Effect of a binge-like dosing regimen of methamphetamine on dopamine levels and tyrosine hydroxylase expressing neurons in the rat brain

• Published in: Progress in neuro-psychopharmacology & biological psychiatry Vol. 89; pp. 303 - 309
• Main Authors: Moreira da Silva Santos, Andreia, Kelly, John P., Dockery, Peter, Doyle, Karen M.
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 08-03-2019
• Subjects: Dopamine; Dopamine metabolites; Hyperthermia; Methamphetamine; Tyrosine hydroxylase; Dopamine metabolites; Tyrosine hydroxylase; Dopamine; Hyperthermia; Methamphetamine
• ISSN: 0278-5846; 1878-4216
• DOI: 10.1016/j.pnpbp.2018.10.003

Methamphetamine, an amphetamine derivative, is a powerful psychomotor stimulant and commonly used drug of abuse. This study examined the effect of binge-like methamphetamine (MA) dosing (4 × 4 mg/kg, s.c., 2 h apart) on regional dopamine and dopaminergic metabolite levels in rat brain at a range of early time points after final dose (2–48 h). Body temperature was elevated when measured 2 h after the last dose. MA increased dopamine levels in the frontal cortex 2 and 24 h after the last dose. The dopamine level was also increased in the amygdala at 24 h. No change was observed in the striatum at any time point, but levels of the dopamine metabolite DOPAC were markedly reduced at 24 and 48 h. Tyrosine hydroxylase expression is induced downstream of dopamine activity, and it is the rate limiting enzyme in dopamine synthesis. The effect of MA binge-like dosing on the volume of tyrosine hydroxylase containing cell bodies and the area fraction of tyrosine hydroxylase containing fibres was also assessed. MA increased the area fraction of tyrosine hydroxylase fibres in the frontal cortex and reduced the volume of tyrosine hydroxylase containing cell bodies 2 h after last dose in the ventral tegmental area and the substantia nigra. An increase in cell body volume in the substantia nigra was observed 48 h after treatment. These findings collectively highlight the importance of the dopaminergic system in methamphetamine induced effects, identify the frontal cortex, amygdala and striatum as key regions that undergo early changes in response to binge-like methamphetamine dosing and provide evidence of time-dependent effects on the cell bodies and fibres of tyrosine hydroxylase expressing neurons.
•Investigation of early effects of binge-like methamphetamine on rat dopamine neurons.•Dopamine and metabolite levels regionally altered in early effects.•Frontal cortex, amygdala and striatum - key regions that undergo early changes.•Time-dependent effects in tyrosine hydroxylase expressing cell bodies and fibres.