Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2014 Aug;25(4):331-5.
doi: 10.1097/FBP.0000000000000053.

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

Jessica M Povroznik  1 , Carolyn C Rudy, Holly C Hunsberger, David E Tosto, Miranda N Reed
Affiliations

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

Jessica M Povroznik et al. Behav Pharmacol. 2014 Aug.

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.

PubMed Disclaimer

Conflict of interest statement

Conflicts of interest

There are no conflicts of interest.

Figures

Fig. 1
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
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.
See this image and copyright information in PMC

References

    1. Adams MM, Smith TD, Moga D, Gallagher M, Wang Y, Wolfe BB, et al. Hippocampal dependent learning ability correlates with N-methyl-D-aspartate (NMDA) receptor levels in CA3 neurons of young and aged rats. J Comp Neurol. 2001;432:230–243. - PubMed
    1. Atack JR, Alder L, Cook SM, Smith AJ, McKernan RM. In vivo labelling of α5 subunit-containing GABA (A) receptors using the selective radioligand [3 H]L-655,708. Neuropharmacology. 2005;49:220–229. - PubMed
    1. Atack JR, Bayley PJ, Seabrook GR, Wafford KA, McKernan RM, Dawson GR. L-655,708 enhances cognition in rats but is not proconvulsant at a dose selective for alpha5-containing GABA (A) receptors. Neuropharmacology. 2006;51:1023–1029. - PubMed
    1. Bailey JM, Johnson JE, Newland MC. Mechanisms and performance measures in mastery-based incremental repeated acquisition: behavioral and pharmacological analyses. Psychopharmacology (Berl) 2010;209:331–341. - PubMed
    1. Bauter MR, Brockel BJ, Pankevich DE, Virgolini MB, Cory-Slechta DA. Glutamate and dopamine in nucleus accumbens core and shell: sequence learning versus performance. Neurotoxicology. 2003;24:227–243. - PubMed

Publication types

MeSH terms