Time and region-dependent manner of increased brain derived neurotrophic factor and TrkB in rat brain after binge-like methamphetamine exposure.

Methamphetamine (MA), a synthetic derivate of amphetamine, has become a major drug of abuse worldwide. This study investigated the effect of binge-like MA dosing (4 x 4 mg/kg, s.c., 2 h (h) apart) at a range of different time points (from 2 h to 7 days after treatment) on brain-derived neurotrophic factor (BDNF) levels and its receptors, TrkB and p75NTR. BDNF levels were significantly increased in the frontal cortex from 2 to 36 h after treatment, returning to normal within 48 h after treatment. In the striatum, BDNF expression was increased at 12 and 24 h after binge-like MA treatment and had returned to normal at 36 h. Increased expression of the TrkB receptor was observed in the frontal cortex at 2, 24 and 48 h after MA treatment and in the striatum at 24 and 48 h after the MA regimen. A significant increase in the p75NTR receptor was also noted in the striatum but not the frontal cortex, and it was less pronounced than the effect on TrkB receptor expression. These findings show that the binge-like regimen of MA affects expression of BDNF and its receptors, particularly the TrkB receptor, in a time and region dependent manner, and highlights the importance of the frontal cortex and the striatum in the response following MA binge-like dosing.

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

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.

Dose-Dependent Effects of Binge-Like Methamphetamine Dosing on Dopamine and Neurotrophin Levels in Rat Brain.

This study investigated the acute effect of a dose range of low-to-moderate binge-like methamphetamine treatments on the regional expression of neurotrophin proteins in the brain and serum 2 h after the last dose, in addition to assessing the behavioural effects and dopamine neurotransmitter changes produced. Male Sprague-Dawley rats received 4 subcutaneous doses of methamphetamine (0.5, 1, 2, and 4 mg/kg, or saline as a control) 2 h apart. Methamphetamine had a dose-dependent stimulatory effect on locomotor activity over the 8 h of observation. A significant increase in dopamine concentration was observed in the frontal cortex with the highest dose of methamphetamine (2 h after the last dose). This effect was dose- and region-specific, as no significant increase was observed with lower doses, nor was a significant change observed in any other brain region tested. A similar dose- and region-specific increase in brain-derived neurotrophic factor (BDNF) was observed in the frontal cortex with the highest-dose regimen. No significant change occurred with lower doses of methamphetamine, or in any other brain region tested. A reduction in BDNF levels in the serum was also observed with the highest concentration, but not with lower doses. Collectively, this data highlights the importance of the frontal cortex in methamphetamine-induced effects, and also the similar dose-response effect of methamphetamine on dopamine and BDNF expression.