Brain Research, 513 (1990) 81-85 81 Elsevier BRES 15330 Concurrent muscarinic and fl-adrenergic blockade in rats impairs place-learning in a water maze and retention of inhibitory avoidance Michael W. Decker, T. Michael Gill and James L. McGaugh Department of Psychobiology and Center for the Neurobiology of Learning and Memory, University of California at Irvine, lrvine, CA 92717 (U.S.A.) (Accepted 29 August 1989) Key words: Muscarinic receptor; fl-Adrenergic receptor; Inhibitory avoidance; Spatial learning; Scopolamine; Propranolol; Neurotransmitter interaction; Rat These experiments examined the effects of separate and concurrent muscarinic cholinergic and fl-adrenergic blockade on inhibitory (passive) avoidance performance and spatial learning in the Morris water maze. Pretraining systemic administration of either scopolamine (0.3 or 1.0 mg/kg) or propranolol (3.0 or 10.0 mg/kg) had no significant effect on one-day retention of step-through inhibitory avoidance training. Similarly, pretraining administration of either 0.3 mg/kg scopolamine or 10 mg/kg propranolol did not affect spatial learning in the Morris water maze. However, combined administration of scopolamine and 10.0 mg/kg of propranolol impaired performance on these tasks. These findings further support a role for interactions between norepinephrine and acetylcholine in the modulation of learning and memory and implicate the participation of fl-adrenergic mechanisms in this interaction. Because cholinergic and noradrenergic deterioration is found in aging and Alzheimer's disease, these results also have implications regarding the role of age-related noradrenergic and cholinergic dysfunction in cognitive decline. INTRODUCTION Interactions between norepinephrine (NE) and acetyl- choline (ACh) in the brain appear to play an important role in neural plasticity. For example, the shift in ocular dominance columns normally observed in kittens with visual input restricted to one eye is unaffected by depletion of either NE or ACh alone but is blocked by combined depletion of these transmitters 7. An interac- tion between NE and ACh also appears to be important in learning and memory. Kruglikov 24 reported that neither lesions of the locus coeruleus (LC) - source of forebrain NE - nor systemic administration of 0.5 mg/kg of the muscarinic antagonist scopolamine affected reten- tion of active avoidance training, but that administration of scopolamine to LC-lesioned rats produced a profound deficit. Similarly, while NE-depletion produced by injec- tion of 6-OHDA into the dorsal noradrenergic bundle does not, by itself, impair radial arm maze performance, this NE-depletion significantly potentiates the disrup- tive effects of scopolamine on this spatial memory task 16. Several interactions between NE and ACh have been established biochemically and electrophysiologically in brain structures thought to be important for learning and memory. NE applied to the cortex enhances the response of cortical neurons to iontophoretically applied mCh 39. NE also decreases the release of ACh from cholinergic terminals in the cortex both in slices and in vivo 31'38, an effect apparently mediated both directly via a-adrenergic receptors on cholinergic terminals and indirectly via NE modulation of GABA release 6. In contrast, NE release in the medial septal area appears to increase ACh turnover in the hippocampus 35, an effect that may be related to changes in hippocampal 0-activity produced by intra- septal application of NE 3°. Even in the striatum, which has sparse noradrenergic input, fl-noradrenergic regula- tion of muscarinic-stimulated dopamine turnover has been reported 4°. Cholinergic-mediated modification of NE function has also been reported. In hippocampal synaptosomal preparations, muscarinic stimulation inhib- its NE synthesis via action at M 1 receptors and NE release via M 2 receptors9; and neurons in the locus coeruleus are influenced by ACh through an action at M 2 receptors 19. To investigate further the interaction of NE and ACh in learning and memory, the present study examined the effects of separate and concurrent administration of the muscarinic cholinergic antagonist scopolamine and the fl-adrenergic antagonist propranolol on two learning and memory tasks - inhibitory (passive) avoidance and spatial learning in the Morris water maze 32. Correspondence.. M. Decker, Center for the Neurobiology of Learning and Memory, Bonney Center, University of California. Irvine, CA 92717, U.S.A. 0006-8993/90/$03.50 © 1990 Elsevier Science Publishers B.V. (Biomedical Division)