Alterations in Brain Extracellular Dopamine and Glycine Levels Following Combined Administration of the Glycine Transporter Type-1 Inhibitor Org-24461 and Risperidone

Abstract

The most dominant hypotheses for the pathogenesis of schizophrenia have focused primarily upon hyperfunctional dopaminergic and hypofunctional glutamatergic neurotransmission in the central nervous system. The therapeutic efficacy of all atypical antipsychotics is explained in part by antagonism of the dopaminergic neurotransmission, mainly by blockade of D(2) dopamine receptors. N-methyl-D-aspartate (NMDA) receptor hypofunction in schizophrenia can be reversed by glycine transporter type-1 (GlyT-1) inhibitors, which regulate glycine concentrations at the vicinity of NMDA receptors. Combined drug administration with D(2) dopamine receptor blockade and activation of hypofunctional NMDA receptors may be needed for a more effective treatment of positive and negative symptoms and the accompanied cognitive deficit in schizophrenia. To investigate this type of combined drug administration, rats were treated with the atypical antipsychotic risperidone together with the GlyT-1 inhibitor Org-24461. Brain microdialysis was applied in the striatum of conscious rats and determinations of extracellular dopamine, DOPAC, HVA, glycine, glutamate, and serine concentrations were carried out using HPLC/electrochemistry. Risperidone increased extracellular concentrations of dopamine but failed to influence those of glycine or glutamate measured in microdialysis samples. Org-24461 injection reduced extracellular dopamine concentrations and elevated extracellular glycine levels but the concentrations of serine and glutamate were not changed. When risperidone and Org-24461 were added in combination, a decrease in extracellular dopamine concentrations was accompanied with sustained elevation of extracellular glycine levels. Interestingly, the extracellular concentrations of glutamate were also enhanced. Our data indicate that coadministration of an antipsychotic with a GlyT-1 inhibitor may normalize hypofunctional NMDA receptor-mediated glutamatergic neurotransmission with reduced dopaminergic side effects characteristic for antipsychotic medication.

Glycine receptor α3 and α2 subunits mediate tonic and exogenous agonist-induced currents in forebrain

“…Our data showing that α3 GlyRs mediate tonic currents in brain suggest that glycine itself probably serves as the main endogenous GlyR ligand in the forebrain. Low micromolar concentrations of ambient glycine are present in the cerebrospinal fluid (59), and there are multiple sources for extracellular glycine, including glycinergic neurotransmission (60), synaptic corelease with glutamate or GABA (61)(62)(63)(64), and release from astrocytes (65,66). Further studies are necessary to determine the specific sources of glycine responsible for the tonic activation of GlyRs.…”

Inhibition of glycine transporter-1 in the dorsal vagal complex improves metabolic homeostasis in diabetes and obesity

“…D -serine, like glycine, is also a co-agonist of the NMDA receptors. However, it is unlikely that D -serine is the endogenous agonist that mediates the effects of GlyT1 inhibition as injection of GlyT1 inhibitor elevates extracellular glycine but not serine and glutamate levels in the brain of rats41. Future studies are necessary to dissect the specific role of glycine versus serine per se as well as in the presence of GlyT1 inhibition in regulating glucose and energy homeostasis.…”

Glycine Transporter-1: A New Potential Therapeutic Target for Schizophrenia

“…Interestingly, the extracellular levels of glutamate were also enhanced. This study suggests that co-administration of an antipsychotic drug with a GlyT-1 inhibitor could normalize hypofunctional NMDA receptor-mediated glutamatergic neurotransmission with reduced dopaminergic side effects characteristic for antipsychotic medication [58].…”

“…Both NFPS and Org24461 (1-10 mg/kg) reversed PCP-induced changes in EEG power spectra in conscious rats. Recently, it has been reported that co-administration of Org24461 and antipsychotic drug risperidone caused a decrease of extracellular dopamine levels accompanied with sustained elevation of extracellular glycine levels [58]. Interestingly, the extracellular levels of glutamate were also enhanced.…”