Amphetamine levels in brain microdialysate, caudate/putamen, substantia nigra and plasma after dosage that produces either behavioral or neurotoxic effects
Clausing, P.; Gough, B.; Holson, R.R.; Slikker, W.; Bowyer, J.F.
Journal of Pharmacology and Experimental Therapeutics 274(2): 614-621
1995
ISSN/ISBN: 0022-3565 PMID: 7636721 Document Number: 446579
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 times 5 mg/kg). In 6-mo-old rats exposed to neurotoxic doses of AMPH sulfate (4 times 5 mg/kg in a 23 degree C environment), extracellular caudate/putamen AMPH rose to levels of 7.9 +- 0.9 mu-M after the first dose and peaked at 15.1 +- 2.5 mu-M 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 mu-M 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 times 15 mg/kg in a 10 degree 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 times 5 mg/kg) given at 23 degree C did. Estimated caudate/putamen extracellular AMPH levels of 2.5 to 5 mu-M after single doses (1 and 2.5 mg/kg) that caused hyperactivity and stereotypic behavior are compatible with the 2 to 10 mu-M AMPH concentrations reported to be necessary to produce pronounced dopamine release in vitro. The results show that: 1) the blockade of AMPH neurotoxicity after 4 times 15 mg/kg produced by inhibiting hyperthermia during AMPH exposure is not the result of reduced caudate/putamen extracellular or tissue AMPH levels; 2) the increased AMPH neurotoxicity in older animals is not due to higher plasma or caudate/putamen tissue levels even though extracellular caudate/putamen levels are greater and 3) the determination of extracellular AMPH concentrations facilitates the comparison of in vivo vs. in vitro experiments.