title: Effects of typical and atypical antipsychotics on human glycine transporters.
abstract: Augmentation strategy in the treatment of schizophrenia with the NMDA receptor co-agonist glycine has demonstrated significant improvement in patient symptoms. Interestingly, the therapeutic efficacy of glycine was more consistent among patients that were not co-administered clozapine suggesting that clozapine modulates glycine levels in brain. Since cerebral glycine concentration in the vicinity of NMDA receptors is thought to be controlled by the glia expressed glycine transporter type 1 (GlyT1), the effects of several typical and atypical antipsychotics on glycine uptake were examined in human placenta choriocarcinoma (JAR) cells expressing human GlyT1a. The selectivity of these compounds was investigated by measuring their inhibitory potency at the closely related glycine transporter type 2 (GlyT2). Typical antipsychotics haloperidol, thioridazine and chlorpromazine non-selectively inhibited [(14)C]glycine uptake mediated by GlyT1a and GlyT2 with potency of 9-21 microM. The atypical antipsychotic, clozapine antagonized glycine transport by human GlyT1a with an IC(50) of 100 microM and was weaker at recombinant GlyT2. Its main metabolites, N-desmethylclozapine and clozapine N-oxide were very weak inhibitors at all glycine transporters. Similarly, olanzapine did not potently block GlyT1a- and GlyT2-mediated uptake. Detailed kinetic analysis of hGlyT1a in the presence and absence of haloperidol and clozapine revealed that both drugs were not competitive inhibitors of glycine uptake. Data also indicated that these compounds did not interact with the Na(+) and Cl(-) sites of hGlyT1a. Our results have revealed the existence of an inhibitory interaction between some antipsychotics and hGlyT1a and raise the possibility that these drugs could interact with GlyT1 function at therapeutic doses.
authors.affiliation: Department of Neuroscience West Point, Merck and Co. Inc., WP26A-3000, PO Box 4, West Point, PA 19486, USA.
authors.forename: Jacinta B
authors.initials: JB
authors.lastname: Williams
authors.forename: Pierre J
authors.initials: PJ
authors.lastname: Mallorga
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Pettibone
authors.forename: Cyrille
authors.initials: C
authors.lastname: Sur
mesh_terms: D026921:Amino Acid Transport Systems, Neutral / Q000037:antagonists & inhibitors*; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001569:Benzodiazepines / Q000494:pharmacology* / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D018118:Chloride Channels / Q000378:metabolism; D002822:Choriocarcinoma / Q000378:metabolism / Q000473:pathology; D003024:Clozapine / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D005998:Glycine / Q000378:metabolism / Q000494:pharmacology; D050487:Glycine Plasma Membrane Transport Proteins; D006220:Haloperidol / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D000077152:Olanzapine; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D018967:Risperidone / Q000494:pharmacology* / Q000627:therapeutic use; D012559:Schizophrenia / Q000188:drug therapy; D015222:Sodium Channels / Q000378:metabolism; D013569:Synapses / Q000378:metabolism; D014594:Uterine Neoplasms / Q000378:metabolism / Q000473:pathology; D000099247:Taurine Transporters
chemical_list: D026921:Amino Acid Transport Systems, Neutral; D014150:Antipsychotic Agents; D001569:Benzodiazepines; D018118:Chloride Channels; D003024:Clozapine; D005998:Glycine; D050487:Glycine Plasma Membrane Transport Proteins; D006220:Haloperidol; D008562:Membrane Glycoproteins; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D000077152:Olanzapine; D016194:Receptors, N-Methyl-D-Aspartate; D018967:Risperidone; D015222:Sodium Channels; D000099247:Taurine Transporters; C493271:SLC6A5 protein, human; C493268:SLC6A9 protein, human; C493269:Slc6a5 protein, rat; C493266:Slc6a9 protein, rat