Kuopion Yliopisto University of Kuopio Department of Neurology Series of Reports No 67, 2003 Juhana Aura Interaction of Muscarinic Acetylcholine and N- Methyl-d-aspartate -type Glutamate Receptors in the Regulation of Spatial Learning and Memory

Degeneration of cholinergic cells in the basal forebrain correlates with the cognitive impairment seen in Alzheimer’s disease (AD), but so far the cognitive improvement of AD patients receiving cholinergic therapy has only been modest at best. In addition, degeneration of glutamate-containing cells has been observed in AD, thus suggesting that dysfunction of glutamatergic receptors may contribute to the cognitive decline of AD patients. The aim of this study was to investigate the role and possible interaction of the cholinergic system and N-methyl-D-aspartate (NMDA) glutamate receptors in the regulation of working memory and spatial navigation in rats. The role of muscarinic and NMDA receptors in the regulation of spatial working memory was studied using the delayed non-matching to position (DNMTP) task and intracerebroventricular administration of the muscarinic receptor antagonists scopolamine, pirenzepine and methoctramine, as well as the NMDA receptor antagonist CPP. The contribution of cholinergic system and NMDA receptors to age-related deficit in spatial navigation was assessed using the Morris water maze task and intraperitoneal administration of Dcycloserine and tetrahydroaminoacridine. The main results were the following. 1) Blockade of muscarinic receptors in the central nervous system with scopolamine and pirenzepine delayindependently disrupted DNMTP performance, suggesting a non-mnemonic effect on performance. Selective blockade of M2 receptors with methoctramine delay-dependently improved performance in the DNMTP task, suggesting a specific, although modest improvement of working memory at long delays. 2) Blockade of central NMDA receptors with CPP resulted in a delay-independent defect, while combined administration of subthreshold doses of CPP and scopolamine disrupted only nonmnemonic task parameters (motor activity, attention or motivation). Combined CPP and pirenzepine administration at subthreshold doses had no effect on DNMTP task performance. These results suggest that combined blockade of central non-M1 receptors and NMDA receptors disrupts non-mnemonic aspects of DNMTP performance. 3) In the prefrontal cortex, CPP dose-dependently disrupted maintenance of working memory, whereas scopolamine disrupted only non-mnemonic parameters. 4) D-cycloserine and tetrahydroaminoacridine alleviated age-related deficit in spatial navigation when administered either separately or in combination with subthreshold doses. 5) However, the alleviating effect of both D-cycloserine and tetrahydroaminoacridine (separately or in combination) disappeared after pre-training under different conditions, including pre-training for non-spatial escape strategies. In contrast, the age-related spatial navigation defect still remained after the pre-training procedures. These results suggest that tetrahydroaminoacridine and D-cycloserine do not themselves alleviate agerelated spatial memory deficit, but may enhance procedural aspects of water maze learning in aged rats. CONCLUSION: Although the conjoint modulation of muscarinic and NMDA receptors most likely has no direct effect on memory functions, the indirect stimulating effects on attention, arousal and motivation might help alleviate cognitive impairment in AD patients. National Library of Medicine Classification: WT155, WT104, QV77, QV126, WM173.7 Medical Subject Heading: Alzheimer disease; aged; cholinergic agents; N-methylaspartate; receptors, cholinergic; muscarinic antagonists; learning; memory; memory, short-term; drug therapy; rats; cognition; drug interactions; spatial behavior This book is dedicated to Annamari and Konrad