Central and peripheral mediation of hypothermia, tremor and salivation induced by muscarinic agonists in mice.
Hypothermia, tremor and salivation induced by muscarinic cholinergic agonists were studied in mice. Oxotremorine-M (quarternary agonist) shows high potency after intracerebroventricular administration, but the potency is low after subcutaneous administration. Oxotremorine potency (non-quarternary agonist) is higher after intracerebroventricular administration than after subcutaneous administration. Scopolamine and atropine (non-quarternary antagonists) antagonize oxotremorine-induced effects more potently after intracerebroventricular than subcutaneous administration. The quarternary antagonists N-methylscopolamine (NMS) and N-methylatropine (NMA) potently antagonize oxotremorine-induced salivation after both subcutaneous and intracerebroventricular administration. Hypothermia is antagonized partially (20-40%) over a large dose range after subcutaneous administration. In ex vivo receptor-binding studies of rat brain tissue, oxotremorine, scopolamine and atropine administered subcutaneously dose-dependently displace 3H-oxotremorine-M. Oxotremorine-M and NMS displace 3H-oxotremorine-M by 21% and 35%, respectively; NMA is ineffective.


CONCLUSIONS
Muscarinic cholinergic-mediated tremor is centrally regulated; hypothermia involves both a central and a peripheral component, the peripheral regulation being relatively less important than the central; central and peripheral regulation of salivation are equally important. Penetration of the blood brain barrier by oxotremorine-M and NMS is shown in the ex vivo binding studies.
Sánchez
C
C
Pharmacological Research, H. Lundbeck A/S, Copenhagen, Denmark.
Meier
E
E
D000818:Animals; D001286:Atropine Derivatives / Q000494:pharmacology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D007035:Hypothermia / Q000378:metabolism*; D007276:Injections, Intraventricular; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D018727:Muscarinic Antagonists; D010095:Oxotremorine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors; D011976:Receptors, Muscarinic / Q000378:metabolism*; D012472:Salivation / Q000187:drug effects*; D012602:Scopolamine Derivatives / Q000494:pharmacology; D014202:Tremor / Q000378:metabolism*
D001286:Atropine Derivatives; D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic; D012602:Scopolamine Derivatives; D010095:Oxotremorine; C042743:oxotremorine M