Differential effects of topiramate on prefrontal glutamatergic transmission when combined with raclopride or clozapine.

Treatment with topiramate may improve negative symptoms in schizophrenia when added to typical antipsychotic drugs (APDs) but not to clozapine. Both dopaminergic and glutamatergic transmissions in the medial prefrontal cortex (mPFC) are facilitated by atypical, but not typical, APDs, which is thought to improve negative symptoms and cognitive dysfunction in schizophrenia. Our previous results show that topiramate increases prefrontal dopamine (DA) outflow when added to the D(2/3) receptorantagonist raclopride. Here, using intracellular recording in vitro, we investigated the effects of topiramate on glutamatergic neurotransmission in the rat mPFC, both when given alone and in combination with raclopride or clozapine. Neither topiramate nor raclopride alone had any effect on N-methyl-D-aspartate (NMDA)-induced currents in pyramidal cells of the mPFC. However, the combination of topiramate and raclopride facilitated the NMDA-induced currents, and this effect was blocked by the D1 receptor antagonist SCH23390. Topiramate also facilitated the effect of a submaximal, but inhibited the effect of a maximal, concentration of clozapine on these currents. The effect of combined topiramate and a submaximal concentration of clozapine could be blocked by SCH23390. In addition, combined topiramate and raclopride facilitated excitatory postsynaptic potentials. In contrast, topiramate inhibited clozapine's facilitating effect on these potentials. These data may help explain the improvement of negative symptoms when topiramate is used as adjunctive therapy in schizophrenic patients receiving typical APDs, but they may also shed light on the observed deterioration of symptoms when topiramate is added to full dose clozapine.

Asenapine, a novel psychopharmacologic agent: preclinical evidence for clinical effects in schizophrenia.

RATIONALE: Asenapine is a novel psychopharmacologic agent being developed for the treatment of schizophrenia and bipolar disorder. MATERIALS AND METHODS: The present study was undertaken to investigate the effects of asenapine using animal models predictive of antipsychotic efficacy (conditioned avoidance response [CAR]) and extrapyramidal side effects (EPS; catalepsy). In parallel, the effects of asenapine on regional dopamine output using in vivo microdialysis in freely moving rats, dopamine output in the core and shell subregions of nucleus accumbens (NAc) using in vivo voltammetry in anesthetized rats, and N-methyl-D: -aspartate (NMDA)-induced currents in pyramidal neurons of the medial prefrontal cortex (mPFC) using the electrophysiological technique intracellular recording in vitro were assessed. RESULTS: Asenapine (0.05-0.2 mg/kg, subcutaneous [s.c.]) induced a dose-dependent suppression of CAR (no escape failures recorded) and did not induce catalepsy. Asenapine (0.05-0.2 mg/kg, s.c.) increased dopamine efflux in both the mPFC and the NAc. Low-dose asenapine (0.01 mg/kg, intravenous [i.v.]) increased dopamine efflux preferentially in the shell compared to the core of NAc, whereas at a higher dose (0.05 mg/kg, i.v.), the difference disappeared. Finally, like clozapine (100 nM), but at a considerably lower concentration (5 nM), asenapine significantly potentiated the NMDA-induced responses in pyramidal cells of the mPFC. CONCLUSIONS: These preclinical data suggest that asenapine may exhibit highly potent antipsychotic activity with very low EPS liability. Its ability to increase both dopaminergic and glutamatergic activity in rat mPFC suggests that asenapine may possess an advantageous effect not only on positive symptoms in patients with schizophrenia, but also on negative and cognitive symptoms.

Inhibition of the glycine transporter GlyT-1 potentiates the effect of risperidone, but not clozapine, on glutamatergic transmission in the rat medial prefrontal cortex.

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.

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.

Clozapine and other atypical, but not typical, antipsychotic drugs (APDs), facilitate both dopaminergic and N-methyl-D-aspartate (NMDA) receptor-mediated glutamatergic transmission in the medial prefrontal cortex (mPFC), which is thought to improve cognition. Switching schizophrenic patients from typical APDs to clozapine may reduce their cigarette smoking. Here, we tested whether nicotine, which facilitates dopamine release, also facilitates NMDA receptor-mediated neurotransmission in the mPFC, when given alone or in combination with a D(2,3) antagonist, raclopride, or a D4 antagonist, 3-(4-[4-chlorophenyl]piperazin-1-yl)methyl-1H-pyrrolo[2,3b]pyridine (L-745,870), using intracellular recording in pyramidal cells of the rat mPFC. Neither nicotine nor raclopride or L-745,870 alone altered NMDA-induced currents in these cells. However, combining nicotine with raclopride or L-745,870 facilitated these currents. Similarly to clozapine the combination of nicotine with raclopride or L-745,870 also markedly potentiated evoked excitatory post-synaptic potentials in the mPFC. Our results support the idea that intense smoking in schizophrenia may represent a form of self-medication with nicotine.