Zonisamide regulates basal ganglia transmission via astroglial kynurenine pathway.

To clarify the anti-parkinsonian mechanisms of action of zonisamide (ZNS), we determined the effects of ZNS on tripartite synaptic transmission associated with kynurenine (KYN) pathway (KP) in cultured astrocytes, and transmission in both direct and indirect pathways of basal ganglia using microdialysis. Interactions between cytokines [interferon-γ (IFNγ) and tumor-necrosis factor-α (TNFα)] and ZNS on astroglial releases of KP metabolites, KYN, kynurenic-acid (KYNA), xanthurenic-acid (XTRA), cinnabarinic-acid (CNBA) and quinolinic-acid (QUNA), were determined by extreme liquid-chromatography with mass-spectrometry. Interaction among metabotropic glutamate-receptor (mGluR), KP metabolites and ZNS on striato-nigral, striato-pallidal GABAergic and subthalamo-nigral glutamatergic transmission was examined by microdialysis with extreme liquid-chromatography fluorescence resonance-energy transfer detection. Acute and chronic ZNS administration increased astroglial release of KYN, KYNA, XTRA and CNBA, but not QUNA. Chronic IFNγ administration increased the release of KYN, KYNA, CNBA and QUNA, but had minimal inhibitory effect on XTRA release. Chronic TNFα administration increased CNBA and QUNA, but not KYN, KYNA or XTRA. ZNS inhibited IFNγ-induced elevation of KYN, KYNA and QUNA, but enhanced IFNγ-induced that of CNBA. TNFα-induced rises in CNBA and QUNA were inhibited by ZNS. ZNS inhibited striato-nigral GABAergic, striato-pallidal GABAergic and subthalamo-nigral glutamatergic transmission via activation of groups II and III mGluRs. ZNS enhanced astroglial release of endogenous agonists of group II mGluR, XTRA and group III mGluR, CNBA. Activated endogenous mGluR agonists inhibited transmission in direct and indirect pathways of basal ganglia. These mechanisms contribute to effectiveness and well tolerability of ZNS as an adjunct treatment for Parkinson's disease during l-DOPA monotherapy. This article is part of the Special Issue entitled 'The Synaptic Basis of Neurodegenerative Disorders'.

Differential mechanisms underlie the regulation of serotonergic transmission in the dorsal and median raphe nuclei by mirtazapine: a dual probe microdialysis study.

RATIONALE: Blockade of α2 adrenoceptors and histamine H1 receptors plays important roles in the antidepressant and hypnotic effects of mirtazapine. OBJECTIVES: However, it remains unclear how mirtazapine's actions at these receptors interact to affect serotonergic transmission in the dorsal (DRN) and median (MRN) raphe nuclei. METHOD: Using dual-probe microdialysis, we determined the roles of α2 and H1 receptors in the effects of mirtazapine on serotonergic transmission in the DRN and MRN and their respective projection regions, the frontal (FC) and entorhinal (EC) cortices. RESULTS: Mirtazapine (<30 µM) failed to alter extracellular serotonin levels when perfused alone into the raphe nuclei, but when co-perfused with a 5-HT1A receptor antagonist, mirtazapine increased serotonin levels in the DRN, MRN, FC, and EC. Serotonin levels in the DRN and FC were decreased by blockade and increased by activation of H1 receptors in the DRN. Serotonin levels in the MRN and EC were not affected by H1 agonists/antagonists perfused in the MRN. The increase in serotonin levels in the DRN and FC induced by DRN H1 receptor activation was attenuated by co-perfusion with mirtazapine. Furthermore, the increase in serotonin levels (DRN/FC) induced by DRN α2 adrenoceptor blockade was attenuated by concurrent DRN H1 blockade, whereas the increase in serotonin levels (MRN/EC) induced by MRN α2 adrenoceptor inhibition was unaffected by concurrent MRN H1 receptor blockade. CONCLUSION: These results suggest that enhanced serotonergic transmission resulting from α2 adrenoceptor blockade is offset by subsequent activation of 5-HT1A receptors and, in the DRN but not MRN, H1 receptor inhibition. These pharmacological actions of mirtazapine may explain its antidepressant and hypnotic actions.

Effect of lamotrigine and carbamazepine on corticotropin-releasing factor-associated serotonergic transmission in rat dorsal raphe nucleus.

Corticotropin-releasing factor (CRF) and serotonin are important transmitters of the pathophysiology of mood disorder. To clarify the mechanisms of action of lamotrigine (LTG) and carbamazepine (CBZ), we determined their effects on serotonin release associated with CRF in rat dorsal raphe nucleus (DRN) and median prefrontal cortex (mPFC) using dual-probe microdialysis. Neither perfusion with CRF1 nor CRF2 antagonists into DRN-affected serotonin release in DRN and mPFC. Perfusion of 10 µM CRF into DRN increased serotonin release in both regions, whereas 0.1 µM CRF decreased and had no effect on serotonin release in DRN and mPFC, respectively. Pre-perfusion with CRF1 antagonist into DRN inhibited 0.1 µM CRF-induced serotonin reduction, whereas pre-perfusion with CRF2 antagonist in DRN inhibited 10 µM CRF-induced serotonin elevation, without affecting 0.1 µM CRF-induced serotonin reduction. LTG perfusion concentration dependently decreased serotonin releases in DRN and mPFC. Therapeutic and supratherapeutic concentrations of CBZ increased and decreased serotonin releases in both regions, respectively. Pre-perfusion with sub-therapeutic concentration LTG inhibited CRF1-induced serotonin reduction without affecting CRF2-induced serotonin release, whereas pre-perfusion with therapeutic concentration of LTG inhibited both CRF1- and CRF2-actions. In contrast, both therapeutic and supratherapeutic concentrations of CBZ inhibited CRF2-induced serotonin release without affecting CRF1-induced serotonin reduction. Neither LTG nor CBZ affected the CRF-induced cAMP production in cells over-expressing CRF1 and CRF2 receptors. This study demonstrated that inhibition of CRF2-receptor-mediated serotonergic transmission is a mechanism shared by LTG and CBZ, two clinically related compounds, whereas LTG but not CBZ inhibits CRF1-receptor-mediated serotonergic transmission. Therefore, these mechanisms may contribute to the clinical actions of these agents.

Clozapine, but not haloperidol, enhances glial D-serine and L-glutamate release in rat frontal cortex and primary cultured astrocytes.

BACKGROUND AND PURPOSE: Deficient transmission at the glutamate NMDA receptor is considered a key component of the pathophysiology of schizophrenia. However, the effects of antipsychotic drugs on the release of the endogenous NMDA receptor partial agonist, D-serine, remain to be clarified. EXPERIMENTAL APPROACH: We determined the interaction between antipsychotic drugs (clozapine and haloperidol) and transmission-modulating toxins (tetanus toxin, fluorocitrate, tetrodotoxin) on the release of L-glutamate and D-serine in the medial prefrontal cortex (mPFC) of freely moving rats, using microdialysis, and primary cultures of astrocytes using extreme high-pressure liquid chromatography. KEY RESULTS: Release of L-glutamate and D-serine in the mPFC and in cultured astrocytes was inhibited by tetanus toxin (a synaptobrevin inhibitor) and fluorocitrate (a glial toxin), whereas tetrodotoxin (a voltage-sensitive Na(+) blocker) inhibited depolarization-induced L-glutamate release in the mPFC without affecting that of D-serine. Clozapine (1 and 5 mg·kg(-1)), but not haloperidol (0.5 and 1 mg·kg(-1)), dose-dependently increased L-glutamate and D-serine release from both astrocytes and mPFC. Clozapine-induced release of L-glutamate and D-serine was also reduced by tetanus toxin and fluorocitrate. Tetrodotoxin reduced clozapine-induced mPFC L-glutamate release but not that of D-serine. Clozapine-induced L-glutamate release preceded clozapine-induced D-serine release. MK-801 (a NMDA receptor antagonist) inhibited the delayed clozapine-induced L-glutamate release without affecting that of D-serine. CONCLUSIONS AND IMPLICATIONS: Clozapine predominantly activated glial exocytosis of D-serine, and this clozapine-induced D-serine release subsequently enhances neuronal L-glutamate release via NMDA receptor activation. The enhanced D-serine associated glial transmission seems a novel mechanism of action of clozapine but not haloperidol.