High doses of methamphetamine that cause disruption of the blood-brain barrier in limbic regions produce extensive neuronal degeneration in mouse hippocampus

Abstract

Histological examination of brain after a single high (40 mg/kg) dose of D-methamphetamine (METH) was used to determine the relationships between blood-brain barrier (BBB) disruption, hyperthermia, intense seizure activity, and extensive degeneration that this exposure often produces. In very hyperthermic mice (body temperatures > 40.5 degrees C) exhibiting status epilepticus, increase in mouse IgG immunoreactivity (IgGIR) in the medial and ventral amygdala was observed within 90 min after METH exposure. In a few instances, where body temperature was in the 40.0 degrees C range, such IgGIR was also seen in animals that had exhibited status epilepticus. Variable increases in IgGIR, which correlated with neurodegeneration, also occurred within 12 h in the hippocampus, indicating BBB disruption in this region also. Degenerating neurons, Fluoro-Jade C (FJ-C) labeled, were first detected 4 h after METH in the amygdala and hippocampus. Extensive neurodegeneration occurred in the amygdaloid and hippocampal pyramidal cell regions in animals with marked IgGIR increase in these regions by 12 and 24 h after METH. A very rapid activation of brain microglia and/or infiltration of macrophages in regions of notable IgGIR increase with intense neurodegeneration were seen within 24 h. The phagocytosis rate of neurons in the hippocampus was so rapid that FJ-C labeling was virtually nonexistent 3 days after METH. METH did not produce IgGIR increase or neurodegeneration in the limbic regions in the absence of hyperthermia and seizures. Thus, high doses of METH can cause damage to the BBB when hyperthermia occurs, resulting in rapid and extensive hippocampal and amygdalar damage. The BBB disruption in the medial amygdala occurs first, and may well be contributing to the induction and severity of seizures, while BBB disruption in the hippocampus is likely a result of the seizures and hyperthermia. This hippocampal damage should be sufficient to compromise learning and memory.