Competitive and noncompetitive NMDA antagonist effects in rats trained to discriminate lever-press counts
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.
Section snippets
Subjects
Twelve rats were used as subjects for evaluating the effects of test compounds on FCN performance. Two strains of rats were used in these studies as an intermediate step before the laboratory chose, and committed to using a single, common strain. Subjects 4-01, 4-02, 4-03, 4-04, 4-09, 4-11, 4-12, 4-13, 4-17 were male Long–Evans hooded rats (360–384 g; Harlan Laboratories, Dublin, VA). The remaining three rats, numbered 4-05, 4-06 and 4-07, were male Sprague–Dawley rats (340–430 g; COBS, Charles
Procedure
The beginning of each experimental session was signaled by the illumination of the stimulus lights above the response levers. Rats were initially trained to lever-press for food pellet delivery according to fixed consecutive number-1 (FCN-1) schedule of reinforcement. Contingencies for preliminary training under an FCN-1 schedule required at least one press of the ‘counting’ lever (left side lever for rats 4-01, 4-02, 4-05, 4-06, 4-09, 4-11; right side lever for rats 4-03, 4-04 and 4-07, 4-12,
FCN performance effects: single drug testing sessions
There was no more than 10% variation from the mean baseline ‘accuracy’ for each individual rat during training sessions prior to testing, indicating that the subjects had acquired the task and stabilized within this range prior to testing. The results for tests with MK-801 are shown in the upper panel of Fig. 1. Two dosages of MK-801 were shown to produce large deficits in performance accuracy, and accuracy was decreased without a concomitant rate reduction. Fig. 1 shows that performance in
Discussion
FCN studies involving the evaluation of putative amnestic agents, such as scopolamine Laties, 1972, Vidyasagar, 1996, benzodiazepines (Evenden, 1998) and Δ9-THC (Mansbach et al., 1996), have reported disruptions of accuracy at doses that do not depress response rates. The present study was undertaken to analyze changes in FCN performance after pharmacologically attenuating NMDA neurotransmission. These results indicate that both competitive and noncompetitive NMDA receptor antagonists can
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