Amphetamine levels in brain microdialysate, caudate/putamen, substantia nigra and plasma after dosage that produces either behavioral or neurotoxic effects.
Extracellular levels of d-amphetamine (AMPH) in caudate/putamen were determined using microdialysis and HPLC quantitation after s.c. doses that produced increased motor activity (1 mg/kg), stereotypic behavior (2.5 mg/kg) or dopamine depletion in the caudate/putamen (4 x 5 mg/kg). In 6-mo-old rats exposed to neurotoxic doses of AMPH sulfate (4 x 5 mg/kg in a 23 degrees C environment), extracellular caudate/putamen AMPH rose to levels of 7.9 +/- 0.9 microM after the first dose and peaked at 15.1 +/- 2.5 microM after the third dose with no further increases after the fourth dose. After one or three doses of 5 mg/kg, peak plasma and tissue levels of AMPH were 1.7 +/- 0.2 and 2.9 +/- 0.3 microM in plasma, 36 +/- 6 and 73 +/- 10 in substantia nigra and 25 +/- 4 and 50 +/- 8 in caudate/putamen, respectively. Caudate/putamen extracellular AMPH levels were about three times higher (in either 6- or 12-mo-old rats) after 4 x 15 mg/kg in a 10 degrees C environment and tissue levels in caudate/putamen and substantia nigra were three to five times higher after three doses of AMPH. However, these higher levels did not produce dopamine depletion in the caudate/putamen, while the lower doses (4 x 5 mg/kg) given at 23 degrees C did. Estimated caudate/putamen extracellular AMPH levels of 2.5 to 5 microM after single doses (1 and 2.5 mg/kg) that caused hyperactivity and stereotypic behavior are compatible with the 2 to 10 microM AMPH concentrations reported to be necessary to produce pronounced dopamine release in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)
Clausing
P
P
Division of Neurotoxicology, National Center for Toxicological Research, Jefferson, Arkansas, USA.
Gough
B
B
Holson
R R
RR
Slikker
W
W
Bowyer
J F
JF
D000818:Animals; D001921:Brain / Q000378:metabolism*; D002421:Caudate Nucleus / Q000378:metabolism; D003913:Dextroamphetamine / Q000493:pharmacokinetics* / Q000633:toxicity; D006863:Hydrogen-Ion Concentration; D008297:Male; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects; D011699:Putamen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013239:Stereotyped Behavior / Q000187:drug effects; D013378:Substantia Nigra / Q000378:metabolism; D013696:Temperature
D003913:Dextroamphetamine