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 foun d 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 affec ting the sodium gradient as well as by molecules resembling its struct ure, e.g. D-carnitine, acetyl-L-carnitine and gamma-aminobutyric acid (GABA). GABA was the most potent inhibitor of L-carnitine uptake. In t he present study we have found that specific GABA uptake blockers, nip ecotic acid, cis-4-hydroxynipecotic (HNA), guvacine, 2,4-diaminobutyri c acid (DABA) and NO 711 inhibit L-carnitine uptake even more potently than GABA. However, apart from NO 711, they caused about the same max imal inhibition, 67.4% at 50 mu M for guvacine, compared to 60.5% by G ABA. NO 711 was extremely potent and blocked 80.5% of the L-carnitine uptake. In contrast, the GABA(A) receptor agonists, isonipecotic acid and isoguvacine, or the antagonist bicuculline, at similar concentrati ons (50 mu M), did not significantly inhibit the uptake of the L-carni tine. However, bicuculline at relatively high concentration (500 mu M) was inhibitory (38%). The GABA(B) receptor agonist, baclofen, or anta gonist, phaclofen, were ineffective, although 5-aminovaleric acid did significantly inhibit uptake at both 50 and 500 mu M, causing 22 and 4 8% inhibition respectively. Like bicuculline, it was not as effective as GABA or the specific GABA uptake blockers. The results indicate tha t 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 bloc kers.