Post-training intrahippocampal infusion of nicotine prevents spatial memory retention deficits induced by the cyclo-oxygenase-2-specific inhibitor celecoxib in rats

Journal of Neurochemistry

Volumn 95, Issue 4, 2005, Pages 1078-1090

  Sharifzadeh, Mohammad ^a,d   Tavasoli, Mahtab ^a   Naghdi, Nasser ^b   Ghanbari, Azam ^a   Amini, Mohsen ^a   Roghani, Ali ^c  

^a TEHRAN UNIVERSITY OF MEDICAL SCIENCES   (Iran)

^b PASTEUR INSTITUTE OF IRAN   (Iran)

^c TEXAS TECH UNIVERSITY   (United States)

^d TEHRAN UNIVERSITY OF MEDICAL SCIENCES   (Iran)

Author keywords

Cyclo oxygenase 2 containing neurons; Dorsal hippocampus; Morris water maze; Stereotaxic surgery

Indexed keywords

ANTIBODY; CELECOXIB; CYCLOOXYGENASE 2; CYCLOOXYGENASE 2 INHIBITOR; NICOTINE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BRAIN TISSUE; CONCENTRATION RESPONSE; CONTROLLED STUDY; DRUG ADMINISTRATION ROUTE; DRUG INFUSION; HIPPOCAMPUS; IMMUNOHISTOCHEMISTRY; IMMUNOREACTIVITY; INTRAHIPPOCAMPAL DRUG ADMINISTRATION; LATENT PERIOD; MALE; MAZE TEST; MEASUREMENT; MEMORY CONSOLIDATION; MEMORY DISORDER; NEUROPROTECTION; NONHUMAN; OPTICAL DENSITY; PRIORITY JOURNAL; QUANTITATIVE ANALYSIS; RAT; SPATIAL MEMORY; SWIMMING; TISSUE SECTION;

ANIMALS; BEHAVIOR, ANIMAL; CYCLOOXYGENASE 2; CYCLOOXYGENASE INHIBITORS; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG ADMINISTRATION SCHEDULE; ESCAPE REACTION; HIPPOCAMPUS; IMMUNOHISTOCHEMISTRY; LOCOMOTION; MALE; MAZE LEARNING; MEMORY DISORDERS; NICOTINE; NICOTINIC AGONISTS; PYRAZOLES; RATS; RATS, WISTAR; REACTION TIME; SULFONAMIDES; TIME FACTORS;

ANIMALIA;

EID: 28244464436     PISSN: 00223042     EISSN: None     Source Type: Journal    
DOI: 10.1111/j.1471-4159.2005.03454.x     Document Type: Article

References (98)

1. Adams J., Collaco-Moraes Y. and de Belleroche J. D. (1996) Cyclooxygenase-2 induction in cereberal cortex: an intracellular response to synaptic excitation. J. Neurochem. 66, 6-13.
2. Addy L. and Levin E. D. (2002) Nicotine interactions with haloperidol, clozapine and risperidone and working memory function in rats. Neuropsychopharmacology 27, 534-541.
3. Aisen P. S., Schafer K. A., Grundman M., Pfeiffer E., Sano M., Davis K. L., Farlow M. R., Jin S., Thomas R. G. and Thai L. J. (2003) Alzheimer's Disease Cooperative Study. Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression. JAMA 289, 2819-2826.
4. Amateau S. K. and McCarthy M. M. (2002) A novel mechanism of dendritic spine plasticity involving estradiol induction of prostaglandin-E2. J. Neurosci. 22, 8586-8596.
5. Baik E. J., Kim E. J., Lee S. H. and Moon C. H. (1999) Cyclooxygenase-2 selective inhibitors aggravate kainic acid induced seizure and neuronal cell death in the hippocampus. Brain Res. 843, 118-129.
6. Bancroft A. and Levin E. D. (2000) Ventral hippocampal alpha4beta2 nicotinic receptors and chronic nicotine effects on memory. Neuropharmacology 39, 2770-2778.
7. Bejanin S., Cervini R., Mallet J. and Berrard S. (1994) A unique gene organization for two cholinergic markers, choline acetyltransferase and a putative vesicular transporter of acetylcholine. J. Biol. Chem. 269, 21 994-21 947.
8. Berrard S., Varoqui H., Cervini R., Israel M., Mallet J. and Diebler M. F. (1995) Coregulation of two embedded gene products, choline acetyltransferase and the vesicular acetylcholine transporter. J. Neurochem. 65, 939-942.
9. Berse B. and Blusztajn J. K. (1995) Coordinated up-regulation of choline acetyltransferase and vesicular acetylcholine transporter gene expression by the retinoic acid receptor alpha, cAMP, and leukemia inhibitory factor/ciliary neurotrophic factor signaling pathways in a murine septal cell line. J. Biol. Chem. 270, 22 101-22 104.
10. Bezzi P. and Volterra A. (2001) A neuron-glia signalling network in the active brain. Curr. Opin. Neurobiol. 11, 387-394.
11. Brioni J. D., Decker M. W., Sullivan J. P. and Arneric S. P. (1997) The pharmacology of (-)-nicotine and novel cholinergic channel modulators. Adv. Pharmacol. 37, 153-214.
12. Bugajski J., Gadek-Michalska A. and Bugajski A. J. (2002) Effect of constitutive- and inducible-cyclooxygenase in the carbachol-induced pituitary-adrenocortical response during social stress. J. Physiol. Pharmacol. 53, 453-462.
13. Chang Y. C., Tsai C. H., Yang S. H., Liu C. M. and Chou M. Y. (2003) Induction of cyclooxygenase-2 mRNA and protein expression in human gingivial fibroblasts stimulated with nicotine. J. Periodontal Res. 38, 496-501.
14. Chen C., Magee J. C. and Bazan N. G. (2002) Cyclooxygenase-2 regulates prostaglandin E2 signaling in hippocampal long-term synaptic plasticity. J. Neurophysiol. 87, 2851-2857.
15. Chen C. C., Sun Y. T., Chen J. J. and Chiu K. T. (2000) TNF-alpha-induced cyclooxygenase-2 expression in human lung epithelial cells: involvement of the phospholipase C-gamma 2, protein kinase C-alpha, tyrosine kinase, NF-kappa B-inducing kinase, and I-kappa B kinase 1/2 pathway. J. Immunol. 1, 2719-2728.
16. Chen C. C., Sun Y. T., Chen J. J. and Chang Y. J. (2001) Tumor necrosis factor-alpha-induced cyclooxygenase-2 expression via sequential activation of ceramide-dependent mitogen-activated protein kinases, and IkappaB kinase1/2 in human alveolar epithelial cells. Mol. Pharmacol. 59, 493-500.
17. De Craen A. J., Gussekloo J., Vrigsen B. and Westendorp R. G. (2005) Meta-analysis of nonsteroidal anti-inflammatory drug use and risk of dementia. Am. J. Epidemiol. 161, 114-120.
18. Decker M. W., Majchrzak M. J. and Anderson D. J. (1992) Effects of nicotine on spatial memory deficits in rats with septal lesion. Brain Res. 572, 281-285.
19. Decker M. W., Brioni J. D., Bannon A. W. and Americ S. P. (1995) Diversity of neuronal nicotinic acetylcholine receptors: lessons from behavior and implications for CNS therapeutics. Minireview Life Sci. 56, 545-570.
20. Decker M. W., Bannon A. W., Curzon P. et al. (1997) ABT-089 [2-methyl-3-(2-(s)-pyrrolidinylmethoxy) pyridine dihydrochloride]: II. A novel cholinergic channel modulator with effects on cognitive performance in rats and monkeys. J. Pharmacol. Exp. Ther. 283, 247-258.
21. Descarries L., Aznavour N. and Hamel E. (2005) The acetylcholine innervation of cerebral cortex: new data on its normal development and its fate in the hAPP (SW,IND) mouse model of Alzheimer's disease. J. Neural Transm. 12, 149-162.
22. 2. J. Neurophysiol. 85, 2498-2508.
23. Dubois R. N., Abramson S. B., Crofford L., Gupta R. A., Simon L. S., Van De Putte L. B. and Lipsky P. E. (1998) Cyclooxygenase in biology and disease. FASEB J. 12, 1063-1073.
24. Engelhardt G., Bogel R., Schnitzler C. and Utzmann R. (1996) Meloxicam: influence on arachidonic acid metabolism, Part II. In vivo findings. Biochem. Pharmacol. 51, 29-38.
25. Erickson J. D., Varoqui H., Schafer M. K., Modi W., Diebler M. F., Weihe E., Rand J., Eiden L. E., Bonner T. I. and Usdin T. B. (1994) Functional identification of a vesicular acetylcholine transporter and its expression from a 'cholinergic' gene locus. J. Biol. Chem. 269, 21 929-21 932.
26. Gatto G., Bencherif M., Lippiello P., Christopher N., Weaver T., Blackwelder W. and Levin E. (1998) Long-lasting cognitive effects of the CNS-selective nicotine agonist PJR-2403. Soc. Neurosci. Abstr. 24, 88.
27. Gorgoni B., Caivano M., Arizmendi C. and Poli V. (2001) The transcription factor C/EBPbeta is essential for inducible expression of the COX-2 gene in macrophages but not in fibroblasts. J. Biol. Chem. 276, 40 769-40 777.
28. Grigoryan G. A., Mitchell S. R, Hodges H., Sinden J. D. and Gray J. A. (1994) Are the cognitive-enhancing effects of nicotine in the rat with lesions to the forebrain cholinergic projection system mediated by an interaction with the noradrenergic system? Pharmacol. Biochem. Behav. 49, 511-521.
29. Haroutunian V., Barnes E. and Davis K. L. (1985) Cholinergic modulation of memory in rats. Psychopharmacology 87, 266-271.
30. Hasselmo M. E. and McGaughy J. (2004) High acetylcholine levels set circuit dynamics for attention and encoding and low acetylcholine levels set dynamics for consolidation. Prog. Brain Res. 145, 207-231.
31. Hefco V, Yamada K., Hefco A., Hritcu L., Tiron A., Olariu A. and Nabeshima T. (2003) Effects of nicotine on memory impairment induced by blockade of muscarinic, nicotinic and dopamine D2 receptors in rats. Eur. J. Pharmacol. 474, 227-232.
32. Herschman H. R. (1996) Prostaglandin synthase 2. Biochim. Biophys. Acta 1299, 125-140.
33. Hiramatsu M., Satoh H., Kameyama T. and Nabeshima T. (1994) Nootropic effect of nicotine on carbon monoxide (CO) induced delayed amnesia in mice. Psychopharmacology 116, 33-39.
34. Hiramatsu M., Yamatsu T., Kameyama T. and Nabeshima T. (2002) Effects of repeated administration of (-) nicotine on AF64A-induced learning and memory impairment in rats. J. Neural Transm. 109, 361-375.
35. Holscher C. (1995) Inhibitors of cyclooxygenase produce amnesia for a passive avoidance task in the chick. Eur. J. Neurosci. 7, 1360-1365.
36. Itoh A., Nitta A., Nadai M., Nishimura K., Hirose M., Hasegawa T. and Nabeshima T. (1996) Dysfunction of cholinergic and dopaminergic neuronal system in β-amyloid protein-infused rats. J. Neurochem. 66, 1113-1117.
37. Kim J. S. and Levin E. D. (1996) Nicotinic, muscarinic and dopaminergic actions in the ventral hippocampus and the nucleus accumbens: effects on spatial working memory in rats. Brain Res. 725, 231-240.
38. Kujubu D. A., Fletcher B. S., Varnum B. C., Lim R. W. and Herschman H. R. (1991) TIS10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue. J. Biol. Chem. 266, 12 866-12 872.
39. Lee T H., Yang J. T., Kato H., Wu J. H. and Chen S. T. (2004) Expression of brain-derived neurotrophic factor immunoreactivity and mRNA in the hippocampal CA1 and cortical areas after chronic ischemia in rats. J. Neurosci. Res. 76, 705-712.
40. Levin E. D. (1992) Nicotinic systems and cognitive function. Psychopharmacology 108, 417-431.
41. Levin E. D. and Rezvani A. H. (2000) Development of nicotinic drug therapy for cognitive disorders. Eur. J. Pharmacol. 393, 141-146.
42. Levin E. D. and Rose J. E. (1990) Anticholinergic sensitivity following chronic nicotine administration as measured by radial-arm maze performance in rats. Behav. Pharmacol. 1, 511-520.
43. Levin E. D. and Simon B. B. (1998) Nicotinic acetylcholine involvement in cognitive function in animals. Psychopharmacology 138, 217-230.
44. Levin E. D., Castonguay M. and Ellison G. D. (1987) Effects of the nicotinic receptor blocker, mecamylamine, on radial arm maze performance in rats. Behav. Neural Biol. 48, 206-212.
45. Levin E. D., Sledge D., Baruah A. and Addy N. A. (2003) Ventral hippocampal NMDA blockade and nicotinic effects on memory function. Brain Res. Bull. 61, 489-495.
46. Levin E. D., Weber E. and Icenogle L. (2004) Baclofen interactions with nicotine in rats: effects on memory. Pharmacol. Biochem. Behav. 79, 343-348.
47. Levin E. D., Wilson W., Rose J. E. and McEvoy J. (1996) Nicotine-haloperidol interactions and cognitive performance in schizophrenics. Neuropsychopharmacology 15, 429-436.
48. Marti Barros D., Ramirez M. R., Dos Reis E. A. and Izquierdo I. (2004) Participation of hippocampal nicotinic receptors in acquisition, consolidation and retrieval of memory for one trial inhibitory avoidance in rats. Neuroscience 126, 651-656.
49. McGehee D. S., Heath M. J., Gelber S., Devay P. and Role L. W. (1995) Nicotine enhancement of fast excitatory synaptic transmission in CNS by presynaptic receptors. Science 269, 1692-1696.
50. Minghetti L. (2004) Cyclooxygenase-2 (COX-2) in inflammatory and degenerative brain diseases. J. Neuropathol. Exp. Neurol. 63, 901-910.
51. Mundy W. R. and Iwamoto E. T. (1988) Nicotine impairs acquisition of radial maze performance in rats. Pharmacol. Biochem. Behav. 30, 119-122.
52. Naghdi N., Nafisy N. and Majlessi N. (2001) The effects of intrahippocampal testosterone and flutamide on spatial localization in the Morris water maze. Brain Res. 897, 44-51.
53. Needleman P., Turk J., Jakschik B. A., Morrison A. R. and Lefkowith J. B. (1986) Arachidonic acid metabolism. Annu. Rev. Biochem. 55, 69-102.
54. Nordberg A. (2001) Nicotinic receptor abnormalities of Alzheimer's disease: therapeutic implications, Biol. Psychiatry 49, 200-210.
55. 3H] acetylcholine binding sites in the frontal cortex of Alzheimer brains. Neurosci. Lett. 72, 115-119.
56. Nordberg A., Alafuzoff I. and Winblad B. (1992) Nicotinic and muscarinic subtypes in the human brain: brain changes with aging and dementia. J. Neurosci. Res. 31, 103-111.
57. Packard M. G., Teather L. A. and Bazan N. G. (1996) Effects of intrastriatal injections of platelet-activating factor and the PAF antagonist BN 52021 on memory. Neurobiol. Learn. Mem. 66, 176-182.
58. Parsons S. M., Prior C. and Marshall I. G. (1993) Acetylcholine transport, storage and release. Int. Rev. Neurobiol. 35, 279-390.
59. Paxinos G. and Watson W. (1997) The Rat Brain in Stereotaxic Coordinates. Academic press, San Diego.
60. Perez De La Mora M., Mendez-Franco J., Salceda R., Aguirre J. A. and Fuxe K. (1991) Neurochemical effects of nicotine on glutamate and GABA mechanisms in the rat brain. Acta Physiol. Scand. 141, 241-250.
61. Potter A., Corwin J., Lang J., Piasecki M., Lenox R. and Newhouse P. A. (1999) Acute effects of the selective cholinergic channel activator (nicotinic agonist) ABT-418 in Alzheimer's disease. Psychopharmacology 142, 334-342.
62. Prendergast M. A. and Buccafusco J. J. (1998) (-)-Nicotine increases mRNA encoding G3PDH and vesicular acetylcholine transporter in vivo. Neuroreport 9, 1385-1389.
63. Puma C., Deschaux O., Molimard R. and Bizot J. C. (1999) Nicotine improves memory in an object recognition task in rats. Eur. Neuropsychopharmacol. 9, 323-327.
64. Quirion R., Martel J. C., Robitaille Y., Etienne P., Wood P., Nair N. P. and Gauthier S. (1986) Neurotransmitter and receptor deficits in senile dementia of Alzheimer type. Can. J. Neurol. Sci. 13, 503-510.
65. Rail J. M., Mach S. A. and Dash P. K. (2003) Intrahippocampal infusion of a cyclooxygenase-2 inhibitor attenuates memory acquisition in rats. Brain Res. 968, 273-276.
66. Rama Sastry B. V., Hemontolor M. E. and Olenick M. (1999) Prostaglandin E2 in human placenta: its vascular effects and activation of prostaglandin E2 formation by nicotine and cotinine. Pharmacology 58, 70-86.
67. Reines S. A., Block G. A., Morris J. C., Liu G., Nessly M. L., Lines C. R., Norman B. A., Baranak C. C. and Rofecoxib Protocol 091 Study Group. (2004) Rofecoxib: no effect on Alzheimer's disease in a 1-year, randomized, blinded, controlled study. Neurology 62, 66-71.
68. Richter-Levin G., Canevari L. and Bliss T. V. (1995) Long term potentiation and glutamate release in the dentate gyrus: links to spatial learning. Behav. Brain Res. 66, 37-40.
69. Roghani A., Feldman J., Kohan S. A., Shirzadi A., Gunderson C. B., Brecha N. and Edwards R. H. (1994) Molecular cloning of putative vesicular transporter for acetylcholine. Proc. Natl Acad. Sci. USA 91, 10 620-10 624.
70. Roghani A., Shirzadi A., Butcher L. L. and Edwards R. H. (1998) Distribution of the vesicular transporter for acetylcholine in the rat central nervous system. Neuroscience 82, 1195-1212.
71. Saareks V., Mucha I., Sievi E., Vapaatalo H. and Riutta A. (1998) Nicotine stereoisomers and cotinine stimulate prostaglandin E2 but inhibit thromboxane B2 and leukotriene E4 synthesis in whole blood. Eur. J. Pharmacol. 353, 87-92.
72. Sansone M., Castellano C., Battaglia M. and Ammasari-Teule M. (1991) Effects of oxiracetam-nicotine combination on active and passive avoidance learning in mice. Pharmacol. Biochem. Behav. 39, 197-200.
73. Schwieler L., Erhardt S., Erhardt C. and Engberg G. (2004) Prostaglandin-mediated control of rat brain kynurenic acid synthesis opposite actions by COX-1 and COX-2 isoforms. J. Neural Transm. 112, 863-872.
74. Shaftel S. S., Olschowka J. A., Hurley S. D., Moore A. H. and O'Banion M. K. (2003) COX-3: a splice variant of cyclooxygenase-1 in mouse neural tissue and cells. Brain Res. Mol. Brain Res. 119, 213-215.
75. Sharifzadeh M., Naghdi N., Khosravani S., Ostad S. N., Sharifzadeh K. and Roghani A. (2005a) Post-training intrahippocampal infusion of the COX-2 inhibitor celecoxib impaired spatial memory retention in rats. Eur. J. Pharmacol. 511, 159-166.
76. Sharifzadeh M., Sharifzadeh K., Naghdi N., Ghahremani M. H. and Roghani A. (2005b) Posttraining intrahippocampal infusion of a protein kinase All inhibitor impairs spatial memory retention in rats. J. Neurosci. Res. 79, 392-400.
77. Shimojo M., Wu D. and Hersh L. B. (1998) The cholinergic gene locus is coordinately regulated by protein kinase A II in PC12 cells. J. Neurochem. 71, 1118-1126.
78. Shin V. Y., Wu W. K., Ye Y. N., So W. H., Koo M. W., Liu E. S., Luo J. C. and Cho C. H. (2004) Nicotine promotes gastric tumor growth and neovascularization by activation of extracellular signal-regulated kinase and cyclooxygenase-2. Carcinogenesis 25, 2487-2495.
79. Singer S., Rossi S., Verzosa S., Hashim A., Lonow R., Cooper T., Sershen H. and Lajtha A. (2004) Nicotine-induced changes in neurotransmitter levels in brain areas associated with cognitive function. Neurochem. Res. 29, 1779-1792.
80. Smith W. L., Marnett L. J. and Dewitt D. L. (1991) Prostaglandin and thromboxane biosynthesis. Pharmacol. Ther. 49, 153-179.
81. Stolerman I. P., Mirza N. R. and Shoaib M. (1995) Nicotine psychopharmacology: addiction, cognition and neuroadaption. Med. Res. Rev. 15, 47-72.
82. Sullivan J. P., Donnelly-Roberts D. D., Briggs C. A. et al. (1997) ABT-089 [2-methyl-3-(2-(s)-pyrrolidinylmethoxy) pyridine dihydrochloride]. I. A potent and selective cholinergic channel modulator with neuroprotective properties. J. Pharmacol. Exp. Ther. 283, 235-246.
83. Talley J. J., Bertenshaw S. R., Brown D. L., Carter J. S., Graneto M. J., Kellogg M. S., Koboldt C. M., Yuan J., Zhang Y. Y. and Seibert K. (2000) (N-[[(5-methyl-3- phenylisoxazol-4-yl)-phenyl]solfonyl]propanamide, sodium salt, parecoxib sodium: a potent and selective inhibitor of COX-2 for parenteral administration. J. Med. Chem. 43, 1661-1663.
84. Teather L. A., Packard M. G. and Bazan N. G. (2002) Post-training cyclooxygenase-2 (COX-2) inhibition impairs memory consolidation. Learn. Mem. 9, 41-47.
85. Thai L. J., Ferris S. H., Kirby L. et al. (2005) A randomized, double-blind, study of rofecoxib in patients with mild cognitive impairment. Neuropsychopharmacology 30, 1204-1215.
86. Toth E. (1996) Effects of nicotine on the level of extracellular amino acids in the hippocampus of rat. Neurochem. Res. 21, 903-907.
87. Toth E., Vizi E. S. and Lajtha A. (1993) Effects of nicotine on levels of extracellular amino acids in regions of the rat brain in vivo. Neuropharmacology 32, 827-832.
88. Turini M. E. and Dubois R. N. (2002) Cyclooxygenase-2: a therapeutic target. Annu. Rev. Med. 53, 35-57.
89. Usdin T. B., Eiden L. E., Bonner T. I. and Erickson J. D. (1995) Molecular biology of the vesicular ACh transporter. Trends Neurosci. 18, 218-224.
90. White J. F. (1996) Synaptic regulation of mesocorticolimbic dopamine neurons. Annu. Rev. Neurosci. 19, 405-436.
91. Whitehouse P. J. and Kalaria R. N. (1995) Nicotinic receptors and neurodegenerative dementing diseases: basic research and clinical implications. Alzheimer Dis. Assoc. Disord. 9, 3-5.
92. Whitehouse P. J., Martino A. M., Antuono P. G., Lowenstein P. R., Coyle J. T., Price D. L. and Kellar K. J. (1986) Nicotinic acetylcholine binding sites in Alzheimer's disease. Brain Res. 371, 146-151.
93. Wonnacott S. (1997) Presynaptic nicotinic ACh receptors. Trends Neurosci. 20, 92-98.
94. Woolf N. J., Milov A. M., Schweitzer E. S. and Roghani A. (2001) Elevation of nerve growth factor and antisense knockdown of TrKA receptor during contextual memory consolidation. J. Neurosci. 21, 1047-1055.
95. Wozniak D. F., Obey J. W., Kettinger L., Price M. and Miller J. P. (1990) Behavioral effects of MK-801 in the rat. Psychopharmacology 101, 47-56.
96. Xie W. L., Chipman J. G., Robertson D. L., Erikson R. L. and Simmons D. L. (1991) Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing. Proc. Natl Acad. Sci. USA 88, 2692-2696.
97. Yin R. and French E. D. (2000) A comparison of the effects of nicotine on dopamine and non-dopamine neurons in the rat ventral tegmental area: an in vitro electrtophysiological study. Brain Res. Bull. 51, 507-514.
98. Zarrindast M. R., Sadegh M. and Shafaghi B. (1996) Effects of nicotine on memory retrieval in mice. Eur. J. Pharmacol. 259, 1-6.