Acute and chronic effects of cholinesterase inhibitors and pilocarpine on the density and sensitivity of central and peripheral alpha 2-adrenoceptors.
The specific binding of the agonists [3H]clonidine and [3H]UK 14304 (bromoxidine) and of the antagonist [3H]RX 821002 (2-metoxy idazoxan) to rat brain membranes, as well as clonidine-induced mydriasis, clonidine-induced inhibition of brain (3,4-dihydroxyphenylalaninme) DOPA synthesis and clonidine-induced inhibition of twitch responses in the vas deferens, was used to evaluate the density and sensitivity of central and peripheral alpha 2-adrenoceptors after prolonged activation of the cholinergic system. Acute (12 h), short-term (4 days) or chronic (7-18 days) treatment with the cholinesterase inhibitors neostigmine (0.1 mg/kg), physostigmine (0.1 mg/kg) and diisopropylfluorophosphate (2 mg/kg) and with the muscarinic receptor agonist pilocarpine (10 mg/kg) did not alter the density of brain alpha 2-adrenoceptors. In contrast, various functional responses mediated by central and peripheral alpha 2-adrenoceptors were potentiated after the repeated treatments. Thus, the inhibitory alpha 2-autoreceptor that modulates the synthesis of brain noradrenaline and the central postsynaptic inhibitory alpha 2-adrenoceptor that induces mydriasis displayed greater responses in vivo after chronic treatment with neostigmine or pilocarpine. These treatments also increased the sensitivity of peripheral presynaptic alpha 2-adrenoceptors in the vas deferens. The results indicate that prolonged activation of central and peripheral cholinergic pathways results in up-regulation of alpha 2-adrenoceptor function without apparent increases in receptor density.
Olmos
G
G
Department of Fundamental Biology and Health Sciences, University of the Balearic Islands, Palma de Mallorca, Spain.
Miralles
A
A
García-Sevilla
J A
JA
Giralt
M T
MT
Pineda
J
J
Asier Garro
M
M
Ugedo
L
L
Menargues
A
A
Obach
R
R
D000316:Adrenergic alpha-Agonists / Q000378:metabolism / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D000068438:Brimonidine Tartrate; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D003000:Clonidine / Q000378:metabolism / Q000494:pharmacology; D004146:Dioxanes / Q000378:metabolism / Q000494:pharmacology; D019329:Idazoxan / Q000031:analogs & derivatives; D066298:In Vitro Techniques; D007531:Isoflurophate / Q000494:pharmacology; D008297:Male; D009388:Neostigmine / Q000494:pharmacology; D010830:Physostigmine / Q000494:pharmacology; D010862:Pilocarpine / Q000378:metabolism / Q000494:pharmacology*; D011810:Quinoxalines / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects* / Q000502:physiology; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors; D014649:Vas Deferens / Q000187:drug effects* / Q000378:metabolism
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D002800:Cholinesterase Inhibitors; D004146:Dioxanes; D011810:Quinoxalines; D011942:Receptors, Adrenergic, alpha; D010862:Pilocarpine; D007531:Isoflurophate; D009388:Neostigmine; D000068438:Brimonidine Tartrate; D010830:Physostigmine; C058525:2-methoxyidazoxan; D014446:Tyrosine 3-Monooxygenase; D003000:Clonidine; D019329:Idazoxan