Local injection of a glutamate uptake inhibitor into the ventral tegmental area produces sensitization to the behavioural effects of d-amphetamine.
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.
Department of Psychology, University of Sheffield, Western Bank, Sheffield S10 2TP, UK.
J
J
Aked
V
V
Coizet
D
D
Clark
P G
PG
Overton
D000818:Animals; D003913:Dextroamphetamine / Q000494:pharmacology*; D003998:Dicarboxylic Acids / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D008845:Microinjections; D009043:Motor Activity / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000502:physiology*
D003998:Dicarboxylic Acids; D018691:Excitatory Amino Acid Antagonists; D010879:Piperazines; D011759:Pyrrolidines; D018698:Glutamic Acid; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; D003913:Dextroamphetamine