Amphetamine and D1 Dopamine Receptor Agonists Produce Biphasic Effects on Glutamate Efflux in Rat Ventral Tegmental Area: Modification by Repeated Amphetamine Administration

Abstract

Amphetamine or selective D1 and D2 dopamine receptor agonists and antagonists were administered to the ventral tegmental area (VTA) through a microdialysis probe to determine their effects on glutamate and aspartate efflux in rats pretreated for 5 days with vehicle or 5 mg/kg (+)‐amphetamine sulfate. In vehicle rats, glutamate efflux declined during 2 h of perfusion with the D1 receptor agonist SKF‐82958 (10 and 100 µM). After SKF‐82958 perfusion ended, glutamate efflux rebounded to basal levels and continued to increase gradually over the next 2 h. A similar biphasic pattern was observed with intra‐VTA amphetamine (10 and 100 µM) and with another D1 agonist (100 µM SKF‐38393). The biphasic effects of SKF‐82958 were prevented by coperfusion with a D1 antagonist (SCH‐23390; 30 µM). Glutamate efflux was unaffected by a D2 agonist (100 µM quinpirole) and by D1 or D2 antagonists administered alone (SCH 23390 and eticlopride; 30 µM). In amphetamine‐pretreated rats tested 2 days after the last injection, both the decrease during SKF‐82958 perfusion and the delayed increase in glutamate efflux were attenuated. In rats tested 12–14 days after the last amphetamine injection, only the decrease during SKF‐82958 perfusion was attenuated. None of these drug treatments produced consistent effects on aspartate efflux. We showed previously that systemic amphetamine (5 mg/kg, i.p.) has no immediate effect on VTA glutamate efflux but produces a delayed increase in glutamate efflux that reaches statistical significance 2–3 h after injection. Because behavioral sensitization can be elicited either by repeated systemic or repeated intra‐VTA administration, neurochemical effects common to both routes (such as the delayed increase in glutamate efflux) are most likely to contribute to its induction.

Dopamine Alters AMPA Receptor Synaptic Expression and Subunit Composition in Dopamine Neurons of the Ventral Tegmental Area Cultured with Prefrontal Cortex Neurons

“…As expected, robust D 2 receptor surface expression was found. D 2 receptors serve as autoreceptors (Wolf and Roth, 1987) and, within the VTA, only DA neurons express D 2 receptors (Meador-Woodruff et al, 1989;Sesack et al, 1994). No D 1 or D 5 receptors were found on the surface of VTA DA neurons in our cultures, indicating that if they exist, levels are very low compared with D 2 receptors.…”

The Endomorphin System and Its Evolving Neurophysiological Role

“…It has been demonstrated that Glu concentrations increased significantly in all tested brain areas in both groups of animals. It was suggested that -opioid receptor agonists could activate dopaminergic neurons through the activation of GABA or Glu neurons in the VTA (Karler et al, 1990, Wolf andXue, 1998;Johnson and North, 1992).…”

Rapid Synaptic Plasticity of Glutamatergic Synapses on Dopamine Neurons in the Ventral Tegmental Area in Response to Acute Amphetamine Injection

“…Psychostimulants promote glutamate efflux in the VTA (Kalivas and Duffy, 1995;Xue et al, 1996;Wolf and Xue, 1998), due to efflux from glutamate transporters and cystine-glutamate exchangers (Wolf and Xue 1999;Baker et al, 2002Baker et al, , 2003. In principle, this rise in extracellular glutamate could contribute to the development of LTP, but studies indicate that this rise does not begin until 2 h after psychostimulant exposure (Xue et al, 1996;Wolf and Xue, 1998). Since we observe increased AMPAR/NMDAR ratios within this time period, the rise in extracellular glutamate may not be required for these early synaptic changes.…”