Vol. 281, Issue 2, 699-706, 1997

Increased Responsiveness of Ventral Tegmental Area Dopamine Neurons to Glutamate after Repeated Administration of Cocaine or Amphetamine Is Transient and Selectively Involves AMPA Receptors¹

Xu-Feng Zhang, Xiu-Ti Hu, Francis J. White and Marina E. Wolf

Department of Neuroscience, Finch University of Health Sciences/The Chicago Medical School, North Chicago, Illinois

It is well established that behavioral sensitization to psychomotor stimulants is associated with adaptations in the mesoaccumbens dopamine (DA) system. We showed previously that the responsiveness of ventral tegmental area (VTA) DA neurons to glutamate was significantly enhanced in amphetamine- and cocaine-pretreated rats tested after 3 days of withdrawal, which suggests that adaptations in excitatory amino acid transmission also contribute to sensitization. The purpose of the present study was to determine the subtype of excitatory amino acid receptor responsible for this effect and to examine its persistence during withdrawal. Extracellular single cell recording and microiontophoresis were used to investigate possible alterations in the ability of glutamate agonists [(S)--amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), N-methyl-D-aspartate (NMDA), and (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-t-ACPD)] to stimulate the firing of VTA DA neurons after 3 days of withdrawal from repeated administration of saline, cocaine or amphetamine. Current-response curves showed that responses to iontophoretic AMPA, but not NMDA or 1S,3R-t-ACPD were significantly enhanced in cocaine- or amphetamine-pretreated rats in that neurons entered into a state of apparent depolarization block at significantly lower iontophoretic currents. When rats were tested for responsiveness to iontophoretic glutamate after 14 days of withdrawal, there was no significant difference between cocaine- or amphetamine- and saline-pretreated rats with respect to glutamate current-response curves. These results suggest that increased responsiveness of AMPA receptors on VTA DA neurons may contribute to sensitization at early withdrawal times, but that this alteration, like others described within the VTA, is transient.