Brain region-specific neurodegenerative profiles showing the relative importance of amphetamine dose, hyperthermia, seizures, and the blood-brain barrier

Abstract

Understanding the neurotoxic effects of acute high-dose exposures of laboratory animals to methamphetamine (METH) and amphetamine (AMPH) is of relevance to understanding the neurotoxicity incurred in humans from overdose or abuse of these substances. We present recent findings on the neurodegenerative effects of both a single high dose of 40 mg/kg and a 4-dose exposure to AMPH in the rat. Comparing these results with those we have previously observed in rodents exposed to either AMPH or METH helps further address how dose, hyperthermia, seizures and blood-brain barrier (BBB) disruption interact to produce neurodegeneration. With regard to the 4-dose paradigm of AMPH exposure in the rat, our recent data, combined with previous findings, clearly show the importance of dose and hyperthermic interactions in producing neurodegeneration. The single high AMPH dose invariably resulted in extreme hyperthermia and brief episodes of clonic-tonic seizure activity in many rats. However, motor behavior indicative of status epilepticus was not observed in rats receiving the 40 mg/kg AMPH, which contrasts with what we have previously seen with 40 mg/kg METH dose in the mouse. This may explain why, unlike the mice given METH, there was minimal BBB disruption in the amygdala of rats. Nonetheless, in some of the surviving rats there was extensive neurodegeneration in the hippocampus and intralaminar and ventromedial/lateral thalamic nuclei. Early BBB disruption was seen in the hippocampus and may play an important role in the subsequent neurodegeneration. The fact that status epilepticus does not occur in rats that have major hippocampal and thalamic degeneration indicates that such damage may also occur in humans exposed to high doses of AMPH or METH in the absence of status epilepticus or prominent motor manifestations of seizure activity.