Interactions of ( sup 3 H)amphetamine with rat brain synaptosomes. II. Active transport

Journal Article · Wed May 01 04:00:00 EDT 1991 · Journal of Pharmacology and Experimental Therapeutics; (USA)

OSTI ID:5544970

Zaczek, R; Culp, S; De Souza, E B ^[1]

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1. Addiction Research Center, Baltimore, MD (USA)

The accumulation of 5 nM d-({sup 3}H)amphetamine (d-({sup 3}H)AMPH) into rat brain synaptosomes was examined using physiological buffer conditions. The accumulation of d-({sup 3}H)AMPH into striatal synaptosomes was saturable, of high affinity, ouabain-sensitive and temperature-dependent, suggesting an active transport phenomenon. Eadee-Hofstee analysis of striatal d-({sup 3}H)AMPH transport (AMT) saturation isotherms indicated an apparent Km of 97 nM and a Vmax of 3.0 fmol/mg tissue/min. Lesion of the striatal dopaminergic innervation led to equivalent decreases of ({sup 3}H) dopamine (DA) transport and AMT, indicating that AMT occurs in DA terminals. Furthermore, AMT was not evident in cerebral cortex, a brain region with a paucity of DA terminals. In competition studies, AMT was stereospecific; d-AMPH (IC50 = 60 nM) was an 8-fold more potent inhibitor of the transport than its I-isomer (IC50 = 466 nM). DA(IC50 = 257 nM), DA uptake blockers and substrates were found to be potent inhibitors of AMT: GBR12909 IC50 = 5 nM; methamphetamine IC50 = 48 nM; methylphenidate IC50 = 53 nM; and cocaine IC50 = 172 nM. In contrast, serotonin was relatively weak in inhibiting AMT (IC50 = 7.9 microM). There was a highly significant (P less than .001; slope = 1.2) linear correlation between the AMT-inhibiting potencies of AMPH analogs and their potencies in stimulating locomotor activity in rodents. AMT may be important in the low dose effects of AMPH such as increased locomotor activity in rodents and stimulant activity in man. Differences between AMT and d-({sup 3}H)AMPH sequestration described earlier, as well as their possible relevance to behavioral and neurochemical sequelae of AMPH administration are also discussed.

• OSTI ID: 5544970
• Journal Information: Journal of Pharmacology and Experimental Therapeutics; (USA), Journal Name: Journal of Pharmacology and Experimental Therapeutics; (USA) Vol. 257:2; ISSN JPETA; ISSN 0022-3565
• Country of Publication: United States
• Language: English

Related Subjects

550501* -- Metabolism-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
AMINES
AMPHETAMINES
ANALEPTICS
ANIMALS
AUTONOMIC NERVOUS SYSTEM AGENTS
BODY
BRAIN
CELL CONSTITUENTS
CELL MEMBRANES
CENTRAL NERVOUS SYSTEM
CENTRAL NERVOUS SYSTEM AGENTS
DRUGS
HYDROGEN COMPOUNDS
ISOTOPE APPLICATIONS
MAMMALS
MEMBRANE TRANSPORT
MEMBRANES
METABOLISM
NERVOUS SYSTEM
ORGANIC COMPOUNDS
ORGANS
RATS
RODENTS
SYMPATHOMIMETICS
TRACER TECHNIQUES
TRITIUM COMPOUNDS
VERTEBRATES