Modulation of prefrontal glutamatergic transmission and "atypicality" of antipsychotic drugs

The glutamate hypothesis of schizophrenia suggests a relationship between hypoactive NMDA receptor-mediated glutamatergic transmission and the pathophysiology of schizophrenia. Previous results have demonstrated that atypical (e.g. clozapine, risperidone, and olanzapine), but not typical (e.g. haloperidol, raclopride, and chlorpromazine) antipsychotic drugs, markedly potentiate NMDA receptormediated glutamateric transmission in the medial prefrontal cortex, an effect which was hypothesized to contribute to the ability of clozapine and other atypical antipsychotic drugs to ameliorate negative symptoms and cognitive dysfunctions in schizophrenia. It has been suggested that intense tobacco consumption by schizophrenic patients may represent a form of self-medication with nicotine. Similarly to clozapine, nicotine has been proposed to improve both negative and cognitive symptoms in schizophrenic patients, and clozapine decreases smoking in these patients. By using electrophysiological techniques in vitro we have examined whether nicotine also facilitates NMDA receptor-mediated transmission in the rat medial prefrontal cortex, alone or in combination with the D2/3 receptor antagonist raclopride or the weak D4 receptor antagonist L-745,870. Neither nicotine nor raclopride or L-745,870 had any effect on NMDA-induced currents in pyramidal cells of the medial prefrontal cortex. However, the combination of nicotine with raclopride or L-745,870 produced a clozapine-like facilitation of the NMDA-induced currents in the medial prefrontal cortex. Similarly to clozapine, these drug combinations also potentiated electrically evoked excitatory potentials in the mPFC. These results suggest that the addition of nicotine to antagonists at D2 and D4 receptors may improve cognitive and negative symptoms in schizophrenic patients. We have also investigated the effect of the glycine transporter-1 (GlyT-1) inhibitor NFPS on the NMDA-induced currents, both when given alone and in combination with either risperidone or clozapine. As reported previously, NFPS alone facilitated these currents. Moreover, NFPS augmented the effect of both a submaximal, and a maximal, concentration of risperidone on the NMDA-induced currents. In contrast, this GlyT-1 inhibitor did not potentiate either the effect of a submaximal or a maximal concentration of clozapine. These data may contribute to explain clinical studies suggesting that the efficacy of risperidone, but not clozapine, can be augmented by adjunctive treatment with agents acting directly or indirectly on the strychnine-insensitive glycine site on the NMDA receptor. Several clinical studies have reported advantageous effects of using antiepileptic drugs as an adjunct to antipsychotic drugs in treatment-resistant schizophrenia. Topiramate, a new anticonvulsant drug is one of them. Previous studies suggest that topiramate may improve general psychopathologic and negative symptoms in schizophrenia when added to a stable medication. Topiramate also reverses weight gain in these patients, a common side effect of clozapine and some other antipsychotic drugs. In this thesis, we have also investigated topiramate on NMDA receptor-mediated glutamatergic transmission in the medial prefrontal cortex, both when given alone and in combination with raclopride or clozapine. Topiramate alone had no effect on the NMDA-induced currents. However, the combination of this anticonvulsant drug with raclopride generated a facilitating effect on these currents, which was blocked by the D1 receptor antagonist SCH23390. Moreover, topiramate facilitated the effect of a submaximal, but inhibited the effect of a maximal concentration of clozapine. The combination of topiramate and raclopride also facilitated excitatory postsynaptic potentials in pyramidal cells of the medial prefrontal cortex. These data may contribute to explain clinical findings demonstrating that topiramate improves negative symptoms when added to typical antipsychotic drugs in the treatment of schizophrenic patients. These data may also have bearing on the deterioration of symptomatology seen with the combined topiramate and clozapine in schizophrenic patients. Finally, we have investigated asenapine, a novel psychopharmacological agent which is developed for treatment of schizophrenia and bipolar disorder, by using a set of preclinical methods, which we previously used to explore antipsychotic drugs. Asenapine induced a dose-dependent suppression of conditioned avoidance response without any associated catalepsy. Our microdialysis studies showed that asenapine increased dopamine output in the medial prefrontal cortex, as well as in the striatum and the nucleus accumbens. A low dose asenapine increased dopamine efflux preferentially in the shell compared to the core of nucleus accumbens, as assessed by in vivo voltammetry. In similarity with clozapine, but at much lower concentrations, asenapine also facilitated the NMDA-induced currents in pyramidal cells of the medial prefrontal cortex. These results propose that asenapine may have a potent antipsychotic activity without generating extrapyramidal side effects, with effects not only on positive, but also on negative and cognitive symptoms. LIST OF PUBLICATIONS I. Jardemark K. , Marcus M.M. , Konradsson Å. , Svensson T.H. The combination of nicotine with the D2 antagonist raclopride or the weak D4 antagonist L-745,870 generates a clozapine-like facilitation of NMDA receptor-mediated neurotransmission in pyramidal cells of the rat medial prefrontal cortex. International Journal of Neuropsychopharmacology. 2005 Jun; 8(2):157-62. II. Å. Konradsson, M.M. Marcus, P. Hertel, T.H. Svensson, K.E. Jardemark. Inhibition of the glycine transporter GlyT-1 potentiates the effect of risperidone, but not clozapine, on glutamatergic transmission in the rat medial prefrontal cortex. Synapse. 2006 Aug; 60(2):102-8. III. Å. Konradsson, M.M. Marcus, T.H. Svensson, K.E. Jardemark. Differential effects of topiramate on prefrontal glutamatergic transmission when combined with raclopride or clozapine. Submitted to International Journal of Neuropsychopharmacology. IV. O. Frånberg, C.Wiker, M.M. Marcus, Å. Konradsson, K. Jardemark, B. Schilström, M. Shahid, E.H. F. Wong, T.H. Svensson. Asenapine, a novel psychopharmacologic agent: preclinical evidence for clinical effects in schizophrenia. Psychopharmacology (Berl) 2007 Oct; [Epub ahead of print]. All previously published papers were reproduced with permission from the publisher.