title: Inhibition of the glycine transporter GlyT-1 potentiates the effect of risperidone, but not clozapine, on glutamatergic transmission in the rat medial prefrontal cortex.
abstract: Clinical studies suggest that the efficacy of the atypical antipsychotic drug (APD) risperidone (but not clozapine) can be augmented by adjunctive treatment with agonists at the glycine site of the N-methyl-D-aspartate (NMDA) receptor. By using intracellular recording, we have investigated the effect of the glycine transporter-1 (GlyT-1) inhibitor N [3-(4'-fluorophenyl)-3-(4'phenylphenylphenoxy) propyl] sarcosine (NFPS) on NMDA-induced currents in pyramidal cells of the medial prefrontal cortex (mPFC), both when given alone and in combination with either risperidone or clozapine. Both risperidone and clozapine enhanced the NMDA-induced currents. The concentration-response curves were biphasic, and the maximal effect of clozapine on the NMDA-induced currents was significantly larger than the maximal effect of risperidone. NFPS also significantly potentiated the NMDA-induced currents, when given alone. Moreover, NFPS (1 microM) augmented the effect of both the maximal (20 nM), and a submaximal (10 nM), concentration of risperidone. In contrast, NFPS did not potentiate either the effect of the maximal (100 nM) or a submaximal (80 nM) concentration of clozapine on the NMDA-induced currents. These data may explain the beneficial clinical results of using glycine reuptake antagonists as adjuvant treatment to risperidone. Our findings also suggest that risperidone and clozapine may affect NMDA receptor-mediated neurotransmission differently in the mPFC.
authors.affiliation: Department of Physiology and Pharmacology, Section of Neuropsychopharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Asa
authors.initials: A
authors.lastname: Konradsson
authors.forename: Monica M
authors.initials: MM
authors.lastname: Marcus
authors.forename: Peter
authors.initials: P
authors.lastname: Hertel
authors.forename: Torgny H
authors.initials: TH
authors.lastname: Svensson
authors.forename: Kent E
authors.initials: KE
authors.lastname: Jardemark
mesh_terms: D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects / Q000502:physiology; D003024:Clozapine / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D018756:GABA Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D005998:Glycine / Q000378:metabolism; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D009924:Organ Culture Techniques; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D018967:Risperidone / Q000494:pharmacology*; D012521:Sarcosine / Q000031:analogs & derivatives / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology
chemical_list: D018492:Dopamine Antagonists; D018756:GABA Antagonists; D050487:Glycine Plasma Membrane Transport Proteins; C435025:N-(3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)-3-(4'-phenylphenoxy)propyl)sarcosine; D016194:Receptors, N-Methyl-D-Aspartate; C493266:Slc6a9 protein, rat; D018698:Glutamic Acid; D003024:Clozapine; D018967:Risperidone; D005998:Glycine; D012521:Sarcosine