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.

Mitochondrial dysfunction and caspase activation in rat cortical neurons treated with cocaine or amphetamine

“…Dopamine, therefore, may not be crucial for amphetamine cytotoxicity. Consistent with this, although amphetamine neurotoxicity generally manifests within monoaminergic systems (Cadet et al, 2003), non-dopaminergic neurons also show evidence of toxicity (Eisch and Marshall, 1998;Jimenez et al, 2004;Krasnova et al, 2005).…”

“…Although the frontal cortex receives dopaminergic input from the mesocortical dopaminergic pathway, there were few or no tyrosine-hydroxylase positive cell bodies present in our neuronal cultures (data not shown). In this context, Eisch and Marshall (1998) previously found methamphetamine-induced cortical neuronal damage to non-monoaminergic neuronal populations does not necessarily arise as a secondary consequence of damage to networked striatal dopaminergic neurons.…”

Histological evidence supporting a role for the striatal neurokinin-1 receptor in methamphetamine-induced neurotoxicity in the mouse brain

“…An alternative hypothesis is that METH-induced post-synaptic degeneration has no causal relationship to pre-synaptic terminal damage. For example, we did not observe Fluoro-Jade B staining at 5 mg/kg of METH (personal observation), a dose that has been shown to induce loss of DA transporter sites and TH in the striatum of rats [11]. A similar dose of METH produced Fluoro-Jade B staining of neurons in the parietal cortex but not in the striatum [12], suggesting that cortical neurons are more sensitive to METH than striatal neurons.…”

Long‐term changes in dopamine‐stimulated gene expression after single‐day methamphetamine exposure

“…Single-day mAMPH dosing regimens similar to that used in the present experiment have been employed in this laboratory and others to characterize long-term behavioral and neural effects of this psychostimulant agent (Belcher et al, 2005;Chapman et al, 2001;Eisch and Marshall, 1998;Marshall et al, 2007;O'Dell et al, 1991;Schröder et al, 2003;Stephans and Yamamoto, 1994). These mAMPH regimens result in longlasting, moderate (ca.…”