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DOSE RESPONSE DEETERMINATION OF NMDA ANTAGONISTS AND GABA AGONIST ON SUSTAINED ATTENTION.
Citation:
Samsam, T E., W M. Oshiro, AND P J. Bushnell. DOSE RESPONSE DEETERMINATION OF NMDA ANTAGONISTS AND GABA AGONIST ON SUSTAINED ATTENTION. Presented at Behavioral Toxicology Society, RTP, NC, 4/20-22/2002.
Description:
We have shown that acute inhalation of toluene impairs sustained attention as assessed with a visual signal detection task (SDT). In vitro studies indicate that the NMDA and GABA systems are primary targets of anesthetic agents and organic solvents such as toluene. Pharmacological interactions between toluene and receptor-specific ligands may indicate which receptor systems are involved in the effects of toluene and other solvents on sustained attention. The present studies were carried out to determine dose-effect relationships for a GABA-A agonist, chlordiazepoxide HCl (CDP), and two NMDA antagonists, MK-801 and memantine. This information will be used at a later time to study interactive effects of these drugs with toluene in the SDT. In Experiment 1, twelve male Long-Evans rats were trained to perform the SDT. Once baseline performance was established, each rat received CDP (0, 3, 5, 8 mg/kg, ip, 30 min prior to testing). In Experiment 2, twelve male Long-Evans rats received MK-801 (0, 0.03, 0.055, 0.10, 0.18 mg/kg, ip, 20 min prior to testing) and memantine (0,1.5, 5, 8, 12, 15 mg/kg, ip, 30 min prior to testing) after achieving baseline performance in the SDT. Each dose of each drug was administered once and the order of administration was randomized and counterbalanced across test chambers. CDP caused a small but significant and dose-related decrease in P(hit) at low signal intensities. No effect of CDP on false alarms or response times was observed. Memantine at 12 and 15 mg/kg decreased P(hit) at the higher signal intensities. The same doses also slightly increased false alarms and significantly increased responses times. 0.18 mg/kg of MK-801 significantly decreased P(hit) while slightly increasing response latencies. False alarms were not effected by MK-801. The observed effects of the high doses of the two NMDA antagonists in the SDT are similar to those associated with high concentrations of toluene which possibly could point toward NMDA as the more likely mediator of the effects of toluene. (This abstract does not necessarily reflect EPA policy. Mention of trade names or commercial products does not constitute endorsement or recommendation of use.)