ABSTRACT
The extracellular signal-regulated kinase (ERK) pathway mediates neuronal plasticity in the CNS. The mood stabilizers lithium and valproate activate the ERK pathway in prefrontal cortex and hippocampus and potentiate ERK pathway-mediated neurite growth, neuronal survival and hippocampal neurogenesis. Here, we examined the role of the ERK pathway in behavioral plasticity related to facets of bipolar disorder. Mice with ERK1 ablation acquired reduced phosphorylation of RSK1, an ERK substrate, in prefrontal cortex and striatum, but not in hippocampus or cerebellum, indicating the ablation-induced brain region-specific ERK signaling deficits. ERK1 ablation produced a behavioral excitement profile similar to that induced by psychostimulants. The profile is characterized by hyperactivity, enhanced goal-directed activity and increased pleasure-related activity with potential harmful consequence. ERK1-ablated mice were hyperactive in multiple tests and resistant to behavioral despair in the forced swim test. These mice displayed more home-cage voluntary wheel running activities, rearings in a large arena and open-arm visits in an elevated plus maze. Treatments with valproate and olanzapine, but not lithium reduced baseline activities in ERK1-ablated mice. All three treatments attenuated amphetamine-induced hyperactivity in ablated mice. These data indicate a profound involvement of ERK1 signaling in behavioral excitement and in the behavioral action of antimanic agents. The extent to which ERK pathway perturbation contributes to the susceptibility, mood switch mechanism(s) and symptom pathophysiology of bipolar disorder requires further investigation. Whether there is a shared mechanism through which mood stabilizers produce their clinical actions on mood, thought and behavioral symptoms of mania also requires further investigation.
Subject(s)
Behavior, Animal/physiology , Extracellular Signal-Regulated MAP Kinases/physiology , Signal Transduction/physiology , Adjuvants, Immunologic , Administration, Oral , Amphetamine/pharmacology , Analysis of Variance , Animals , Antipsychotic Agents/pharmacology , Behavior, Animal/drug effects , Benzodiazepines/pharmacology , Central Nervous System Stimulants/pharmacology , Enzyme Inhibitors/pharmacology , Lithium Chloride/administration & dosage , Locomotion/drug effects , Locomotion/genetics , Maze Learning/drug effects , Maze Learning/physiology , Mice , Mice, Knockout , Mitogen-Activated Protein Kinase 3/deficiency , Olanzapine , Ribosomal Protein S6 Kinases, 90-kDa/genetics , Ribosomal Protein S6 Kinases, 90-kDa/metabolism , Signal Transduction/genetics , Swimming , Valproic Acid/pharmacologyABSTRACT
Capillary ion analysis (CIA) is a form of capillary electrophoresis that uses the differential electrophoretic mobility of ions to perform a separation of an ionic mixture. Application of this technique for detection of lithium concentrations in plasma and tissues of Poecilia was the purpose of this investigation. CIA was performed using a 75 microm ID x 60 cm length fused-silica capillary and a run electrolyte of 67.7 mg hydroxyisobutyric acid (HIBA), 52.8 mg 18-crown-6-ether and 64 microL UV-CAT-1 reagent (4-methylbenzylamine) in a volume of 100 mL water (18 (M)omega) with a voltage of 20 kV using ultraviolet absorption detection at 214 nm. Migration times were: potassium, 2.98 min; calcium, 3.48 min; sodium, 3.60 min; barium (internal standard), 4.15 min and lithium, 4.26 min. Lithium and barium migration times were stable and reproducible. Correlation coefficients (r) between peak area ratios of lithium/barium for concentrations ranging from 0.1 to 2.0 mM were from 0.976 to 0.996. Coefficients of variation (CV) for lithium concentrations ranged from 4.07 to 15.71% between days and 4.38 to 7.76% within-day. Application of this methodology for determination of lithium concentrations in the plasma, brains and livers of fish dosed with lithium for 23 days are presented. CIA is applicable to analysis of lithium concentrations in biological fluids and tissues of fish.
