Baclofen and phaclofen modulate GABA release from slices of rat cerebral cortex and spinal cord but not from retina

The effects of (−)‐baclofen, muscimol and phaclofen on endogeneous γ‐aminobutyric acid (GABA) release from rat cortical slices, spinal cord slices and entire retinas were studied.The spontaneous resting release of GABA from the three tissues was 3 to 6 pmol mg−1wet wt 10 min−1Depolarization of cortical slices with KCl (50 mM) (high‐K) produced an 8 fold increase in GABA release but high‐K did not evoke an increased release of GABA from spinal slices or retinas.When rats were injected with γ‐vinyl‐GABA (250 mg kg−1i.p.) (GVG) 18 h before death, the tissue GABA stores were increased 3 to 6 fold and high‐K then evoked striking Ca‐dependent releases of GABA from all three tissues. Thus, in subsequent experiments, unless otherwise stated, the nervous tissues were taken from GVG‐treated rats.(−)‐Baclofen (10 μm) significantly reduced the K‐evoked release of GABA from cortical and spinal slices but retinal release was not affected, even at a concentration of (±)‐baclofen of 1 mM. For cortical slices, the IC50for baclofen was approximately 5.2 μmThe inhibitory effect of baclofen on GABA release from cortical slices also occurred in slices prepared from saline‐injected rats, indicating that GVG treatment did not qualitatively affect the results.The inhibitory effect of (−)‐baclofen on the K‐evoked release of GABA from cortical and spinal slices was antagonised by phaclofen (500 μm), confirming that baclofen was producing its effects by acting at the GABAB‐receptor.Phaclofen (500 μm) increased the spontaneous resting release of GABA from cortical slices taken from GVG‐treated rats but not from saline‐injected rats. Phaclofen did not increase GABA release from spinal slices or retinas taken from GVG‐treated rats.Baclofen (10 μm) significantly reduced the K‐evoked release from cortical slices of glutamate, aspartate, glycine and taurine.Muscimol (10 μm) and δ‐aminolaevulinic acid (10 μm) had no effect on either the resting or K‐evoked release of GABA from cortical slices prepared from saline‐injected or GVG‐treated rats.The results obtained with cortical and spinal slices are consistent with the presence of inhibitory GABAB‐autoreceptors. The phaclofen‐induced increase in GABA release from cortical slices taken from GVG‐treated rats, but not from saline‐injected rats, implies that under conditions of high GABA release, considerable feedback inhibition is occurring via activation of the GABABinhibitory autoreceptors. No evidence was found for GABAB‐autoreceptors on retinal GABAergic amacrine cells or for GABAA‐autoreceptors in cortical slices or spinal cord slices.