Striatal dopamine release in vivo following neurotoxic doses of methamphetamine and effect of the neuroprotective drugs, chlormethiazole and dizocilpine.
Level 5 - mechanism / opinion, no new human data
Bench and animal research without human clinical data
PubMed 8467354 · doi:10.1111/j.1476-5381.1993.tb12847.x
What was done
Rats were administered methamphetamine (15 mg/kg, i.p., every 2 hours for 4 doses) alone or with pretreatment of chlormethiazole (50 mg/kg, i.p.) or dizocilpine (1 mg/kg, i.p.) 15 minutes before each dose. Striatal dopamine and cortical/hippocampal 5-hydroxytryptamine (5-HT) levels were measured 3 days later. In vivo microdialysis in the striatum tracked extracellular dopamine, DOPAC, and HVA. In vitro dopamine release was evaluated in striatal prisms exposed to chlormethiazole (100–1000 µM) with methamphetamine (100 µM) or K+ (35 mM).
What was found
Methamphetamine caused a 36% loss in striatal dopamine and a 43% and 47% loss in cortical and hippocampal 5-HT, respectively. Chlormethiazole provided complete protection, whereas dizocilpine provided substantial protection against these monoamine losses. Methamphetamine increased in vivo striatal dopamine release by ~7,000% after the first dose and ~4,000% after the third dose; chlormethiazole attenuated this release by ~40% and decreased DOPAC and HVA dialysate levels further, while dizocilpine had no effect on dopamine release. In vitro, chlormethiazole did not alter methamphetamine- or K+-evoked dopamine release.
Why it matters
The study shows that chlormethiazole prevents methamphetamine-induced monoaminergic neurotoxicity, an effect associated with dampening excessive in vivo dopamine release via a mechanism distinct from NMDA receptor antagonism.
Limits
This is an animal and in vitro tissue study, so applicability to human methamphetamine toxicity remains unverified. The abstract does not report animal sample sizes (n), measures of variance, or exact statistical significance values.
Cited by
- context Methamphetamine consumption causes a thousandfold increase in dopamine release within moments.