Local injection of a glutamate uptake inhibitor into the ventral tegmental area produces sensitization to the behavioural effects of d-amphetamine

Neuroscience. 2005;134(2):361-7. doi: 10.1016/j.neuroscience.2005.04.044.


Circumstantial evidence suggests that sensitization to the behavioral effects of d-amphetamine is mediated by increased glutamate levels in the ventral tegmental area. To test this directly, the present study examined whether increasing glutamate levels in the ventral tegmental area with a glutamate uptake inhibitor is sufficient, in the absence of d-amphetamine administration, to elicit sensitization to a subsequent d-amphetamine challenge. Rats were treated bilaterally once a day for 2 days with either intra-ventral tegmental area L-trans-pyrollidine-2,4-dicarboxylic acid (50 nmol), saline, L-trans-pyrollidine-2,4-dicarboxylic acid coadministered with the competitive N-methyl-d-aspartate antagonist (+/-)-3-(2-carboxy-piperazin-4-yl)-propyl-1-phosphonic acid; CPP, 0.5 nmol), or CPP alone (0.5 nmol; all 1.0 microl/side). Following a 2 day withdrawal period, all rats were administered systemic d-amphetamine (1 mg/kg, i.p.). Repeated intra-ventral tegmental area injection of L-trans-pyrollidine-2,4-dicarboxylic acid sensitized animals to the behavioral effects of a systemic d-amphetamine challenge, an action which was blocked by co-administration of CPP. The results directly implicate ventral tegmental area glutamate in the process of sensitization to d-amphetamine. Furthermore, they demonstrate that inhibition of glutamate uptake produces the neuroadaptations necessary to induce sensitization, adding support to the contention that d-amphetamine sensitizes by modulating glutamate uptake.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dextroamphetamine / pharmacology*
  • Dicarboxylic Acids / pharmacology
  • Excitatory Amino Acid Antagonists / administration & dosage
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Glutamic Acid / metabolism*
  • Male
  • Microinjections
  • Motor Activity / drug effects
  • Piperazines / pharmacology
  • Pyrrolidines / pharmacology
  • Rats
  • Rats, Inbred Strains
  • Ventral Tegmental Area / drug effects
  • Ventral Tegmental Area / physiology*


  • Dicarboxylic Acids
  • Excitatory Amino Acid Antagonists
  • Piperazines
  • Pyrrolidines
  • Glutamic Acid
  • 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid
  • Dextroamphetamine