Preferential blockade of cholecystokinin-8S-induced increases in aspartate and glutamate levels by the CCK(B) receptor antagonist, L-365,260, in rat brain.
In the present studies, the ability of a locally delivered cholecystokinin (CCK) receptor agonist and systemically delivered antagonists to modulate extracellular levels of aspartate and glutamate in the frontal cortex of anaesthetised rats and frontal cortex and caudate-putamen of freely moving rats was investigated using an in vivo microdialysis technique. In the anaesthetised rats, local application of sulphated CCK octapeptide (CCK-8S, 10 microM) into the frontal cortex enhanced extracellular aspartate levels to a maximum of 265+/-16% of the basal levels, whereas glutamate levels were increased to a maximum of 168+/-7% of the basal levels. Given 40 min prior to the cortical perfusion of 10 microM of CCK-8S, the CCK(B) receptor antagonist, L-365,260 (20 mg/kg, s.c.), limited the rise in cortical aspartate by over half to 170+/-10% of the basal levels. However, this same dose of L-365,260 still allowed CCK-8S to increase glutamate by 44+/-15% above the basal levels. Whereas the enhanced glutamate levels were totally unaffected by systemic administration of the CCK(A) receptor antagonist, L-364,718 (20 mg/kg, -40 min, s.c.), this treatment was able to limit the elevation in aspartate to 220+/-4% of the basal levels. In the freely moving rats, local perfusion of CCK-8S (10 microM) increased aspartate and glutamate levels to maxima of 275+/-12% and 225+/-14% of the basal levels, respectively, in the frontal cortex. In the caudate-putamen, aspartate and glutamate levels were also elevated by CCK-8S (10 microM) to 248+/-15% and 185+/-12% of the basal levels, respectively. The respective increase in aspartate and glutamate induced by CCK-8S (10 microM) were limited to 140+/-10% and 124+/-6% (frontal cortex), of the basal levels, and 162+/-15% and 143+/-8% (caudate-putamen), by 40 min pretreatment with L-365,260 (20 mg/kg, s.c.). In conclusion, CCK-8S was able to enhance both aspartate and glutamate overflow in the frontal cortex of anaesthetised rats, and frontal cortex and caudate-putamen of freely moving rats. These increases were preferentially offset by the selective CCK(B) receptor antagonist, L-365,260, since no influence could be discerned using the selective CCK(A) receptor antagonist, L-364,718.
Ge
J
J
Department of Pharmacology, School of Medical Sciences, University of Bristol, UK. geji@am.alba.umc.akzonobel.nl
Long
S K
SK
Kilpatrick
I C
IC
D000818:Animals; D001224:Aspartic Acid / Q000032:analysis / Q000378:metabolism*; D001570:Benzodiazepinones / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D018698:Glutamic Acid / Q000032:analysis / Q000378:metabolism*; D008297:Male; D017551:Microdialysis; D010671:Phenylurea Compounds; D051381:Rats; D017208:Rats, Wistar; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D012844:Sincalide / Q000031:analogs & derivatives* / Q000494:pharmacology
C090019:8-sulfocholecystokinin octapeptide; D001570:Benzodiazepinones; D010671:Phenylurea Compounds; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; D001224:Aspartic Acid; C058121:L 365260; D018698:Glutamic Acid; D012844:Sincalide