Action on noradrenergic transmission of an anticholinesterase: 9-amino-1,2,3,4-tetrahydroacridine.
The mechanism by which 9-amino-1,2,3,4-tetrahydroacridine (THA) inhibits beta-adrenoceptor linked cyclic AMP formation and its possible relationship with the cholinergic system were studied. In addition, the effect of THA on alpha 1-adrenoceptor coupled transduction systems was also investigated. THA was not able to influence the concentration-response curve for forskolin indicating that it is not acting on the catalytic subunit of the adenylate cyclase complex. On the other hand a cholinergic component seems to participate in the action of THA on beta-adrenoceptor stimulated adenylate cyclase activity since the blockade of muscarinic receptors with atropine (10 microM) partially prevented the reduction in cyclic AMP formation attained by THA in the hippocampus, in isoprenaline-stimulated conditions. This effect is not reproducible by another potent anticholinesterase physostigmine. Moreover, THA at concentrations up to micromolar did not affect alpha 1-adrenoceptor stimulated cyclic AMP formation or phosphoinositide hydrolysis. In conclusion, the neuropharmacological profile of THA is not to be restricted to the cholinergic system and its effectiveness in improving age-associated cognitive deterioration may involve an action on the beta-adrenoceptor coupled signal transduction system. Moreover, the action of THA on the beta-adrenergic and cholinergic systems in the brain could be relevant to the amelioration of cognitive deterioration and could lead to the development of new therapeutic strategies.
Vivas
N M
NM
Departament de Farmacologia i Psiquiatria, Universitat Autònoma de Barcelona, Spain.
Màrmol
F
F
Sallés
J
J
Badia
A
A
Dierssen
M
M
D000818:Animals; D001481:Basal Metabolism; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D006868:Hydrolysis; D066298:In Vitro Techniques; D008297:Male; D010716:Phosphatidylinositols / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013268:Stimulation, Chemical; D013619:Tacrine / Q000494:pharmacology*
D010716:Phosphatidylinositols; D018340:Receptors, Adrenergic, alpha-1; D005576:Colforsin; D013619:Tacrine; D000242:Cyclic AMP