ABSTRACT
The Group I metabotropic glutamate receptor subtype 5 (mGluR5) is widely distributed in the brain with dense expression in the cerebral cortex, hippocampus, and basal ganglia. These receptors have been implicated in psychiatric and neurological disorders such as schizophrenia, Fragile X syndrome, addiction, anxiety/depression, Parkinson's disease and neuropathic pain. The present study evaluated the effects of the mGluR5 negative allosteric modulators (NAMs) 4-difluoromethoxy-3-(pyridine-2-ylethynyl)phenyl)5H-pyrrolo[3,4-b]pyridine-6(7H)-yl methanone (GRN-529) and methyl (3aR,4S,7aR)-4-hydroxy-4-[(3-methylphenyl)ethynyl]octahydro-1H-indole-1-carboxylate (AFQ056) on polysomnographic (PSG) and quantitative electroencephalographic (qEEG) measures in freely moving rats. Furthermore, the anxiolytic profile of GRN-529 was characterized in anesthetized rats by measuring stimulation-induced hippocampal theta oscillation. The present findings demonstrate that inhibition of mGluR5 via its allosteric site profoundly modulates high-level neuronal network activities as indicated by changes in sleep-wake activity and power distribution of qEEG. Both GRN-529 and AFQ056 reduced the total time spent in rapid-eye movement with AFQ056 producing a significant increase in wakefulness at the highest dose tested. Additionally, qEEG revealed significant compound-induced increases in delta power concomitant with more subtle decreases in theta and alpha band power. Receptor occupancy (RO) studies revealed that GRN-529 and AFQ056 at all doses resulted in over 45% mGluR5 occupancy. Furthermore, GRN-529 dose-dependently decreased elicited hippocampal theta frequency, consistent with previous findings using clinically active anxiolytic compounds. The described changes in neurophysiological signals identified in freely moving rats may be considered suitable translational biomarkers for the clinical evaluation of mGluR5 NAMs.
Subject(s)
Brain Waves/physiology , Eye Movements/physiology , Receptor, Metabotropic Glutamate 5/metabolism , Algorithms , Allosteric Regulation/drug effects , Animals , Benzamides/blood , Benzamides/chemistry , Benzamides/pharmacokinetics , Benzamides/pharmacology , Brain Waves/drug effects , Cerebral Cortex/drug effects , Cerebral Cortex/physiology , Dose-Response Relationship, Drug , Excitatory Amino Acid Antagonists/blood , Excitatory Amino Acid Antagonists/pharmacology , Eye Movements/drug effects , Indoles/blood , Indoles/chemistry , Indoles/pharmacology , Male , Protein Binding/drug effects , Pyridines/blood , Pyridines/chemistry , Pyridines/pharmacokinetics , Pyridines/pharmacology , Rats , Rats, Sprague-Dawley , Receptor, Metabotropic Glutamate 5/antagonists & inhibitors , Tritium/pharmacokineticsABSTRACT
While forest ecosystem classification work in Quebec has traditionally concentrated on inventory and mapping, more effort is now being placed on developing field guides similar to those produced in other Canadian provinces. As part of a project to produce a practical forest ecosystem field guide for the Amos Lowlands Ecological Region in northwestern Quebec, existing sub-regional ecological studies were exploited in order to develop a regional classification of forest ecosystems, or forest stations. Review of four fundamental studies provided a list of 107 ecological phases, each representing a particular combination of forest composition, surface deposit type and moisture regime. A series of silvicultural and environmental interpretations were developed and values for each were attributed to the ecological phases. Cluster analysis was then performed to classify phases into 29 broader units. A large, regional biophysical database which became available later in the project provided a means of validating and effectively modifying the classification. The justifications for using the original approach are discussed.
ABSTRACT
In Quebec, forest stations are defined as forest units that are reasonably homogeneous in terms of forest composition and site characteristics - as expressed by surficial deposit and moisture regime - and within which similar operational constraints for silvicultural potential and productivity levels may be expected. In the course of developing a field guide to the forest stations of the Amos Lowlands Ecological Region in northwestern Quebec, classifications of 12 site types and 72 forest stations (38 forest cover types or 16 general cover types) were developed. The classifications were based on a hybrid approach involving cluster analysis of forest ecological units inventoried in subregional studies, classical classification and ordination analyses performed on a regional biophysical inventory database, and empirically associating forest cover types to site types. The guide, while similar to other published forest ecosystem classification guides, emphasizes forest dynamics by presenting forest stations common to a given site type according to their successional stage. Field keys and general interpretations of forest potential and operational constraints are included in the guide. A summary description of the guide and accompanying documents is provided. A first draft has been distributed recently for feedback from industrial and government foresters and researchers in the region. Analyses of inventory data is continuing and modifications will be incorporated into a second draft before publication in 1995.
