5 research outputs found
The antipsychotic-like effects of the mGlu group III orthosteric agonist, LSP1-2111, involves 5-HT1A signalling
RATIONALE: Several studies have suggested that modulation of the glutamatergic system via metabotropic glutamate receptors (mGlu) could be a new way to achieve antipsychotic-like activity. LSP1-2111, the group III mGlu receptor orthosteric agonist, with a high affinity towards mGlu(4) receptors, was previously shown to exhibit antipsychotic-like action in animal models displaying positive symptoms of schizophrenia. OBJECTIVES: Here, we decided to investigate the possible role of LSP1-2111 in models of negative (social interaction) and cognitive (NOR) symptoms of psychosis. We also investigated the involvement of 5-HT(1A) receptors in the LSP1-2111-induced antipsychotic effects. Apart from the above-mentioned models of negative and cognitive symptoms, MK-801 and amphetamine-induced hyperactivity tests, plus the DOI-induced head twitches in mice as models for positive symptoms of psychosis, were used in this part of the investigations. RESULTS: LSP1-2111 (0.5, 2, and 5Â mg/ kg) dose-dependently inhibited MK-801-induced deficits in social interaction and NOR tests. The effects of the drug were antagonized by 5-HT(1A) antagonist, WAY100635 (0.1Â mg/kg). A similar inhibition of LSP1-2111-induced effects was observed in models of positive symptoms of schizophrenia. Moreover, the concomitant administration of subeffective doses of LSP1-2111 (0.3-0.5Â mg/kg) with a subeffective dose of 5-HT(1A) agonist, (R)-(+)-8-Hydroxy-DPAT (0.01Â mg/kg), induced a clear antipsychotic-like effect in all of the procedures used. CONCLUSIONS: Altogether, we propose that the activation of group III mGlu receptors may be a promising target for the development of novel antipsychotic drugs, towards not only positive but also negative and cognitive symptoms. The action of the compound is 5-HT(1A)-dependent
mGlu5-GABAB interplay in animal models of positive, negative and cognitive symptoms of schizophrenia
The antipsychotic-like effects of mGlu4 receptor positive allosteric modulators in rodents
BACKGROUND AND PURPOSE: Because agonists at metabotropic glutamate receptors exert beneficial effects in schizophrenia, we have assessed the actions of Lu AF21934 and Lu AF32615, two chemically distinct, selective and brain-penetrant positive allosteric modulators (PAMs) of the mGlu(4) receptor, in several tests reflecting positive, negative and cognitive symptoms of schizophrenia in rodents. EXPERIMENTAL APPROACH: Hyperactivity induced by MK-801 or amphetamine and head twitches induced by 2,5-dimethoxy-4-iodoamphetamine (DOI) in mice were used as models for positive symptoms. Disruption of social interaction and spatial delayed alternation tests induced by MK-801 in rats were used as models for negative and cognitive symptoms of schizophrenia, respectively. KEY RESULTS: Lu AF21934 (0.1â5 mg·kg(â1)) and Lu AF32615 (2â10 mg·kg(â1)) dose-dependently inhibited hyperactivity induced by MK-801 or amphetamine. They also antagonized head twitches and increased frequency of spontaneous excitatory postsynaptic currents (EPSCs) in brain slices, induced by DOI. In mice lacking the mGlu(4) receptor (mGlu(4)(â/â)) mice, Lu AF21934 did not antagonize DOI-induced head twitches. MK-801-induced disruption in the social interaction test was decreased by Lu AF21934 at 0.5 mg·kg(â1) and by Lu AF32615 at 10 mg·kg(â1). In the delayed spatial alternation test, Lu AF21934 was active at 1 and 2 mg·kg(â1), while Lu AF32615 was active at 10 mg·kg(â1). CONCLUSIONS AND IMPLICATIONS: We propose that activation by PAMs of the mGlu(4) receptor is a promising approach to the discovery of novel antipsychotic drugs
The antipsychotic-like effects in rodents of the positive allosteric modulator Lu AF21934 involve 5-HTA receptor signaling : mechanistic studies
RATIONALE: Diverse preclinical studies suggest the potential therapeutic utility of the modulation of the glutamatergic system in brain via metabotropic glutamate (mGlu) receptors. Lu AF21934, a positive allosteric modulator of the mGlu4 receptor, was previously shown to reverse behavioral phenotypes in animal models thought to mimic positive, negative, and cognitive symptoms of schizophrenia. OBJECTIVES: To begin elucidating the brain circuitry involved in mGlu4 receptor pharmacology and add mechanistic support to Lu AF21934-induced phenotypic responses, the potential involvement of 5-HT(1A) receptors in these antipsychotic-like effects was explored. The tests used were the following: MK-801-induced hyperactivity and 2,5-dimethoxy-4-iodoamphetamine (DOI)-induced head twitches in mice, for positive symptoms; MK-801-induced disruptions of social interactions for negative symptoms; and novel object recognition and spatial delayed alteration test for cognitive symptoms. The microdialysis studies in which the effect of Lu AF21934 on MK-801-induced dopamine and serotonin release was investigated. RESULTS: The effects caused by Lu AF2193 were inhibited by administration of the selective 5-HT(1A) receptor antagonist WAY100635 (0.1Â mg/kg). That inhibition was observed across all models used. Moreover, the concomitant administration of sub-effective doses of Lu AF21934 and a sub-effective dose of the selective 5-HT(1A) receptor agonist tool compound (R)-(+)-8-hydroxy-DPAT hydrobromide (0.01Â mg/kg) induced a clear antipsychotic-like effect in all the procedures used. Lu AF21934 (5Â mg/kg) also inhibited MK-801-induced increase in dopamine and 5-HT release. CONCLUSIONS: The actions of Lu AF21934 are 5-HT(1A) receptor-dependent. Activation of the mGlu4 receptor may be a promising mechanism for the development of novel antipsychotic drugs, efficacious toward positive, negative, and cognitive symptoms. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00213-014-3657-4) contains supplementary material, which is available to authorized users