Original article 207 Cholinergic modulation of memory in the basolateral amygdala involves activation of both m1 and m2 receptors A.E. Power a,b , C.K. McIntyre a , A. Litmanovich a and J.L. McGaugh a Muscarinic cholinergic activation is a critical component of basolateral amygdala (BLA)-mediated modulation of memory consolidation. The receptor(s) mediating this activation during consolidation have not been elucidated. This study investigated the roles of muscarinic subtype 1 (m1) and subtype 2 (m2) receptors in memory enhance- ment, by post-training intra-BLA infusions of the non- selective muscarinic agonist oxotremorine. Rats received intra-BLA infusions of either oxotremorine alone (10 lg in 0.2 ll per side), oxotremorine together with the selective m1 antagonist telenzipine (1.7, 5.0, 17 or 50nmol/side), oxotremorine with the selective m2 antagonist methoctra- mine (1.7, 5.0, 17 or 50nmol/side), oxotremorine with a combination of the above doses of telenzipine and methoctramine, or only vehicle, immediately after inhibitory avoidance training. Performance on a 48-hour retention test was significantly enhanced in oxotremorine-treated rats relative to vehicle-infused controls. Intra-BLA co- infusion of oxotremorine with either telenzipine (5, 17 or 50 nmol/side) or methoctramine (17 or 50 nmol/side) blocked the oxotremorine-induced enhancement. Combi- nations of these antagonists did not act additively to block memory enhancement by oxotremorine. These findings indicate that modulation of memory consolidation induced by cholinergic influences within the BLA requires activation of both m1 and m2 receptor synapses. Plausible mechan- isms for m1- and m2-mediated influences on BLA circuitry are discussed. Behavioural Pharmacology 14:207–213  c 2003 Lippincott Williams & Wilkins. Behavioural Pharmacology 2003, 14:207–213 Keywords: muscarinic receptors, acetylcholine consolidation, memory modulation, inhibitory avoidance, rat a Center for the Neurobiology of Learning and Memory and Department of Neurobiology and Behavior and b Reeve-Irvine Research Center and Department of Anatomy and Neurobiology, University of California, Irvine, California, USA. Sponsorship: This research was supported by a USPHS Research Grant from NIMH, MH 12526 (J.L.M.), a Schneiderman graduate fellowship (A.E.P.) and an NSRA from NIMH, MH 12646 (J.L.M. and C.K.M.). Correspondence and requests for reprints to Ann E. Power, Reeve-Irvine Research Center and Department of Anatomy and Neurobiology, University of California, Irvine, CA 92697-4292, USA. E-mail: apower@uci.edu Received 4 December 2002 Accepted as revised 1 March 2003 Introduction Extensive evidence indicates that post-training drug and hormone treatments modulate memory consolidation (McGaugh, 1966, 1989; Gold and van Buskirk, 1978; Sternberg et al., 1985) and that such memory modulatory effects are mediated by the basolateral group of nuclei in the amygdala (BLA) (Gallagher and Kapp, 1978; Gallagher et al., 1981; Liang et al., 1986a, b; Cahill and McGaugh, 1991; Parent and McGaugh, 1994; McGaugh et al., 1993; Roozendaal et al., 1996, 1997; Roozendaal and McGaugh, 1997; Power et al., 2002). Post-training memory modulatory treatments have been shown to involve activation of muscarinic cholinergic receptors in the BLA (Baratti et al., 1984 Dalmaz et al., 1993, Introini- Collison et al., 1996; Vazdarjanova and McGaugh, 1999; Power et al., 2000; Passani et al., 2001; Cangioli et al., 2002), by afferent cholinergic projections from the nucleus basalis magnocellularis (Power and McGaugh, 2002). Subtype 1 muscarinic (m1) and subtype 2 muscarinic (m2) receptors are generally considered to induce excitatory and inhibitory responses, respectively (Brann et al., 1987; Peralta et al., 1988;). There are high densities of both the m1 and m2 receptor types in the BLA (Spencer et al., 1986). Transmission electron microscope imaging has demonstrated both asymmetric (presumed excitatory) and symmetric (presumed inhibitory) choli- nergic synapses in the BLA (Wainer et al., 1984; Li et al., 2001). Although m2 receptors may function as presynap- tic autoreceptors (Starke, 1981; Briggs and Cooper, 1982; Galarraga et al., 1999), the prevalence of symmetric cholinergic synapses in the BLA (Wainer et al., 1984; Li et al., 2001) suggests that m2 receptors in the BLA may directly mediate a sizable portion of cholinergic signals to postsynaptic neurons in the BLA. The specific contribu- tions of m1 and m2 receptor signaling pathways in the BLA, in mediating the critical role of muscarinic cholinergic signaling in the BLA during memory mod- ulatory processes (Dalmaz et al., 1993, Introini-Collison et al., 1996; Power et al., 2000; Power and McGaugh, 2002; McIntyre et al., 2003), has not as yet been investigated. The current experiment investigated whether enhance- ment of memory with increased intra-BLA muscarinic cholinergic activation, immediately after training, re- 0955-8810  c 2003 Lippincott Williams & Wilkins DOI: 10.1097/01.fbp.0000073702.15098.21 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.