Neuroscience 2005 Abstract
| Presentation Number: | 444.8 |
|---|---|
| Abstract Title: | Mescaline-induced scratching, a model sensitive to antipsychotic drugs, depends on glutamatergic neurotransmission, but not dopamine D<sub>2</sub>/D<sub>3</sub> receptor stimulation. |
| Authors: |
van Gaalen, M. M.*1
; Wicke, K. M.1
; Behl, B.1
; Gross, G.1
1CNS Pharmacology, Abbott GmbH and Co. KG, Ludwigshafen, Germany |
| Primary Theme and Topics |
Disorders of the Nervous System - Cognitive, Emotional and Behavioral State Disorders -- Schizophrenia: Animal models |
| Session: |
444. Schizophrenia: Glutamate Dysfunction Models I Poster |
| Presentation Time: | Monday, November 14, 2005 11:00 AM-12:00 PM |
| Location: | Washington Convention Center - Hall A-C, Board # TT60 |
| Keywords: | SCHIZOPHRENIA, GLUTAMATE, GLYCINE, SEROTONIN RECEPTOR |
Mescaline-induced scratching (MiS) in mice can be blocked by several antipsychotics, such as haloperidol, risperidone and clozapine. Here we investigate the contribution of dopaminergic, serotonergic and glutamatergic neurotransmission to this behavior.
Mescaline-induced scratching is not attenuated by the dopamine D2-like receptor antagonists, sulpiride (30 mg/kg ip) and amisulpride (20 mg/kg ip), or by the selective D3 antagonist, A-437203, suggesting that MiS does not depend on dopamine D2 or D3 receptor stimulation. The 5-HT2 antagonist ketanserin, however, blocks MiS at doses of >0.1 mg/kg. Given that haloperidol, risperidone and clozapine block both, D2 and 5-HT2A receptors, it is likely that these effects are due to antagonism of 5-HT2A, but not D2-like receptors.
MiS can be blocked by glutamate mGluR2/3 receptor agonists and potentiators, indicating a role of glutamatergic neurotransmission in this model (Gross at al., SfN 2004, Progr. No. 1030.16). Here we show that blockade of AMPA receptors with NBQX dose-dependently prevents MiS (significant at 30 mg/kg). We further investigated the role of NMDA receptors in MiS. In order to enhance NMDA receptor function we tested the glycine transporter GlyT1 inhibitor SSR 504734. The glycine concentration at excitatory synapses appears to be highly regulated by GlyT1, and its inhibition enhances extracellular glycine levels and NMDA receptor function. SSR 504734 (>10 mg/kg) reduced MiS significantly. It can be speculated that NMDA receptor blockade would induce scratching. However, PCP did not induce such effects.
Taken together, these results demonstrate that the inhibitory effects of several antipsychotic compounds on MiS are due to 5-HT2 receptor but not dopamine D2-like receptor antagonism. Furthermore, this behavior depends on glutamatergic neurotransmission and may thus be sensitive to new antipsychotics addressing the glutamatergic imbalance in schizophrenia.
Funded by Abbott Laboratories.
Mescaline-induced scratching is not attenuated by the dopamine D2-like receptor antagonists, sulpiride (30 mg/kg ip) and amisulpride (20 mg/kg ip), or by the selective D3 antagonist, A-437203, suggesting that MiS does not depend on dopamine D2 or D3 receptor stimulation. The 5-HT2 antagonist ketanserin, however, blocks MiS at doses of >0.1 mg/kg. Given that haloperidol, risperidone and clozapine block both, D2 and 5-HT2A receptors, it is likely that these effects are due to antagonism of 5-HT2A, but not D2-like receptors.
MiS can be blocked by glutamate mGluR2/3 receptor agonists and potentiators, indicating a role of glutamatergic neurotransmission in this model (Gross at al., SfN 2004, Progr. No. 1030.16). Here we show that blockade of AMPA receptors with NBQX dose-dependently prevents MiS (significant at 30 mg/kg). We further investigated the role of NMDA receptors in MiS. In order to enhance NMDA receptor function we tested the glycine transporter GlyT1 inhibitor SSR 504734. The glycine concentration at excitatory synapses appears to be highly regulated by GlyT1, and its inhibition enhances extracellular glycine levels and NMDA receptor function. SSR 504734 (>10 mg/kg) reduced MiS significantly. It can be speculated that NMDA receptor blockade would induce scratching. However, PCP did not induce such effects.
Taken together, these results demonstrate that the inhibitory effects of several antipsychotic compounds on MiS are due to 5-HT2 receptor but not dopamine D2-like receptor antagonism. Furthermore, this behavior depends on glutamatergic neurotransmission and may thus be sensitive to new antipsychotics addressing the glutamatergic imbalance in schizophrenia.
Funded by Abbott Laboratories.
Sample Citation:
[Authors]. [Abstract Title]. Program No. XXX.XX. 2005 Neuroscience Meeting Planner. Washington, DC: Society for Neuroscience, 2005. Online.
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