2-3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline and Memory-Disorders

Non-competitive antagonists of the N-methyl-d-aspartate receptor (NMDA) such as phencyclidine (PCP) elicit schizophrenia-like symptoms in healthy individuals. Similarly, PCP dosing in rats produces typical behavioral phenotypes that mimic human schizophrenia symptoms. Although schizophrenic behavioral phenotypes of the PCP model have been extensively studied, the underlying alterations of intrinsic neuronal properties and synaptic transmission in relevant limbic brain microcircuits remain elusive. Acute brain slice electrophysiology and immunostaining of inhibitory neurons were used to identify neuronal circuit alterations of the amygdala and hippocampus associated with changes in extinction of fear learning in rats following PCP treatment. Subchronic PCP application led to impaired long-term potentiation (LTP) and marked increases in the ratio of NMDA to 2-amino-3(5-methyl-3-oxo-1,2-oxazol-4-yl)propionic acid (AMPA) receptor-mediated currents at lateral amygdala (LA) principal neurons without alterations in parvalbumin (PV) as well as non-PV, glutamic acid decarboxylase 67 (GAD 67) immunopositive neurons. In addition, LTP was impaired at the Schaffer collateral to CA1 hippocampal pathway coincident with a reduction in colocalized PV and GAD67 immunopositive neurons in the CA3 hippocampal area. These effects occurred without changes in spontaneous events or intrinsic membrane properties of principal cells in the LA. The impairment of LTP at both amygdalar and hippocampal microcircuits, which play a key role in processing relevant survival information such as fear and extinction memory concurred with a disruption of extinction learning of fear conditioned responses. Our results show that subchronic PCP administration in rats impairs synaptic functioning in the amygdala and hippocampus as well as processing of fear-related memories.

Topics: Action Potentials; Amygdala; Animals; Area Under Curve; Biophysics; Disease Models, Animal; Electric Stimulation; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; Extinction, Psychological; Fear; Glutamate Decarboxylase; Hippocampus; In Vitro Techniques; Male; Memory Disorders; Neurons; Parvalbumins; Patch-Clamp Techniques; Phencyclidine; Quinoxalines; Rats; Rats, Long-Evans; Rats, Sprague-Dawley; Schizophrenia; Synaptic Transmission; Time Factors

A subset of glutamate receptors that are specifically sensitive to the glutamate analog N-methyl-D-aspartate (NMDA) are molecular coincidence detectors, necessary for activity-dependent processes of neurodevelopment and in sensory and cognitive functions. The activity of these receptors is modulated by the endogenous amino acid D-serine, but the extent to which D-serine is necessary for the normal development and function of the mammalian nervous system was previously unknown. Decreased signaling at NMDA receptors has been implicated in the pathophysiology of schizophrenia based on pharmacological evidence, and several human genes related to D-serine metabolism and glutamatergic neurotransmission have been implicated in the etiology of schizophrenia. Here we show that genetically modified mice lacking the ability to produce D-serine endogenously have profoundly altered glutamatergic neurotransmission, and relatively subtle but significant behavioral abnormalities that reflect hyperactivity and impaired spatial memory, and that are consistent with elevated anxiety.

Topics: Acoustic Stimulation; Anesthetics, Local; Animals; Behavior, Animal; Benzylamines; Biotin; Chromatography, High Pressure Liquid; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; GABA Antagonists; Glutamic Acid; Hippocampus; In Vitro Techniques; Inhibition, Psychological; Lidocaine; Maze Learning; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Neurons; Patch-Clamp Techniques; Phosphinic Acids; Psychomotor Performance; Quinoxalines; Racemases and Epimerases; Rotarod Performance Test; Space Perception

The effects of soman, a potent irreversible inhibitor of acetylcholinesterase, on central neuropathology in rats were studied in relation with subsequent spatial memory impairments. In a first step, it was found that, without treatment, neuropathology and learning impairment were observed only in rats which experienced convulsions. Then, treatment consisting of atropine sulfate, and/or TCP and/or NBQX was administered to intoxicated animals at infraanticonvulsant doses to obtain a graded subsequent neuropathology and to appreciate an eventual relation between neuropathology and spatial memory impairment. Thus, a correlation between neuropathology in the hippocampal CA1 region and spatial learning performance was found, the degradation of performance of rat being directly related to the amplitude of their neural damage. A threshold was emphasized : below a certain degree of neural loss, no memory impairment was found. Only treatment with tritherapy (atropine + TCP + NBQX) was able to improve the different parameters of spatial learning, despite no effect on the convulsions of the animals.

Topics: Animals; Antidotes; Atropine; Behavior, Animal; Cholinergic Antagonists; Convulsants; Dose-Response Relationship, Drug; Drug Interactions; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Hippocampus; Male; Maze Learning; Memory Disorders; Neuroprotective Agents; Phencyclidine; Quinoxalines; Rats; Rats, Wistar; Soman; Spatial Behavior; Survival Rate; Time Factors