Methamphetamine neurotoxicity: Dissociation of striatal dopamine terminal damage from parietal cortical cell body injury

Abstract

Methamphetamine (m-AMPH) administration injures both striatal dopaminergic terminals and certain nonmonoaminergic cortical neurons. Fluoro-Jade histochemistry was used to label cortical cells injured by m-AMPH in order to identify factors that contribute to the cortical cell body damage. Rats given four injections of m-AMPH (4 mg/kg) at 2-h intervals showed hyperthermia (mean = 40.0 +/- 0.10 degrees C) and increased behavioral activation relative to animals given saline (SAL). Three days later, m-AMPH-treated animals showed indices of injury to striatal DA terminals (depletion of tyrosine hydroxylase immunoreactivity) and parietal cortical cell bodies (appearance of Fluoro-Jade stained cells). Pretreatment with a dopamine (DA) D1, D2, or N-methyl-D-aspartate (NMDA) receptor antagonist, or administration of m-AMPH in a 4 degrees C environment, prevented or attenuated m-AMPH-induced hyperthermia, behavioral activation, and injury to striatal DA terminals and parietal cortical cell bodies. Animals pretreated with a DA transport inhibitor prior to m-AMPH showed hyperthermia, behavioral activation, and parietal cortical cell body injury, but they did not show striatal DA terminal injury. Pretreatment with a 5HT transport inhibitor failed to prevent m-AMPH-induced damage to striatal DA terminals or parietal cortical cell bodies. Animals given four injections of SAL in a 37 degrees C environment became hyperthermic, but showed no injury to striatal DA terminals or cortical cell bodies. The ability of the DA transport inhibitor to block m-AMPH-induced striatal DA damage, but not cortical injury, and the inability of hyperthermia alone to cause the cortical cell body injury suggests that m-AMPH-induced behavioral activation and hyperthermia may both be necessary for the subsequent parietal cortical cell body damage.

Impaired Formation of Stimulus–Response, But Not Action–Outcome, Associations in Rats with Methamphetamine-Induced Neurotoxicity

“…To what extent it is striatal DA loss alone that contributes to the deficits vs the DA loss in conjunction with altered/diminished excitatory drive from damaged somatosensory cortex remains to be determined. Fortunately, there are manipulations that can be performed in future studies in an attempt to dissociate the role of these two aspects of METH-induced neurotoxicity on the formation of S-R associations underlying instrumental behavior (Eisch and Marshall, 1998a;O'Dell and Marshall, 2002). Taken together, these findings suggest that disruption of DA and/or glutamatergic input to DL striatum induced by METH likely contributes to the impaired formation of habitual behavior observed in the context of METH-induced neurotoxicity, consistent with impaired formation of habitual behavior in Parkinson's disease patient (Knowlton et al, 1996;Moody et al, 2010).…”

Amphetamine-related drugs neurotoxicity in humans and in experimental animals: Main mechanisms

“…Pharmacological agents that block D 2 -like receptors, can partially or completely protect against METH-induced toxicity and can also prevent the hyperthermic response (Albers and Sonsalla, 1995;Eisch and Marshall, 1998;Metzger et al, 2000). Thus, sulpiride, a D 2 -like receptor antagonist, dose-dependently blocked METH-induced toxicity in mice, and eticlopride and raclopride (other D 2 -like receptor antagonists) prevented METH-induced depletion of the striatal DA content (O"Dell et al, 1993;Metzger et al, 2000).…”

Functional and Structural Brain Changes Associated with Methamphetamine Abuse

“…However, neuronal cell death has been reported in rats treated with acute doses of MA resembling a binge dose pattern in the striatum [50], medial prefrontal cortex (PFC) [51] and in somatosensory cortices [52,53,54]. Moreover, loss of pyramidal neurons in the cortex and hippocampus has been observed in rats treated with escalating doses prior to a high dose challenge of MA [55].…”