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

Abstract

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.