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

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Abstract
1 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. 2 The spontaneous resting release of GABA from the three tissues was 3 to 6 pmol mg−1 wet wt 10 min−1 Depolarization 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. 3 When rats were injected with γ-vinyl-GABA (250 mg kg−1 i.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. 4 (−)-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 IC50 for baclofen was approximately 5.2 μm The 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. 5 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. 6 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. 7 Baclofen (10 μm) significantly reduced the K-evoked release from cortical slices of glutamate, aspartate, glycine and taurine. 8 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. 9 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 GABAB inhibitory autoreceptors. No evidence was found for GABAB-autoreceptors on retinal GABAergic amacrine cells or for GABAA-autoreceptors in cortical slices or spinal cord slices.