Inhibition of L-carnitine uptake into primary rat cortical cell cultures by GABA and GABA uptake blockers.
L-carnitine plays a central role in mitochondrial function and is found to be differentially distributed in the brain. We have shown before that the uptake of L-carnitine into cultured rat cortical neurones was temperature-dependent, as well as potently inhibited by factors affecting the sodium gradient as well as by molecules resembling its structure, e.g. D-carnitine, acetyl-L-carnitine and gamma-aminobutyric acid (GABA). GABA was the most potent inhibitor of L-carnitine uptake. In the present study we have found that specific GABA uptake blockers, nipecotic acid, cis-4-hydroxynipecotic (HNA), guvacine, 2,4-diaminobutyric acid (DABA) and NO 711 inhibit L-carnitine uptake even more potently than GABA. However, apart from NO 711, they caused about the same maximal inhibition, 67.4% at 50 microM for guvacine, compared to 60.5% by GABA. NO 711 was extremely potent and blocked 80.5% of the L-carnitine uptake. In contrast, the GABAA receptor agonists, isonipecotic acid and isoguvacine, or the antagonist bicuculline, at similar concentrations (50 microM), did not significantly inhibit the uptake of the L-carnitine. However, bicuculline at relatively high concentration (500 microM) was inhibitory (38%). The GABAB receptor agonist, baclofen, or antagonist, phaclofen, were ineffective, although 5-aminovaleric acid did significantly inhibit uptake at both 50 and 500 microM, causing 22 and 48% inhibition respectively. Like bicuculline, it was not as effective as GABA or the specific GABA uptake blockers. The results indicate that the uptake of L-carnitine by rat cortical neurones occurs in part by a process that can be potently inhibited by GABA and GABA uptake blockers.
Virmani
M A
MA
Research & Development, Neuroendocrinology, Sigma-Tau, Pomezia, Italy.
Conti
R
R
Spadoni
A
A
Rossi
S
S
Arrigoni-Martelli
E
E
D000818:Animals; D002331:Carnitine / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism*; D005260:Female; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology*; D009539:Nicotinic Acids / Q000494:pharmacology; D009557:Nipecotic Acids / Q000494:pharmacology; D011247:Pregnancy; D011392:Proline / Q000031:analogs & derivatives*; D051381:Rats; D017207:Rats, Sprague-Dawley; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology* / Q000502:physiology*
D014179:Neurotransmitter Uptake Inhibitors; D009539:Nicotinic Acids; D009557:Nipecotic Acids; C030278:nipecotic acid; C015910:guvacine; D005680:gamma-Aminobutyric Acid; D011392:Proline; C010983:homoproline; D002331:Carnitine