ABSTRACT
Abnormalities in the signaling of the N-methyl-d-aspartate subtype of the glutamate receptor (NMDAR) within cortical and limbic brain regions are thought to underlie many of the complex cognitive and affective symptoms observed in individuals with schizophrenia. The M1 muscarinic acetylcholine receptor (mAChR) subtype is a closely coupled signaling partner of the NMDAR. Accumulating evidence suggests that development of selective positive allosteric modulators (PAMs) of the M1 receptor represent an important treatment strategy for the potential normalization of disruptions in NMDAR signaling in patients with schizophrenia. In the present studies, we evaluated the effects of the novel and highly potent M1 PAM, VU6004256, in ameliorating selective prefrontal cortical (PFC)-mediated physiologic and cognitive abnormalities in a genetic mouse model of global reduction in the NR1 subunit of the NMDAR (NR1 knockdown [KD]). Using slice-based extracellular field potential recordings, deficits in muscarinic agonist-induced long-term depression (LTD) in layer V of the PFC in the NR1 KD mice were normalized with bath application of VU6004256. Systemic administration of VU6004256 also reduced excessive pyramidal neuron firing in layer V PFC neurons in awake, freely moving NR1 KD mice. Moreover, selective potentiation of M1 by VU6004256 reversed the performance impairments of NR1 KD mice observed in two preclinical models of PFC-mediated learning, specifically the novel object recognition and cue-mediated fear conditioning tasks. VU6004256 also produced a robust, dose-dependent reduction in the hyperlocomotor activity of NR1 KD mice. Taken together, the current findings provide further support for M1 PAMs as a novel therapeutic approach for the PFC-mediated impairments in schizophrenia.
Subject(s)
Cholinergic Agents/pharmacology , Heterocyclic Compounds, 4 or More Rings/pharmacology , Nerve Tissue Proteins/deficiency , Nootropic Agents/pharmacology , Prefrontal Cortex/drug effects , Prefrontal Cortex/metabolism , Receptors, N-Methyl-D-Aspartate/deficiency , Action Potentials/drug effects , Action Potentials/physiology , Animals , Cholinergic Agents/pharmacokinetics , Cognition Disorders/drug therapy , Cognition Disorders/metabolism , Conditioning, Psychological/drug effects , Conditioning, Psychological/physiology , Disease Models, Animal , Drug Evaluation, Preclinical , Fear/drug effects , Fear/physiology , Gene Knockdown Techniques , Heterocyclic Compounds, 4 or More Rings/pharmacokinetics , Long-Term Synaptic Depression/drug effects , Long-Term Synaptic Depression/physiology , Male , Mice, 129 Strain , Mice, Inbred C57BL , Mice, Transgenic , Motor Activity/drug effects , Motor Activity/physiology , Nerve Tissue Proteins/genetics , Nootropic Agents/pharmacokinetics , Pyramidal Cells/drug effects , Pyramidal Cells/metabolism , Receptors, N-Methyl-D-Aspartate/genetics , Recognition, Psychology/drug effects , Recognition, Psychology/physiology , Tissue Culture TechniquesABSTRACT
Yoku-kan-san-ka-chimpi-hange (YKCH) is a drug used for insomnia in Japanese traditional herbal medicine. The present study evaluated the effects of YKCH on sleep by all-night polysomnography using the double-blind method. Yoku-kan-san-ka-chimpi-hange increased the total sleep time significantly, and tended to cause an increase in sleep efficiency and of stage 2 sleep, as well as a decrease of sleep latency and of stage 3 + 4 sleep. There was no apparent influence on rapid eye movement (REM) sleep. In terms of non-REM sleep, the effects of YKCH exhibit a profile similar to those of benzodiazepines.