Dopaminergic innervation to the nucleus accumbens was investigated following a neurotoxic regimen of methamphetamine (MA) treatment. Four 10 mg/kg doses of MA were administered s.c. to male Sprague-Dawley rats with a 2 h interval between doses. Rectal temperatures were monitored for the induction of MA-induced hyperthermia. Three days or 2 weeks after MA treatment the animals were sacrificed by transcardial perfusion and processed for tyrosine hydroxylase (TH-IR) and glial fibrillary acidic protein immunoreactivity (GFAP-IR). MA treatment produced a severe loss of TH-IR throughout the striatum, including the nucleus accumbens. However, within the nucleus accumbens, there was substantial sparing of TH-IR in the shell, while in the core immunoreactivity was almost entirely lost. Furthermore, astrogliosis, as demonstrated by GFAP-IR, was prevalent in the core but present only in sparse patches in the medial and lateral shell. Thus, dopaminergic innervation to the nucleus accumbens core undergoes degeneration following MA treatment, while innervation to the shell is resistant to the neurodegenerative effects of MA.