Modafinil improves performance in the multiple T-Maze and modifies GluR1, GluR2, D2 and NR1 receptor complex levels in the C57BL/6J mouse

Abstract

Modafinil has been shown to modify behavioural and cognitive functions and to effect several brain receptors. Effects, however, were not observed at the receptor protein complex level and it was therefore the aim of the study to train mice in the multiple T-Maze (MTM) as a paradigm for spatial memory and to determine paralleling brain receptor complex levels. Sixty C57BL/6J mice were used in the study and divided into four groups (trained drug injected; trained vehicle injected; yoked drug injected; yoked vehicle injected). Animals obtained training for 4 days and were killed 6 h following the last training session on day 4. Hippocampi were dissected from the brain, membrane fractions were prepared by ultracentrifugation and were run on blue-native gels and immunoblotted with antibodies against major brain receptors. Modafinil treatment led to decreased latency and increased average speed, but not to changes in pathlength and number of correct decisions in the MTM. Drug effects were modifying receptor complexes of GluR1, GluR2, D2 and NR1. Training effects on receptor complex levels were observed for GluR3, D1 and nicotinic acetylcholine receptor alpha 7 (Nic7). GluR1 levels were correlating with GluR2 and D1 levels were correlating with D2 and NR1. Involvement of the glutamatergic, NMDA, dopaminergic and nicotinergic system in modafinil and memory training were herein described for the first time. A brain receptor complex pattern was revealed showing the concerted action following modafinil treatment.

Modafinil restores methamphetamine induced object-in-place memory deficits in rats independent of glutamate N -methyl- d -aspartate receptor expression

“…More recently, modafinil increased extracellular glutamate in the nucleus accumbens of cocaine experienced rats (Mahler et al, 2012). Modafinil does not bind to GluN receptors (Nguyen et al), but does modify NMDA receptor complexes in the hippocampus of mice as indicated by an increase in GLuN1 complexes (Sase et al, 2012). We found no meth or modafinil induced differences in receptor expression in the hippocampus following the OIP place task.…”

“…Modafinil does not directly bind to GluN receptors (Nguyen et al, 2011), but does modify GluN receptor complexes (Sase et al, 2012). Thus, we also determined whether modafinil would affect the expression of GluN receptors in the prefrontal cortex, perirhinal cortex, and hippocampus.…”

A novel familial 9q31.2q32 microdeletion: Muscle cramping, somnolence, fatigue, sensorineural hearing loss, pubertal delay, and short stature

“…30 Modafinil also increases receptor complex levels of several AMPA subtypes in mice. 31 Given that modafinil was effective in a patient with FRRS1L haploinsufficiency, this may suggest a link between FRRS1L, AMPA, and fatigue symptoms in 9q31.2q32 deletions.…”

Conformational Transitions in the Glycine-Bound GluN1 NMDA Receptor LBD via Single-Molecule FRET

“…These receptors mediate ion transport in the cellular membrane and are considered potential drug targets for treatment of a number of neurological diseases including Alzheimer's and Parkinson's (1)(2)(3)(4)(5)(6). The NMDAR is unique among the glutamate receptors in that it forms hetero-tetrameric complexes using two glycine-binding GluN1 subunits, and two other subunits, either the glutamate-binding subunit GluN2 or the glycine-binding GluN3 subunit (7)(8)(9)(10)(11)(12)(13)(14)(15)(16).…”