Muscarinic cholinergic influences in memory consolidation Ann E. Power, a, * Almira Vazdarjanova, b and James L. McGaugh c a Reeve-Irvine Research Center and Department of Anatomy and Neurobiology, University of California, Irvine, CA 92697-4292, USA b Arizona Research Laboratories, Division of Neural Systems, Memory and Aging, University of Arizona, Tucson, AZ 85724-5115, USA c Center for the Neurobiology of Learning and Memory and Department of Neurobiology and Behavior, University of California, Irvine, CA 92697-3800, USA Received 9 July 2003; revised 29 July 2003; accepted 29 July 2003 Abstract The central cholinergic system and muscarinic cholinergic receptor (mR) activation have long been associated with cognitive function. Although mR activation is no doubt involved in many aspects of cognitive functioning, the extensive evidence that memory is influenced by cholinergic treatments given after training either systemically or intra-cranially clearly indicates that cholinergic activation via mRs is a critical component in modulation of memory consolidation. Furthermore, the evidence indicates that activation of mRs in the basolateral amygdala (BLA) plays an essential role in enabling other neuromodulatory influences on memory consolidation. Memory can also be affected by posttraining activation of mRs in the hippocampus, striatum and cortex. Evidence of increases in hippocampal and cortical acetylcholine (ACh) levels following learning experiences support the view that endogenous ACh release is involved in long-term memory consolidation. Furthermore, the findings indicating that mR drug treatments influence plasticity in the hippocampus and in sensory cortices strongly suggest that mR activation is involved in the storage of information in these brain regions. Ó 2003 Elsevier Inc. All rights reserved. Keywords: Acetylcholine; Basolateral amygdala; Nucleus basalis magnocellularis; Multiple memory systems 1. Introduction Interest in the role of acetylcholine (ACh) in cognitive processes began just a little over a half-century ago, before ACh was generally accepted as a bona fide neu- rotransmitter. The first reports of studies of the in- volvement of ACh in learning and memory to our knowledge were studies reporting the effects of the ir- reversible acetylcholinesterase (AChE) inhibitor di-iso- propylfluorophosphate (DFP) on learning in rats (Platt & Wickens, 1950; Russell, 1960) and studies investigat- ing the relationship between brain AChE and maze performance (Krech, Rosenzweig, Bennett, & Krueckel, 1954; McGaugh, 1959). The findings of these early studies suggested that learning performance varied with brain ACh levels at the time of training. Subsequently, several laboratories reported that the cholinergic re- ceptor antagonists atropine and scopolamine adminis- tered before training impaired ratsÕ performance on various types of tasks (Bure  sov a, 1964; Carlton, 1963; Herz, 1960; Whitehouse, 1964). The behavioral effects were likely due to influences on cholinergic functioning within the brain as the peripherally active quaternary compounds methylscopolamine and methylatropine did not impair the ratsÕ performance. Other studies reported that low doses of the reversible AChE inhibitor physo- stigmine injected systemically before training enhanced learning performance (Bure  s, 1962; Cardo, 1959). These early findings strongly suggested that increases in brain cholinergic functioning enhanced cognitive functioning and that decreases impaired such function- ing. But, the findings provide few, if any, insight into the bases of the performance impairing and enhancing ef- fects of drugs affecting cholinergic functioning. As the drugs were administered before behavioral testing they could have acted by influencing sensory processing, at- tention and motivation as well as by influencing brain processes underlying the storage of new information Neurobiology of Learning and Memory 80 (2003) 178–193 www.elsevier.com/locate/ynlme * Corresponding author. Fax: 1-949-824-9272. E-mail address: apower@uci.edu (A.E. Power). 1074-7427/$ - see front matter Ó 2003 Elsevier Inc. All rights reserved. doi:10.1016/S1074-7427(03)00086-8