Inhibitory effects of D2 agonists by striatal injection on excessive release of dopamine and hyperactivity induced by Bay K 8644 in rats.
We investigated by means of behavioral and neurochemical studies the effects of either D(1) or D(2) agonist on excessive dopamine release and hyperactivity induced by the microinjection of Bay K 8644, and an L-type Ca(2+) channel stimulant, into the rat caudate putamen under a novel environmental condition. Hyperactivity (locomotor activity and rearing counts) and significant increases in extracellular dopamine levels induced by Bay K 8644 were concomitantly observed. D(1) agonist, SKF81297, administered into the caudate putamen did not block Bay K 8644-induced hyperactivity measured by monitoring both animal activity and increases in extracellular dopamine levels detected by microdialysis. Pretreatment with the D(2) agonists, bromocriptine, talipexole and pramipexole, into the caudate putamen significantly blocked Bay K 8644-induced hyperactivity for 45 min after Bay K 8644 administration, although the single administration of these agonists significantly potentiated locomotor activity and rearing behavior. Furthermore, these agonists significantly suppressed Bay K 8644-induced extracellular dopamine levels. Our results indicate that these D(2) agonists (1) act on postsynaptic neuronal D(2) receptors under conditions of normal or low dopamine release in the caudate putamen, and (2) act on presynaptic D(2) receptors (autoreceptors) when excessive levels of dopamine are released or hyperdopamine neuronal activity is induced. Consequently, the effect of D(2) agonists in the clinical treatment of Parkinson's disease may be due to stimulation of postsynaptic D(2) receptors rather than presynaptic autoreceptors.
Maruya
H
H
Department of Internal Medicine III, Tokyo Medical University, 6-7-1 Nishi-Shinjujku, Shinjuku-ku, Tokyo 160-0023, Japan.
Watanabe
Y
Y
Okita
M
M
Lawlor
G F
GF
Utsumi
H
H
Niitsuma
T
T
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002120:Calcium Channel Agonists / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D006948:Hyperkinesis / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D017551:Microdialysis / Q000379:methods; D009043:Motor Activity / Q000187:drug effects; D017072:Neostriatum / Q000033:anatomy & histology / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000378:metabolism
D002120:Calcium Channel Agonists; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D017448:Receptors, Dopamine D2; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D004298:Dopamine