Fig. 4. Dopamine D2 receptors are involved in FC-mediated depression of synaptic output.
A Co-administration of glutamine was not sufficient to prevent synaptic depression mediated by FC. B Depression of PS amplitude was accompanied by increased PPR, indicative of reduced probability of transmitter release. C Inhibition of glutamate receptors using the NMDA receptor antagonist APV, or the mGluR2/3 antagonist LY 341495, was insufficient to block FC-mediated depression of evoked potentials. D Carbenoxolone and PPADS depressed PS amplitude by themselves, but did not prevent FC-mediated depression. E Pre-treatment with antagonists targeting GABAA receptors (Bic), cannabinoid 1 receptors (AM251), µ-opioid receptors (CTAP), gap junction coupling (carbenoxolone, CBX), or purinergic P2 receptors (PPADS), were insufficient to block FC-mediated depression. F Example traces showing evoked PSs during APV-treated baseline (black) and following APV + FC perfusion (gray). Calibration: 0.2 mV, 2 ms. G Pre-treatment with a cocktail of the dopamine D1 and D2 receptor antagonists SCH23390 and sulpiride inhibited synaptic depression mediated by FC, as did sulpiride pre-treatment alone. H A low concentration of the glutamate transporter inhibitor TFB-TBOA, which should act selectively on astrocytic glutamate uptake, significantly depressed PS amplitude in a manner blocked by sulpiride. I While FC was insufficient to increase PPR in slices pretreated in sulpiride, the effect was still present in slices incubated in a cocktail of sulpiride and SCH23390. J TFB-TBOA significantly increased PPR in both control slices, and in slices pre-treated with sulpiride. Data are based on at least four animals/treatment and presented as mean values ± SEM. n number of recordings. *p < 0.05, **p < 0.01, ***p < 0.001. K Schematic drawing showing how a reduced activity of astrocytes might result in decreased probability of transmitter release. Metabolic inhibition of astrocytes reduces ATP levels and GS function, and will lead to reduced uptake of glutamate, potassium, and possibly also dopamine. Fluorocitrate also impairs astrocyte calcium signaling, resulting in reduced release of gliotransmitters, including the endogenous antagonist kynurenic acid. These changes will lead to elevated levels of glutamate and dopamine in the extracellular space, and activation of dopamine D2 receptors, which will act to further suppress glutamate release. TCA tricarboxylic acid cycle, GS glutamine synthetase, Gln glutamine, Glu glutamate, DA dopamine.