Amphetamine-induced glutamate efflux in the rat ventral tegmental area is prevented by MK-801, SCH 23390, and ibotenic acid lesions of the prefrontal cortex

J Neurochem. 1999 Oct;73(4):1529-38. doi: 10.1046/j.1471-4159.1999.0731529.x.


We showed previously that amphetamine challenge produces a delayed increase in glutamate efflux in the ventral tegmental area of both naive and chronic amphetamine-treated rats. The present study examined the mechanisms underlying this response. The NMDA receptor antagonist MK-801 (0.1 mg/kg, i.p.) or the D1 dopamine receptor antagonist SCH 23390 (0.1 mg/kg, i.p.), given 30 min before acute amphetamine (5 mg/kg, i.p.), prevented amphetamine-induced glutamate efflux. Neither antagonist by itself altered glutamate efflux. Ibotenic acid lesions of the prefrontal cortex similarly prevented amphetamine-induced glutamate efflux, while producing a trend toward decreased basal glutamate levels (82.8% of sham group). Previous work has shown that the doses of NMDA and D1 receptor antagonists used in this study prevent the induction of behavioral sensitization when coadministered repeatedly with amphetamine, and that identical prefrontal cortex lesions performed before repeated amphetamine prevent the induction of ambulatory sensitization. Thus, treatments that prevent acute amphetamine from elevating glutamate efflux in the ventral tegmental area also prevent repeated amphetamine from eliciting behavioral sensitization. These findings suggest that repeated elevation of glutamate levels during a chronic amphetamine regimen may contribute to the cascade of neuroadaptations within the ventral tegmental area that enables the induction of sensitization.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amphetamine / antagonists & inhibitors
  • Amphetamine / pharmacology*
  • Animals
  • Benzazepines / pharmacology
  • Dizocilpine Maleate / pharmacology
  • Ibotenic Acid / toxicity
  • Kinetics
  • Male
  • Microdialysis
  • Motor Activity / drug effects*
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / physiology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Dopamine D1 / drug effects
  • Receptors, Dopamine D1 / physiology
  • Receptors, N-Methyl-D-Aspartate / drug effects
  • Receptors, N-Methyl-D-Aspartate / physiology
  • Tegmentum Mesencephali / drug effects
  • Tegmentum Mesencephali / metabolism*


  • Benzazepines
  • Receptors, Dopamine D1
  • Receptors, N-Methyl-D-Aspartate
  • Ibotenic Acid
  • Dizocilpine Maleate
  • Amphetamine