Effects of an α5GABAA inverse agonist on MK-801-induced learning deficits in an incremental repeated acquisition task

Abstract

N-methyl-D-aspartate receptors (NMDARs) are essential for several kinds of synaptic plasticity and play a critical role in learning and memory. Deficits in NMDAR functioning may be partially responsible for the learning and memory deficits associated with aging and numerous diseases. Administration of MK-801, a noncompetitive NMDAR antagonist, is commonly used as a preclinical model of NMDAR dysfunction. The objective of this study was to assess the effects of α5GABAA receptor inhibition on learning deficits in the incremental repeated acquisition (IRA) task induced by acute MK-801 administration. The IRA task, commonly used to examine factors that affect learning, begins with a single response and increments to progressively longer chains throughout a single session as behavior meets preset criteria. MK-801 (0.03-0.5 mg/kg, intraperitoneally), administered 10 min pretesting, produced a significant dose-dependent decrease in measures of IRA performance at doses greater than or equal to 0.25 mg/kg. The MK-801-induced deficit was attenuated after treatment with an α5GABAA receptor inverse agonist, L-655,708 (1 mg/kg, intraperitoneally). The present study provides the focus for, and supports the feasibility of, further in-depth definitive studies examining α5GABAA receptor inhibition as a suitable candidate for the attenuation of NMDAR-related deficits.

Fig. 1

(a) Accuracy, (b) chain length, and (c) total number of responses of incremental repeated acquisition performance and learning chains at baseline. Effects of MK-801 on (d) accuracy, (e) chain length, and (f) total number of responses emitted. Effects of L-655,708 on (g) accuracy, (h) chain length, and (i) total number of responses emitted. **Performance versus learning, P <0.001; *P <0.05 versus baseline.

Fig. 2

Effects of 0.25 mg/kg MK-801 in combination with 1 mg/kg L-655,708 on accuracy, chain length, and total number of responses. ^#P < 0.05; *P <0.01.