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R Zaczek, S Culp, H Goldberg, DJ Mccann and EB De Souza
Neuroscience Branch, NIDA, Addiction Research Center, Baltimore, Maryland.
Previous studies have identified a saturable site of d-[3H]amphetamine sequestration (AMSEQ) in rat brain synaptosomes. The present study characterized AMSEQ with respect to its subcellular, neuronal and regional distributions, ontogenetic development, pharmacological specificity and factors required for its maintenance. Although AMSEQ was reduced when assays were performed in Krebs' buffer incubated at 37 degrees C as compared to assays performed in isotonic Tris-sucrose buffer incubated at room temperature, the pharmacological profiles of AMSEQ were virtually identical under both conditions. AMSEQ was negligible in tissues outside the central nervous system, enriched in synaptosomes and partially reduced by striatal kainic acid lesion, indicating neuronal localization. The distribution of AMSEQ in the central nervous system was heterogenous. Highest levels were present in hypothalamus with progressively lower levels noted in parietal cortex, frontal cortex, striatum, thalamus, hippocampus, midbrain, cerebellum, pons-medulla and spinal cord. With regard to its ontogeny, AMSEQ increased early in neonatal life, reaching adult levels by postnatal day 14. Although the effects of amphetamine to abolish the transynaptosomal pH gradient suggest a possible role for this gradient in the maintenance of AMSEQ, the pharmacological profile of AMSEQ indicates that other factors are involved. An interaction with an intrasynaptosomal acid, such as N-acetylaspartate, may account for AMSEQ maintenance. AMSEQ did not possess a stereospecific preference for either d-(IC50 = 177 microM) or I-amphetamine (IC50 = 173 microM). However, the pharmacological profile of AMSEQ indicated structural specificity with antidepressants being relatively potent inhibitors. The saturation analysis and pharmacological characteristics of AMSEQ (i.e., low affinity and lack of stereospecificity) suggest that AMSEQ may be related to high dose, nonstereospecific effects of amphetamine, such as stereotypy in rats and psychosis in humans. The relative high potency of antidepressants in inhibiting AMSEQ suggests the importance of this phenomenon in the therapeutic effects of these drugs. Furthermore, the link between antidepressants and AMSEQ may provide insight into the comorbidity of major depression and drug abuse.
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