Elsevier

Biological Psychiatry

Volume 59, Issue 7, 1 April 2006, Pages 635-642
Biological Psychiatry

Original article
Different Adaptations in Ventral Tegmental Area Dopamine Neurons in Control and Ethanol Exposed Rats After Methylphenidate Treatment

https://doi.org/10.1016/j.biopsych.2005.08.021Get rights and content

Background

Methylphenidate (MPH) is a psychostimulant effective in treating attention-deficit/hyperactivity disorder (ADHD). Repeated MPH treatment may increase substance abuse risk because of adaptations in dopaminergic (DA) function associated with sensitization to subsequent stimulant exposure. However, this possibility is based on observations in normal animals and may not apply to animals with attention problems linked to compromised DA function such as prenatal ethanol exposed (PE) animals.

Methods

The electrical activity of ventral tegmental area (VTA) DA neurons was studied after the cessation of repeated MPH treatment at a threshold dose (1 mg/kg/day for 3 weeks) in PE and control rats.

Results

In control rats, there was a continuous increase in VTA DA neuron excitability post-MPH treatment, characterized by a transient increase in population activity (1 day posttreatment) followed by decreased population activity (30–60 days posttreatment) in most of the animals due to depolarization inactivation. In PE rats, MPH treatment decreased the excessive excitability of VTA DA neurons and resulted in prolonged normalization in the population activity (1–60 days posttreatment). These changes were not mediated by altered sensitivity of somatodendritic DA autoreceptors.

Conclusions

Repeated MPH treatment produced distinctly different effects on VTA DA neuron activity in control and PE animals. These results suggest that repeated MPH treatment for ADHD may not lead to increased substance abuse risk in special populations such as individuals with fetal alcohol spectrum disorder.

Section snippets

Prenatal Ethanol Treatment and Cross Fostering

The procedures of prenatal ethanol treatment and cross fostering are described in detail in previous studies (Choong and Shen 2004a, Choong and Shen 2004b). Time-pregnant rats were administered ethanol via intragastric intubation between gestation day 8 and 20 with a daily dose of 0 g/kg or 6 g/kg ethanol (20% wt/vol in .9% saline) during weekdays by two intubations at 0 g/kg or 3 g/kg. A single daily dose of 0 g/kg or 4 g/kg ethanol was given during weekends due to limited resources. The 0

Results

Repeated MPH treatment differentially altered VTA DA neuron population activity in control and PE animals. In the control group, repeated MPH treatment lead to a significant 53% increase in VTA DA neuron population activity 1 day posttreatment (n = 10) when compared with that observed in repeated saline-treated control animals recorded 1 day posttreatment (n = 11; Fisher LSD post hoc test following one-way ANOVA, p < .01; Figure 1A). The increase was not observed 7 (n = 11) or 30 to 60 days (n

Discussion

In the present study, we demonstrated that repeated MPH treatment at a low, clinically relevant dose (1 mg/kg, SC; Kuczenski and Segal 2002) during adolescence produced long-lasting adaptational changes in the excitability in VTA DA neurons after cessation of treatment in adulthood. These changes were distinctly different in control and PE animals. In control animals, MPH treatment led to an initial increase in the population activity 1 day posttreatment, which subsided 7 and 30 to 60 days

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