Competitive and noncompetitive NMDA antagonist effects in rats trained to discriminate lever-press counts

Abstract

The glutamate activated N-methyl-d-aspartate (NMDA) receptor may play a role in short-term memory processing. Among the evidence for this is that NMDA antagonists can impair accuracy in fixed consecutive number (FCN) tasks. This study was designed to further characterize this effect by examining NMDA antagonists differing in their cellular mechanisms of action. Rats were trained to respond under an FCN operant schedule, which required eight presses on one lever (counting lever) before one press at an alternate lever (reinforcement lever) would produce food reinforcement. The effects of three noncompetitive [MK-801 (0.01–0.56 mg/kg); phencyclidine (0.3–3.0 mg/kg); memantine (1–10 mg/kg)] and two competitive [SDZ EAA 494 (0.3–3.0 mg/kg) and NPC 17742 (2.0–16 mg/kg)] NMDA antagonists were analyzed. MK-801 and phencyclidine decreased accuracy at doses not reducing response rates. Memantine, and both of the competitive antagonists, also reduced accuracy, but did so only at doses that markedly reduced response rates. These results suggest that both the affinity and the site bound on the NMDA glutamate receptor by antagonists can determine their effects on FCN performance. Subsequent studies investigated whether SCH 23390, a dopamine D1 receptor antagonist, and NMDA could modulate the effects by phencyclidine and SDZ EAA 494, respectively, on FCN performance.

Introduction

N-methyl-d-aspartate (NMDA) receptors are ligand-gated ion channel complexes with several binding sites for modulating ionic flux. Selective antagonists can attenuate neurotransmission by binding to the transmitter (glutamate) recognition site, to the co-transmitter (glycine) recognition site, to a site within the ion channel or to polyamine modulatory sites. Recent years have seen considerable interest in studies designed to elucidate the modulatory functions of NMDA receptors in learning and memory processes.

One way to characterize the role of the NMDA receptor in short-term memory is to study behavior that is thought to involve short-term memory and then manipulate NMDA receptor-mediated neurotransmission using pharmacologic agents that bind selectively to its modulatory centers. NMDA antagonist compounds have been tested in a variety of species and results indicate their ability to disrupt performance in memory-sensitive behavioral tasks. This has been demonstrated in studies involving maze navigation Morris et al., 1986, Morris et al., 1989, Murray, 1995, delayed matching to sample Karbon et al., 1992, Deacon and Rawlins, 1995, Doyle et al., 1998, Miller and Desimone, 1994, Stanhope et al., 1995, time discrimination Berz et al., 1992, Paule, 1994 and repeated acquisition Cohn et al., 1992, Moerschbaecher and Thompson, 1980. Understudied have been the effects of NMDA antagonists on counting behavior. Counting behavior can be assessed in laboratory animals by using an operant conditioning schedule that requires the subject to discriminate the number of lever-presses emitted (count discrimination tasks), or to discriminate cycles of lever-press sequences (targeted percentile or cyclic ratio tasks). Counting free operant schedules has been routinely used to assess memory impairment Boysen et al., 1995, Capaldi and Miller, 1988, Davis and Perusse, 1988, Gibbon et al., 1997, but only three of many available noncompetitive NMDA antagonist compounds have been tested using this procedural design, and no competitive agents have been tested.

The study described here compared the effects of competitive NMDA antagonists, which bind at the same site as the endogenous transmitter, to noncompetitive antagonists, which bind at intrachannel sites, using a ratio-based count discrimination procedure called the fixed consecutive number (FCN) procedure. FCN procedures require a subject to emit a specified number of responses on one lever (counting lever) before a response at another lever (reinforcement lever) results in reinforcement. Performances under FCN operant schedules are disrupted by treatments that presumably impair short-term memory Doty et al., 1992, Idrobo et al., 1988, Vidyasagar, 1996. Because dopamine neurotransmission is influenced by acute and chronic administrations of channel-blocking NMDA antagonist compounds Espaze et al., 2000, He et al., 1993, a rationale existed to assess the pharmacologic specificity of the NMDA antagonist-induced accuracy disruptions we observed. We thus evaluated the effects of SCH 23390, a dopamine D1 receptor antagonist, on the effects of PCP on FCN performance. Antagonism of D1 receptors was specifically explored because a very dense population of D1 receptors exists in cortical regions of the brain where short-term memory is putatively mediated El-Ghundi et al., 1999, Goldman-Rakic, 1992, Smith et al., 1998. Additionally, we co-administered the selective agonist, NMDA, with the competitive NMDA antagonist, SDZ EAA 494, to help determine whether NMDA receptors were the principle mediators of these accuracy-disrupting effects.