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dc.contributor.authorKiefer-Day, Jennifer Sue
dc.date.accessioned2012-06-15T19:01:12Z
dc.date.available2012-06-15T19:01:12Z
dc.date.issued1991
dc.identifier.urihttp://hdl.handle.net/10713/1637
dc.descriptionUniversity of Maryland, Baltimore. Ph.D. 1991en_US
dc.description.abstractThe acetylcholinesterase inhibitor tetrahydroaminoacridine (THA or Tacrine{dollar}\sp{lcub}\rm TM{rcub}{dollar}) is reported to enhance cognition in animals and some humans. As there is substantial evidence to support the involvement of the cholinergic system in memory, we investigated the effects of THA on muscarinic cholinergic receptors and their associated second messenger systems. Acute in vitro studies demonstrated that THA had the capacity to block muscarinic receptor mediated phosphoinositide hydrolysis and inhibition of cyclic AMP formation. Saturation binding studies revealed that the compound inhibited radioligand binding to muscarinic receptors through a mixed competitive/noncompetitive interaction. THA displayed a rank order of potency of M{dollar}\sb2{dollar} {dollar}>{dollar} M{dollar}\sb1{dollar} {dollar}>{dollar} M{dollar}\sb3{dollar}, but was a poor discriminator between muscarinic receptor subtypes. As demonstrated by steep displacement curves, however, marked changes in receptor occupancy may occur within a relatively narrow dose range. Thus, the slight selectivity of THA for the M{dollar}\sb2{dollar} receptor, which has been proposed to negatively regulate acetylcholine release, could complement its anticholinesterase properties to further augment cholinergic neurotransmission. Alternatively, concurrent blockade of postsynaptic receptors (whose function is essential for normal cognition) would oppose the beneficial effects of cholinesterase inhibition or presynaptic receptor blockade. Long term studies were also conducted as THA would normally be taken on a chronic basis. While THA (0.3-3 mg/kg) improves performance in animal cognition tests, a loss of efficacy and overt side effects occur at high doses. Furthermore, high dose THA treatment induces muscarinic receptor down-regulation over time. In contrast, we found that low dose THA treatment (0.3-3 mg/kg administered to mice for up to 32 days) did not alter the number of brain muscarinic receptors or the phosphoinositide response to muscarinic receptor agonists. Moreover, brain levels of THA were sufficient to inhibit 78-80% of acetylcholinesterase activity, regardless of treatment duration as measured 20 min after a 3 mg/kg dose. Thus, at a therapeutically relevant dose, THA inhibited the activity of brain acetylcholinesterase substantially, but did not affect the density of muscarinic receptors or their ability to activate second messenger systems. We conclude that the inconsistent reports of the efficacy of THA as a memory enhancer are unrelated to muscarinic receptor down-regulation, but may be related to receptor blockade.en_US
dc.language.isoen_USen_US
dc.subjectHealth Sciences, Mental Healthen_US
dc.subjectHealth Sciences, Pharmacologyen_US
dc.subject.meshAcetylcholinesterase Inhibitorsen_US
dc.subject.meshCognitionen_US
dc.subject.meshMemoryen_US
dc.subject.meshTacrineen_US
dc.titleCholinergic pharmacology of tetrahydroaminoacridine (THA or Tacrine(registered trademark))en_US
dc.typedissertationen_US
dc.contributor.advisorEl-Fakahany, Esam E.
dc.identifier.ispublishedYes
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