Altered neurotransmission in the mesolimbic
dopamine (DA) system has been suggested to be the underlying cause of attention problems commonly observed in children with
fetal alcohol spectrum disorder (
FASD).
Methylphenidate is effective in treating attention problems in children with
FASD. However, the underlying mechanism is currently unknown. We have shown previously that reduced ventral tegmental area (VTA) DA neuron activity in prenatal
ethanol-exposed animals can be normalized by DA agonist treatment. In the present study, we investigated the possibility that similar mechanism mediates the effect of
methylphenidate using the in vivo extracellular single-unit recording technique in anesthetized animals. We observed that reduced VTA DA neuron activity in prenatal
ethanol-exposed animals was normalized by
methylphenidate. The effect of
methylphenidate was mediated by increased extracellular levels of DA instead of
norepinephrine because this effect was not altered by the coadministration of
prazosin, an alpha(1) receptor antagonist, and was mimicked by the application of DA transporter blockers,
nomifensine and 1-2(-[bis(4-flurophenyl)methoxy]ethyl)-4-(3-phenyl)
piperazine dihydrochloride (
GBR 12909). These observations support our hypothesis that depolarization inactivation is the cause of prenatal
ethanol exposure-induced reduction in VTA DA neuron activity. We speculate that
methylphenidate normalized the activity of VTA DA neurons by increasing extracellular DA levels in the VTA and the activation of somatodendritic DA
autoreceptors. As a result, the depolarization inactivation was removed by hyperpolarization. The normalized VTA DA neuron activity in prenatal
ethanol-exposed animals may contribute to a restoration of DA neurotransmission and the
therapeutic effect of
methylphenidate in attention problems in children with
FASD.