Ontogeny of methamphetamine-induced neurotoxicity and associated hyperthermic response

Abstract

Methamphetamine (MA) administration to adult rats results in neurotoxicity characterized by depletion of caudate-putamen (CP) dopamine (DA) and serotonin (5-HT) and an accompanying increase in glial fibrillary acidic protein (GFAP) content. The severity of MA-induced neurotoxicity correlates with the accompanying thermoregulatory response, i.e., a hyperthermic response facilitates neurotoxicity while a hypothermic response is neuroprotective. In the following study, the thermoregulatory and neurotoxic effects of MA administration (4×10 mg/kg) were investigated in developing rats at postnatal days (PND) 20, 40 and 60. Rats at PND 20 and PND 40 were administered MA at ambient temperatures of 22°C and 30°C; and PND 60 rats were administered MA at 22°C only. Temperatures were measured and thermal responses were compared by calculating the total thermal response (TTR) induced by MA treatment. MA administration to PND 60 rats at 22°C induced a hyperthermic response, resulted in a 47% reduction of neostriatal DA and a 49% increase of GFAP content. Administration of MA to PND 40 rats at 22°C failed to induce a hyperthermic response and did not result in reduced DA or increased GFAP. However, administration of MA to PND 40 rats at 30°C induced hyperthermia, reduced neostriatal DA by 54% and increased GFAP by 70%. MA administration to PND 20 rats at either 22°C or 30°C did not result in DA depletion or increased GFAP, even though MA administration to PND 20 rats at 30°C induced hyperthermia. These results demonstrate that the induction of hyperthermia is necessary to exhibit MA-induced neurotoxicity at PND 40; however, PND 20 rats are resistant to the DA depleting effects of MA despite the induction of hyperthermia.