Abstract
RationaleDiverse 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.ObjectivesTo 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-HT1A 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.ResultsThe effects caused by Lu AF2193 were inhibited by administration of the selective 5-HT1A receptor antagonist WAY100635 (0.1 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-HT1A receptor agonist tool compound (R)-(+)-8-hydroxy-DPAT hydrobromide (0.01 mg/kg) induced a clear antipsychotic-like effect in all the procedures used. Lu AF21934 (5 mg/kg) also inhibited MK-801-induced increase in dopamine and 5-HT release.ConclusionsThe actions of Lu AF21934 are 5-HT1A 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 materialThe online version of this article (doi:10.1007/s00213-014-3657-4) contains supplementary material, which is available to authorized users.
Highlights
The glutamatergic system represents the basic excitatory neurotransmission mechanism in the brain
Activation of the mGlu4 receptor may be a promising mechanism for the development of novel antipsychotic drugs, efficacious toward positive, negative, and cognitive symptoms
The present studies expand on our recent reports showing that the selective mGlu4 receptor positive allosteric modulator (PAM), Lu AF21934, and Lu AF32615, exhibited antipsychotic-like activity in animal models broadly used with drugs showing clinical efficacy in schizophrenia (Sławińska et al 2013)
Summary
The glutamatergic system represents the basic excitatory neurotransmission mechanism in the brain. Drugs known as psychotomimetics (dopaminergic and serotonergic agonists) evoke only positive symptoms of schizophrenia These observations support the involvement of the glutamatergic system in the Psychopharmacology (2015) 232:259–273 pathophysiology of psychotic disorders (Bickel and Javitt 2009; Javitt and Zukin 1991; Javitt et al 2004). According to the glutamatergic hypothesis, blockade of NMDA receptors expressed on GABAergic neurons leads to the inhibition of GABAergic control over pyramidal neurons in the thalamocortical pathway. This would lead to abnormal glutamate release and to the overactivation of cortical and subcortical structures (Krystal et al 2002; Moghaddam and Jackson 2003; Conn et al 2009). The reharmonization of such enhanced release may lead to the normalization of glutamate efflux and to the reversal of the symptoms of schizophrenia (Conn et al 2009)
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