braestrup C., Squires R. F. Specific benzodiazepine receptors in rat brain characterized by high-affinity (3H)diazepam binding. Proc Natl Acad Sci U S A. 1977 Sep;74(9):3805–3809. doi: 10.1073/pnas.74.9.3805. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Caccia S., Carli M., Garattini S., Poggesi E., Rech R., Samanin R. Pharmacological activities of clobazam and diazepam in the rat: relation to drug brain levels. Arch Int Pharmacodyn Ther. 1980 Feb;243(2):275–283. [PubMed] [Google Scholar]
  4. Champney T. H., Champney J. A. Novel anticonvulsant action of chronic melatonin in gerbils. Neuroreport. 1992 Dec;3(12):1152–1154. doi: 10.1097/00001756-199212000-00031. [DOI] [PubMed] [Google Scholar]
  5. Colwell C. S., Levine M. S. Excitatory synaptic transmission in neostriatal neurons: regulation by cyclic AMP-dependent mechanisms. J Neurosci. 1995 Mar;15(3 Pt 1):1704–1713. doi: 10.1523/JNEUROSCI.15-03-01704.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Dan'ura T., Kurokawa T., Yamashita A., Yanagiuchi H., Ishibashi S. Inhibition of rat brain adenylate cyclase activity by benzodiazepine through the effects on Gi and catalytic proteins. Life Sci. 1988;42(4):469–475. doi: 10.1016/0024-3205(88)90086-0. [DOI] [PubMed] [Google Scholar]
  7. De Vivo M., Maayani S. Characterization of the 5-hydroxytryptamine1a receptor-mediated inhibition of forskolin-stimulated adenylate cyclase activity in guinea pig and rat hippocampal membranes. J Pharmacol Exp Ther. 1986 Jul;238(1):248–253. [PubMed] [Google Scholar]
  8. Golombek D. A., Fernández Duque D., De Brito Sánchez M. G., Burin L., Cardinali D. P. Time-dependent anticonvulsant activity of melatonin in hamsters. Eur J Pharmacol. 1992 Jan 21;210(3):253–258. doi: 10.1016/0014-2999(92)90412-w. [DOI] [PubMed] [Google Scholar]
  9. Guardiola-Lemaître B., Lenègre A., Porsolt R. D. Combined effects of diazepam and melatonin in two tests for anxiolytic activity in the mouse. Pharmacol Biochem Behav. 1992 Feb;41(2):405–408. doi: 10.1016/0091-3057(92)90118-y. [DOI] [PubMed] [Google Scholar]
  10. Kitamura Y., Nomura Y., Segawa T. Possible involvement of inhibitory GTP binding regulatory protein in alpha 2-adrenoceptor-mediated inhibition of adenylate cyclase activity in cerebral cortical membranes of rats. J Neurochem. 1985 Nov;45(5):1504–1508. doi: 10.1111/j.1471-4159.1985.tb07219.x. [DOI] [PubMed] [Google Scholar]
  11. 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]
  12. Marangos P. J., Patel J., Boulenger J. P., Clark-Rosenberg R. Characterization of peripheral-type benzodiazepine binding sites in brain using [3H]Ro 5-4864. Mol Pharmacol. 1982 Jul;22(1):26–32. [PubMed] [Google Scholar]
  13. Niles L. P., Hashemi F. S. Pharmacological inhibition of forskolin-stimulated adenylate cyclase activity in rat brain by melatonin, its analogs, and diazepam. Biochem Pharmacol. 1990 Dec 15;40(12):2701–2705. doi: 10.1016/0006-2952(90)90590-h. [DOI] [PubMed] [Google Scholar]
  14. Niles L. P., Ye M., Pickering D. S., Ying S. W. Pertussis toxin blocks melatonin-induced inhibition of forskolin-stimulated adenylate cyclase activity in the chick brain. Biochem Biophys Res Commun. 1991 Jul 31;178(2):786–792. doi: 10.1016/0006-291x(91)90177-9. [DOI] [PubMed] [Google Scholar]
  15. Olianas M. C., Onali P. Pertussis toxin attenuates D2 inhibition and enhances D1 stimulation of adenylate cyclase by dopamine in rat striatum. J Neurochem. 1987 May;48(5):1443–1447. doi: 10.1111/j.1471-4159.1987.tb05683.x. [DOI] [PubMed] [Google Scholar]
  16. Olsen R. W., Tobin A. J. Molecular biology of GABAA receptors. FASEB J. 1990 Mar;4(5):1469–1480. doi: 10.1096/fasebj.4.5.2155149. [DOI] [PubMed] [Google Scholar]
  17. Papanicolaou J., Summers R. J., Vajda F. J., Louis W. J. Anticonvulsant effects of clonidine mediated through central alpha2-adrenoceptors. Eur J Pharmacol. 1982 Jan 22;77(2-3):163–166. doi: 10.1016/0014-2999(82)90013-9. [DOI] [PubMed] [Google Scholar]
  18. Parola A. L., Yamamura H. I., Laird H. E., 3rd Peripheral-type benzodiazepine receptors. Life Sci. 1993;52(16):1329–1342. doi: 10.1016/0024-3205(93)90168-3. [DOI] [PubMed] [Google Scholar]
  19. Pierrefiche G., Zerbib R., Laborit H. Anxiolytic activity of melatonin in mice: involvement of benzodiazepine receptors. Res Commun Chem Pathol Pharmacol. 1993 Nov;82(2):131–142. [PubMed] [Google Scholar]
  20. Salomon Y., Londos C., Rodbell M. A highly sensitive adenylate cyclase assay. Anal Biochem. 1974 Apr;58(2):541–548. doi: 10.1016/0003-2697(74)90222-x. [DOI] [PubMed] [Google Scholar]
  21. Scheinin H., Virtanen R., MacDonald E., Lammintausta R., Scheinin M. Medetomidine--a novel alpha 2-adrenoceptor agonist: a review of its pharmacodynamic effects. Prog Neuropsychopharmacol Biol Psychiatry. 1989;13(5):635–651. doi: 10.1016/0278-5846(89)90051-1. [DOI] [PubMed] [Google Scholar]
  22. Tallman J. F., Paul S. M., Skolnick P., Gallager D. W. Receptors for the age of anxiety: pharmacology of the benzodiazepines. Science. 1980 Jan 18;207(4428):274–281. doi: 10.1126/science.6101294. [DOI] [PubMed] [Google Scholar]
  23. Tenn C. C., Niles L. P. Central-type benzodiazepine receptors mediate the antidopaminergic effect of clonazepam and melatonin in 6-hydroxydopamine lesioned rats: involvement of a GABAergic mechanism. J Pharmacol Exp Ther. 1995 Jul;274(1):84–89. [PubMed] [Google Scholar]
  24. Ying S. W., Niles L., Pickering D., Ye M. Involvement of multiple sulfhydryl groups in melatonin signal transduction in chick brain. Mol Cell Endocrinol. 1992 May;85(1-2):53–63. doi: 10.1016/0303-7207(92)90124-o. [DOI] [PubMed] [Google Scholar]

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