Methylphenidate and amphetamine modulate differently the NMDA and AMPA glutamatergic transmission of dopaminergic neurons in the ventral tegmental area.

Behavioral and neurochemical studies suggest that the induction of behavioral sensitization to psychostimulants involves transient changes at the synapses of the ventral tegmental area's dopaminergic neurons (VTA-DA). Differences in the behavioral response to amphetamine (Amph) and methylphenidate (MPD) were observed. In an attempt to understand these behavioral differences at the neuronal level, the dose-response characteristics of these two psychostimulants on electrophysiologically identified VTA-DA neurons at the glutamatergic synapse were investigated. Miniature excitatory post-synaptic currents (mEPSCs) and electrically induced EPSCs were recorded from horizontal midbrain slices of rats that had been pretreated intraperitoneally (i.p.) with saline (control), Amph (2.5, 5.0, 10.0 or 20.0 mg/kg), or MPD (2.5, 5.0, 10.0 or 20.0 mg/kg) 24 h before the recording. Perfusion of Amph through the bath (2.5, 5.0, 10.0 or 20.0 microM) increased the frequency (p<0.01) and the amplitude (p<0.05) of mEPSCs in dose-response characteristics, while MPD perfusion through the bath (2.5, 5.0, 10.0, or 20.0 microM) increased only the frequency (p<0.05) of the mEPSC. Both psychostimulants increased the prefrontal cortex's (PFC) glutamatergic EPSC in the VTA-DA neurons. However, only the higher doses of MPD induced significant effects (p<0.05) on the N-methyl-D-aspartate (NMDA) receptor-mediated EPSC but had no effects on the EPSC mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA/kainate) receptors. Contrarily, Amph increased both kinds of mediated EPSC, but mainly the EPSC mediated by AMPA/kainate receptors (p<0.01). These electrophysiological differences could represent the underlying mechanism responsible for the differences of behavioral effects, such as behavioral sensitization, elicited by MPD and Amph.