ABSTRACT
Seasonal influenza outbreaks and recurrent influenza pandemics present major challenges to public health. By studying immunological responses to influenza in different host species, it may be possible to discover common mechanisms of susceptibility in response to various influenza strains. This could lead to novel therapeutic targets with wide clinical application. Using a mouse-adapted strain of influenza (A/HK/1/68-MA20 [H3N2]), we produced a mouse model of severe influenza that reproduces the hallmark high viral load and overexpression of cytokines associated with susceptibility to severe influenza in humans. We mapped genetic determinants of the host response using a panel of 29 closely related mouse strains (AcB/BcA panel of recombinant congenic strains) created from influenza-susceptible A/J and influenza-resistant C57BL/6J (B6) mice. Combined clinical quantitative trait loci (QTL) and lung expression QTL mapping identified candidate genes for two sex-specific QTL on chromosomes 2 and 17. The former includes the previously described Hc gene, a deficit of which is associated with the susceptibility phenotype in females. The latter includes the phospholipase gene Pla2g7 and Tnfrsf21, a member of the TNFR superfamily. Confirmation of the gene underlying the chromosome 17 QTL may reveal new strategies for influenza treatment.
Subject(s)
Chromosomes, Mammalian/genetics , Influenza A Virus, H3N2 Subtype , Influenza, Human/genetics , Quantitative Trait Loci , 1-Alkyl-2-acetylglycerophosphocholine Esterase , Alleles , Animals , Chromosome Mapping , Chromosomes, Mammalian/immunology , Disease Models, Animal , Disease Susceptibility , Female , Genotype , Host Specificity , Humans , Influenza, Human/immunology , Influenza, Human/virology , Lung/immunology , Lung/virology , Male , Mice , Mice, Congenic , Mice, Inbred C57BL , Phenotype , Phospholipases A2/genetics , Phospholipases A2/immunology , Receptors, Tumor Necrosis Factor/genetics , Receptors, Tumor Necrosis Factor/immunology , Sex FactorsABSTRACT
Phencyclidine (PCP), an antagonist at the N-methyl-D-aspartate subtype of ionotropic glutamatergic receptors, decreases gamma-aminobutyric acid (GABA)ergic inhibition, suggesting that changes in GABAergic receptor function underlie behavioral and cognitive deficits resulting from repeated administration of PCP. To test this hypothesis, male Sprague-Dawley rats treated with PCP (4.5 mg/kg, intraperitoneal, twice a day for 7 consecutive days) or saline were tested in behavioral and cognitive tasks 7 days after injections. The PCP group showed increased amphetamine (1.5 mg/kg)-stimulated locomotor activity, and exhibited a greater number of errors in the double Y-maze memory task, when compared with controls. Subchronic PCP treatment increased [H]muscimol-binding sites and decreased affinity for [H]muscimol binding in frontal cortex, hippocampus, and striatum in comparison with controls. There were no changes in the expression of glutamic acid decarboxylase or the GABA membrane transporter protein. These data show that subchronic PCP administration induces an impaired performance of a previously learned task and an enhanced response to amphetamine in the rat. The observed changes in GABAA receptors in the rat brain are consistent with the notion that alterations in GABAergic receptor function contribute to the behavioral and cognitive impairments associated with repeated exposure to PCP.
Subject(s)
Excitatory Amino Acid Antagonists/pharmacology , GABA-A Receptor Antagonists , Maze Learning/drug effects , Motor Activity/drug effects , Phencyclidine/pharmacology , Amphetamine/pharmacology , Animals , Corpus Striatum/drug effects , Corpus Striatum/metabolism , Drug Administration Schedule , Drug Interactions , Frontal Lobe/drug effects , Frontal Lobe/metabolism , GABA Plasma Membrane Transport Proteins/metabolism , Glutamate Decarboxylase/metabolism , Hippocampus/drug effects , Hippocampus/metabolism , Male , Muscimol/analysis , Phencyclidine/administration & dosage , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptors, GABA-A/metabolismABSTRACT
AMPA receptor antagonists disrupt avoidance responding, but their day-to-day effect on this behavior has not been elucidated. This study compared the multisession effect of the AMPA/kainate receptor antagonist CNQX with that of the typical antipsychotic haloperidol on the expression of avoidance responding. Rats (N = 199) were trained to move to safety on presentation of a tone in one-way active conditioned avoidance and were tested across 5 sessions. Intracerebroventricular (icv) injection of CNQX (20-min injection-test interval) produced a dose-dependent, immediate block of avoidance responding, compared with the extinction-like decline of avoidance responding produced by haloperidol (intraperitoneal [ip], 60-min injection-test interval; icv, 60 but not 20-min injection-test interval). Previous exposure to CNQX significantly reduced its efficacy, illustrating that its effects may not be specific to the conditioned safety-related stimuli that control responding in conditioned avoidance, as proposed for antidopaminergic compounds. The new multisession profile of disrupted avoidance responding illustrated by CNQX suggests different roles for glutamatergic and dopaminergic neurotransmission in conditioned avoidance responding. Results are consistent with a role for AMPA receptors in maintaining the expression of learning.
