Repeated administration of tacrine to normal rats: Effects on cholinergic, glutamatergic, and GABAergic receptor subtypes in rat brain using receptor autoradiography

• Published in: Neurochemistry international Vol. 31; no. 5; pp. 693 - 703
• Main Authors: Sihver, Wiebke, Günther, Peter, Schliebs, Reinhard, Bigl, Volker
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.11.1997; Elsevier
• Subjects: Animals; Autoradiography; Biological and medical sciences; Brain - drug effects; Brain - metabolism; Brain Chemistry - drug effects; Cholinergic system; Drug Administration Schedule; Female; Hemicholinium 3 - metabolism; Injections, Intraperitoneal; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Rats; Rats, Wistar; Receptors, Cholinergic - drug effects; Receptors, GABA - drug effects; Receptors, Glutamate - drug effects; Tacrine - administration & dosage; Tritium; Cerebral cortex; Rat; Interaction; Rodentia; Central nervous system; Glutamate receptor; Glutamate; In vitro; Vertebrata; Cholinergic receptor; Mammalia; Animal; Neurotransmitter; GABA; Anticholinesterase agent; Gabaergic receptor A; Tacrine; Brain (vertebrata); Cholinergic transmission
• ISSN: 0197-0186; 1872-9754
• DOI: 10.1016/S0197-0186(97)00010-7

Tacrine, a potent acetylcholinesterae inhibitor, has been reported to improve cognitive function in patients with Alzheimer's disease. The present investigation was conducted to elucidate in vivo any interaction between tacrine-induced cortical cholinergic hyperactivity and glutamatergic and GABAergic neurotransmission, which might influence the therapeutic potential of tacrine. Seven days after a daily dosage of 10 mg/kg tacrine i.p. quantitative receptor autoradiography was performed in coronal sections throughout the brain. Repeated administration of tacrine resulted in decreased binding to high-affinity choline uptake, nicotinic and M 2-muscarinic acetylcholine receptor sites in a number of cortical regions, while reductions in M 1-muscarinic receptor binding were restricted to the cingulate and entorhinal cortex as well as caudate-putamen. Moreover, tacrine injections decreased cortical AMPA receptor binding throughout the brain, while NMDA, kainate, and GABA A receptor binding remained unchanged. Tacrine administration alters cortical AMPA receptor binding in the opposite direction to that observed in patients with Alzheimer's disease, suggesting that tacrine may exert a reversal in up/down-regulation of cortical glutamate receptor subtypes in Alzheimer patients. However, the drug-induced reductions in cortical high-affinity choline uptake sites as well as in nicotinic and in muscarinic acetylcholine receptor binding might partially counteract the cognition-enhancing effects of tacrine produced by acetylcholinesterase inhibition.