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

Abstract

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 x 4mg/kg, s.c., 2 hours apart) on regional dopamine and dopaminergic metabolite levels in rat brain at a range of early time points after final dose (2 -48 hours). Body temperature was elevated when measured 2 hours after the last dose. MA increased dopamine levels in the frontal cortex 2 and 24 hours after the last dose. The dopamine level was also increased in the amygdala at 24 hours. 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 hours. 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 hours 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 hours 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.

Interactions between gut microbiota and berberine, a necessary procedure to understand the mechanisms of berberine

“…The phenylalanine-tyrosine-dopa-dopamine pathway is the main dopamine synthesis pathway. The conversion of tyrosine into dopamine by tyrosine hydroxylase (TH) is the rate-limiting process of dopamine synthesis, and tetrahydrobiopterin acts as a coenzyme in this process [ 137 ]. Dopamine is mainly synthesized in brain neurons, but the metabolic pathway of phenylalanine-tyrosine-dopa-dopamine in microorganisms has also been confirmed [ 138 ].…”

Methamphetamine Self-Administration Differential Effects on Mesolimbic Glutathione Levels, Mitochondrial Respiration and Dopamine Neuron Firing Activity

“…METH also disrupts the function of the vesicular monoamine transporter (VMAT2), inhibiting vesicular storage and promoting an increase in cytoplasmic dopamine (Brown et al, 2000; Rau et al, 2006). However, the effects of METH on these enzymes are region specific and depend on the dose, frequency, and exposure time (Fibiger and Mogeer, 1971; Haughey et al, 1999; Moreira da Silva Santos et al, 2019). Following injection, METH plasma concentrations peak within a few minutes and have a long half-life (about 10 hours) which contributes to its addictive properties and produces neurotoxic effects (Cruickshank and Dyer, 2009).…”