Stereoselective accumulation of hydroxylated metabolites of amphetamine in rat striatum and hypothalamus.

The stereoselective accumulation of alpha-methyl-p-tyramine (AMPT) and alpha-methyl-p-octopamine (AMPO) in rat striatum and hypothalamus after acute and chronic administration of the (+)- and (-)-isomers of amphetamine (Amphet) and the acute administration of (+)- and (-)-AMPT has been investigated by chemical ionization gas chromatography mass spectrometry (c.i.g.c.m.s.). Two h after the administration of (+)- or (-)-AMPT (5 mg kg-1 i.p.), the concentrations of the isomers in striatal tissue were approximately equal; 18 h later, the concentration of the (+)-isomer was 10 times that of the (-)-isomer. The concentrations of AMPO in the striatum and hypothalamus 20 h after administration of (+)-AMPT were 68 ng g-1 and 484 ng g-1 respectively. After the administration of the (-)-isomer of AMPT, small quantities of AMPO were detected in both brain areas. Twenty h after the last of 7 daily injections of (+)-Amphet (5 mg kg-1, i.p.), the concentration of AMPO in the hypothalamus was 5.4 times the concentration at 20 h after one injection. In the striatum, the corresponding ratio for AMPO was 3.5 and for AMPT was 2.5. These data indicate that, although both isomers of AMPT formed from Amphet administered systemically, cross the blood brain barrier, the (+)-isomers AMPT and AMPO are preferentially stored in striatal and hypothalamic aminergic nerve terminals. The accumulations of AMPT and AMPO in rat striatum and hypothalamus after chronic administration of Amphet demonstrates that these metabolites persist in neuronal storage in these brain areas for days after administration. The half-lives of (+)-AMPT and (+)-AMPO in striatal neuronal storage, calculated from this data, were 1.5 days and 2.5 days, respectively. The corresponding half-life for hypothalamic (+)-AMPO was 7 days. 7. These findings suggest the involvement of accumulated AMPT and AMPO in the development of behavioural augmentation to repeated injections of Amphet (Randrup & Munkvad, 1970).