Vol. 281, Issue 2, 928-940, 1997

N-Methyl-D-Aspartate Receptors in Associative Eyeblink Conditioning: Both MK-801 and Phencyclidine Produce Task- and Dose-Dependent Impairments¹

Lucien T. Thompson and John F. Disterhoft

Department of Cell and Molecular Biology and the Institute for Neurosciences, Northwestern University Medical School, Chicago, Illinois

The effects of N-methyl-D-aspartate receptor blockade on two major variants of rabbit eyeblink conditioning were evaluated using a selective noncompetitive antagonist, [5R, 10S]-[+]-5-methyl-10,11-dihydro-5H-dibenzo[a, d] cyclo-hepten-5,10-imine hydrogen maleate; dizocilpine (MK-801) or phencyclidine (PCP), a drug of abuse. Either MK-801 or PCP (given daily) impaired rabbits' ability to associate tone conditioned stimuli with airpuff unconditioned stimuli, with the severity of impairment exhibiting clear dose and task dependencies. Trace-conditioned rabbits given  80 µg/kg of MK-801 or 1.0 mg/kg of PCP failed to reach a criterion of 80% conditioned responses during training, with significant impairments seen at intermediate doses. Delay-conditioned rabbits, although dose-dependently slowed, successfully acquired the task, even when given doses of MK-801 or PCP that completely blocked acquisition in trace conditioning. Additionally, even low doses of MK-801 (10 µg/kg) or of PCP (0.1 mg/kg) severely altered conditioned response timing in trace but not in delay conditioning, resembling effects observed after hippocampal lesions. Doses of MK-801 or PCP that impaired acquisition also severely impaired extinction of both trace- and delay-conditioned eyeblink responses. However, neither MK-801 nor PCP altered retention or timing of previously learned responses. Higher doses of MK-801 (200 µg/kg) or of PCP (2.0 mg/kg) dose-dependently impaired unconditioned response performance, although lower doses of MK-801 (160 µg/kg) or of PCP (1.0 mg/kg) had no effects on unconditioned responses or on nonassociative pseudoconditioned responses. The deficits observed indicate that although not necessary for retention, N-methyl-D-aspartate receptor activation may facilitate acquisition of delay-conditioning. N-methyl-D-aspartate receptor activation appears to be necessary for acquisition of trace conditioning, and for extinction in either paradigm.