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.

Contribution of GABAA receptor subunits to attention and social behavior

“…The doses of L-655,708 (0.5-1.0 mg/kg) that we used are similar to the doses that have previously been found to improve performance in the Morris water maze [35]. Similarly, others found that L-655,708, at the dose range used in the current study, reversed deficits in social interaction caused by chronic stress [49] and learning deficits following administration of the NMDA receptor antagonist MK-801 [50]. Although we cannot rule out the possibility that a higher dose L-655,708 could have affected 5CSRTT performance, it seems unlikely.…”

Basmisanil, a highly selective GABAA-α5 negative allosteric modulator: preclinical pharmacology and demonstration of functional target engagement in man

“…Initially, it was proposed that selective GABA A -α5 NAMs may be beneficial for Alzheimer’s Disease and mild cognitive impairment 16 . Since then, further preclinical studies suggest that GABA A -α5 NAMs may attenuate cognitive impairment associated with Down syndrome (DS) 17 , 18 , cognitive impairment associated with schizophrenia (CIAS) as shown by improvements in preclinical models of NMDA dysfunction 19 – 21 and cognitive impairment after anesthesia 22 . In addition, studies in mice and rats have shown that after ischemic stroke there is increased GABA A -α5 mediated tonic inhibition in the peri-infarct area and that reduction of GABA A -α5 activity enhances functional recovery after stroke 23 – 25 .…”

Negative modulation of α5 GABAA receptors in rats may partially prevent memory impairment induced by MK-801, but not amphetamine- or MK-801-elicited hyperlocomotion

“…Besides phencyclidine, dizocilpine (MK-801) is another experimentally widely used NMDA receptor antagonist, and MK-801-induced cognitive impairments have been validated as a rodent model related to human cognitive deficits associated with dementia (Van der Staay et al, 2011) and schizophrenia (Adell et al, 2012; Andine et al, 1999). Although the MK-801-induced memory deficit model has been assessed as the second most commonly (after scopolamine) used deficit model in preclinical cognition research (Van der Staay et al, 2011), the published results of testing the selective α 5 GABA A receptor negative modulators in animals treated with MK-801 are limited to only one study, using the incremental repeated acquisition task which allows for the assessment of effects on learning at various levels of task-difficulty (Povroznik et al, 2014). Such data are expected to be of special relevance in the pursuit of novel therapies for cognitive aspects of neuropsychiatric disorders, beginning with the premise that α 5 GABA A receptors located at the base of dendritic spines of pyramidal cells in the hippocampus and neocortex are strategically located to modulate excitatory glutamatergic input that arrives at the spines of these cells (Rudolph and Möhler, 2014).…”