1. Neostriatal neurones were recorded intracellularly from a rat corticostriatal slice preparation. Depolarizing postsynaptic potentials (DPSPs) were evoked by either cortical or intrastriatal stimulation. 2. Kynurenic acid (600μM), an antagonist of excitatory amino acids, reduced the cortically-evoked DPSPs by 88% while the intrastriatally evoked potentials were reduced by 48%. Bicuculline (100μM) produced only a slight inhibition of the cortically evoked DPSPs (12%), but clearly depressed intrastriatal potentials (52%). 3. The effects of (-)-baclofen, a γ-aminobutyric acid (GABA) (B) receptor agonist, were studied on the cortically evoked DPSPs. In all the tested neurones (-)-baclofen, added to the superfusion medium, caused a concentration-dependent decrease of these potentials (half-maximal effect (EC50) = 800nM). This effect was not affected by bicuculline. (-)-Baclofen did not change the membrane potential, the input resistance, current-evoked firing frequency, or postsynaptic responses to exogenously applied glutamate. 4. The effects of (-)-baclofen on the DPSPs were compared to those produced by application of GABA and muscimol. GABA and muscimol decreased the DPSPs and caused a membrane depolarization coupled with a decrease of the membrane resistance. Bicuculline (100μM) blocked the GABA-induced changes of the membrane potential and of the resistance, but not the decrease of the synaptic potentials. All the effects produced by muscimol were blocked by bicuculline. 5. Following intrastriatal stimulation a residual kynurenate-insensitive potential persisted; this potential was blocked by bicuculline (100μM). (-) -Baclofen produced a dose-dependent decrease of this potential (EC50 = 800nM) . The postsynaptic responses to exogenously applied GABA were unchanged by (-) -baclofen. 6. The amplitude of kynurenate and bicuculline-sensitive DPSPs were stable at a frequency of 0.1Hz. At frequencies between 0.3 and 3Hz both these potentials were attenuated with the second stimulus and after about five stimuli a steady state was reached. Membrane potential and input resistance were not affected by these frequencies of stimulation. 7. Application of the GABA uptake inhibitor nipecotic acid (100-300μM) clearly reduced the amplitude of both kynurenate- and bicuculline-sensitive DPSPs evoked at low frequencies of stimulation (0.01-0.3Hz), but had lower effects at higher stimulation rates (1-3Hz). Application of nipecotic acid increased the duration of membrane responses to exogenously applied GABA. 8. Applications of either 2-hydroxy-saclofen (100μM) or phaclofen (0.7-1mM), antagonists of the GABA(B) receptors, produced a parallel shift to the right of the dose-response curve of the effect of (-)-baclofen on the bicuculline-sensitive DPSPs, but did not significantly antagonize the effect of this agonist on the kynurenate-sensitive DPSPs. 2-Hydroxy-saclofen produced an increase in the amplitude of bicuculline-sensitive DPSPs, while it decreased the amplitude of kynurenate-sensitive potentials. 2-Hydroxy-saclofen reduced the frequency-dependent effect of nipecotic acid on the bicuculline-sensitive DPSPs, but not the action of nipecotic acid on kynurenate-sensitive synaptic depolarizations. 9. We conclude that in the neostriatum GABA(B) receptors mediate the reduction of both cortical glutamatergic transmission and of intrastriatal GABAergic inputs. Since these actions are not coupled to any detectable change in the postsynaptic membrane properties or membrane responses to exogenously applied transmitters, we argue that they occur on neuronal terminals. The increased synaptic concentration of endogenous GABA obtained by either stimulating at high frequencies or blocking the GABA uptake system causes extended presynaptic effects. It is proposed that in the neostriatum endogenous GABA exerts a negative feedback regulation on its own release and on the release of glutamate. These regulatory mechanisms are differentially affected by antagonists of GABA(B) receptors.
|Number of pages||19|
|Journal||Journal of Physiology|
|Publication status||Published - 1991|
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