ABSTRACT
The progression of epileptiform activity following soman (GD) exposure is characterized by a period of excessive cholinergic activity followed by excessive glutamatergic activity resulting in status epilepticus, which may lead to neuropathological damage and behavioral deficits. Caramiphen edisylate is an anticholinergic drug with antiglutamatergic properties, which conceptually may be a beneficial therapeutic approach to the treatment of nerve agent exposure. In the present study, rats were exposed to 1.2 LD50 GD or saline, treated with atropine sulfate (2mg/kg, im) and HI-6 (93.6mg/kg, im) 1min after GD exposure, and monitored for seizure activity. Rats were treated with diazepam (10mg/kg, sc) and caramiphen (0, 20 or 100mg/kg, im) 30min after seizure onset. Following GD exposure, performance was evaluated using a battery of behavioral tests to assess motor coordination and function, sensorimotor gating, and cognitive function. Caramiphen as adjunct to diazepam treatment attenuated GD-induced seizure activity, neuropathological damage, and cognitive deficits compared to diazepam alone, but did not attenuate the GD-induced sensorimotor gating impairment. These findings show that physiological, behavioral, and neuropathological effects of GD exposure can be attenuated by treatment with caramiphen as an adjunct to therapy, even if administration is delayed to 30min after seizure onset.
Subject(s)
Anticonvulsants/therapeutic use , Cholinesterase Inhibitors/toxicity , Cognition Disorders/drug therapy , Cyclopentanes/therapeutic use , Seizures/drug therapy , Soman/toxicity , Animals , Atropine/therapeutic use , Body Temperature/drug effects , Body Weight/drug effects , Brain/drug effects , Brain/pathology , Cognition Disorders/chemically induced , Diazepam/therapeutic use , Drug Therapy, Combination , Locomotion/drug effects , Male , Maze Learning/drug effects , Oximes/therapeutic use , Pyridinium Compounds/therapeutic use , Rats , Rats, Sprague-Dawley , Seizures/chemically inducedABSTRACT
Genes and proteins of the Fos family are used as markers of neuronal activity and can be modulated by stress. This study investigated whether social defeat (SD) or exposure to an olfactory cue associated with the SD experience activated Fos and FosB/DeltaFosB (ΔFosB) expression in brain regions implicated in the development of post-traumatic stress disorder. Mice exposed to acute SD showed more Fos positive cells in the basolateral amygdala (BLA), CA1 of the hippocampus and the medial prefrontal cortex (mPFC) 1h after SD, and had greater expression of the more persistent FosB/ΔFosB protein in the BLA 24 h after SD compared to controls. Mice exposed to an olfactory cue 24 h or 7 days after SD had higher levels of Fos expression in all three regions 1h after exposure to the cue, and displayed increased avoidance behavior compared to controls. While the avoidance response dissipated with time (less at 7 day vs 24 h after social defeat), Fos expression in the mPFC and CA1 in response to an olfactory cue was greater at 7 days relative to 24 h after social defeat. The results suggest additional processing of the cue-stress association and may provide further support for a role of the mPFC in fear inhibition. These findings may have implications for brain regions and circuitry involved in the avoidance of cues associated with a stressful event that may lead to context-dependent adaptive or maladaptive behavior.
Subject(s)
Brain/physiopathology , Cues , Olfactory Perception/physiology , Proto-Oncogene Proteins c-fos/metabolism , Social Behavior , Stress, Psychological/physiopathology , Amygdala/physiopathology , Animals , Avoidance Learning/physiology , CA1 Region, Hippocampal/physiopathology , Immunohistochemistry , Male , Mice, Inbred C57BL , Prefrontal Cortex/physiopathology , Social Dominance , Time FactorsABSTRACT
Therapy of seizure activity following exposure to the nerve agent soman (GD) includes treatment with the anticonvulsant diazepam (DZP), an allosteric modulator of γ-aminobutyric acid A (GABA(A)) receptors. However, seizure activity itself causes the endocytosis of GABA(A) receptors and diminishes the inhibitory effects of GABA, thereby reducing the efficacy of DZP. Treatment with an N-methyl-d-aspartic acid (NMDA) receptor antagonist prevents this reduction in GABAergic inhibition. We examined the efficacy of the NMDA receptor antagonist caramiphen edisylate (CED; 20mg/kg, im) and DZP (10mg/kg, sc), administered both separately and in combination, at 10, 20 or 30min following seizure onset for attenuation of the deleterious effects associated with GD exposure (1.2 LD(50); 132µg/kg, sc) in rats. Outcomes evaluated were seizure duration, neuropathology, acetylcholinesterase (AChE) activity, body weight, and temperature. We also examined the use of the reversible AChE inhibitor physostigmine (PHY; 0.2mg/kg, im) as a therapy for GD exposure. We found that the combination of CED and DZP yielded a synergistic effect, shortening seizure durations and reducing neuropathology compared to DZP alone, when treatment was delayed 20-30min after seizure onset. PHY reduced the number of animals that developed seizures, protected a fraction of AChE from GD inhibition, and attenuated post-exposure body weight and temperature loss independent of CED and/or DZP treatment. We conclude that: 1) CED and DZP treatment offers considerable protection against the effects of GD and 2) PHY is a potential therapeutic option following GD exposure, albeit with a limited window of opportunity.
Subject(s)
Anticonvulsants/pharmacology , Cyclopentanes/pharmacology , Diazepam/pharmacology , Seizures/drug therapy , Soman/toxicity , Acetylcholinesterase/metabolism , Animals , Anticonvulsants/administration & dosage , Body Temperature/drug effects , Body Weight/drug effects , Cholinergic Antagonists/administration & dosage , Cholinergic Antagonists/pharmacology , Cholinesterase Inhibitors/toxicity , Cyclopentanes/administration & dosage , Diazepam/administration & dosage , Dose-Response Relationship, Drug , Drug Synergism , Male , Rats , Rats, Sprague-Dawley , Seizures/chemically induced , Time FactorsABSTRACT
We have produced ultracold heteronuclear KRb molecules by the process of photoassociation in a two-species magneto-optical trap. Following decay of the photoassociated KRb*, the molecules are detected using two-photon ionization and time-of-flight mass spectroscopy of KRb+. A portion of the metastable triplet molecules thus formed are magnetically trapped. Photoassociative spectra down to 91 cm(-1) below the K(4s)+Rb(5p(1/2)) asymptote have been obtained. We have made assignments to all eight of the attractive Hund's case (c) KRb* potential curves in this spectral region.