Differential effects of AMPA receptor potentiators and glycine reuptake inhibitors on antipsychotic efficacy and prefrontal glutamatergic transmission
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The α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor positive allosteric modulators (AMPA-PAMs), Org 24448 and Org 26576, and the glycine transporter-1 (GlyT-1) inhibitor Org 25935 are developed for treatment of schizophrenia.
Here we examined experimentally the ability of co-administration of these AMPA-PAMs or the GlyT-1 inhibitor to augment the antipsychotic activity and effect on cortical N-methyl-d-aspartate (NMDA) receptor-mediated transmission of risperidone, olanzapine, or haloperidol.
We examined antipsychotic efficacy using the conditioned avoidance response (CAR) test, extrapyramidal side effect liability using a catalepsy test, and cortical NMDA receptor-mediated glutamatergic transmission using intracellular electrophysiological recording technique in vitro.
Both AMPA-PAMs enhanced the suppression of CAR induced by risperidone or olanzapine, and Org 24448 also enhanced the effect of haloperidol. In contrast, the GlyT-1 inhibitor did not cause any behaviorally significant effect in the CAR test. However, the GlyT-1 inhibitor, but not the AMPA-PAMs, produced a large facilitation of NMDA-induced currents. All three drugs potentiated the effect of risperidone but not haloperidol on these currents. The GlyT-1 inhibitor also facilitated the effect of olanzapine. All drugs potentiated the effect of risperidone on electrically stimulated excitatory postsynaptic potentials (EPSP) in cortical pyramidal cells, whereas only the GlyT inhibitor facilitated the effect of olanzapine.
Our results suggest that the AMPA-PAMs, when compared to the GlyT-1 inhibitor, show differential effects in terms of augmentation of antipsychotic efficacy, particularly when combined with risperidone or olanzapine. Both AMPA-PAMs and the GlyT-1 inhibitor may also improve negative symptoms and cognitive impairments in schizophrenia, in particular when combined with risperidone.
KeywordsAMPA receptor potentiators GlyT1 inhibitor Org 24448 Org 26576 Org 25935 Schizophrenia Antipsychotic
This work was supported by the Swedish Research Council grant nos. 4747 and 15049, the Karolinska Institutet, and a research grant from Department of Molecular Pharmacology, MSD, Newhouse, UK.
Conflict of interest
Apart from the grant received from MSD, there is no conflict of interest. Kent Jardemark is employee at the Karolinska Institutet and Chalmers University of Technology. Torgny H. Svensson, Monica M. Marcus, and Anna Malmerfelt are employees at the Karolinska Institutet, and Mohammed Shahid is a previous employee at Department of Molecular Pharmacology, MSD, Newhouse, UK. All experiments were approved by and conducted in accordance with the local Animal Ethics Committee, Stockholm North and the Karolinska Institutet, Sweden.
- Ahlenius S, Hillegaart V (1986) Involvement of extrapyramidal motor mechanisms in the suppression of locomotor activity by antipsychotic drugs: a comparison between the effects produced by pre- and post-synaptic inhibition of dopaminergic neurotransmission. Pharmacol Biochem Behav 24:1409–1415PubMedCrossRefGoogle Scholar
- Damgaard T, Larsen DB, Hansen SL, Grayson B, Neill JC, Plath N (2010) Positive modulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors reverses sub-chronic PCP-induced deficits in the novel object recognition task in rats. Behav Brain Res 207:144–150PubMedCrossRefGoogle Scholar
- Jardemark K, Marcus MM, Konradsson A, Svensson TH (2005) 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. Int J Neuropsychopharmacol 8:157–162PubMedCrossRefGoogle Scholar
- Jardemark K, Ninan I, Svensson TH, Wang RY (2002) Differential effects of atypical and typical antipsychotic drugs on NMDA-receptor-mediated neurotransmission in pyramidal cells of the rat medial prefrontal cortex. Nord J Psychiatry 56:20Google Scholar
- Jordan GR, McCulloch J, Shahid M, Hill DR, Henry B, Horsburgh K (2005) Regionally selective and dose-dependent effects of the ampakines Org 26576 and Org 24448 on local cerebral glucose utilisation in the mouse as assessed by 14C-2-deoxyglucose autoradiography. Neuropharmacology 49(2):254–264PubMedCrossRefGoogle Scholar
- Li CC (1964) Change-over design. Introduction to experimental statistics. McGraw-Hill, New York, pp 207–226Google Scholar
- Marcus MM, Wiker C, Franberg O, Konradsson-Geuken A, Langlois X, Jardemark K, Svensson TH (2010) Adjunctive alpha2-adrenoceptor blockade enhances the antipsychotic-like effect of risperidone and facilitates cortical dopaminergic and glutamatergic, NMDA receptor-mediated transmission. Int J Neuropsychopharmacol 13:891–903PubMedCrossRefGoogle Scholar
- Paxinos G, Watson C (2007) The rat brain in sterotaxic coordinates, 6th edn. Academic, LondonGoogle Scholar
- Siegel S, Castellan NJ Jr (1988) Nonparametric statistics for the behavioral sciences. McGraw-Hill, New YorkGoogle Scholar