Abstract
Schizophrenia is a mental disorder that affects approximately 1–2% of the population and develops in early adulthood. The disease is characterized by positive, negative, and cognitive symptoms. A large percentage of patients with schizophrenia have a treatment-resistant disease, and the risk of developing adverse effects is high. Many researchers have attempted to introduce new antipsychotic drugs to the clinic, but most of these treatments failed, and the diversity of schizophrenic symptoms is one of the causes of disappointing results. The present review summarizes the results of our latest papers, showing that the simultaneous activation of two receptors with sub-effective doses of their ligands induces similar effects as the highest dose of each compound alone. The treatments were focused on inhibiting the increased glutamate release responsible for schizophrenia arousal, without interacting with dopamine (D2) receptors. Ligands activating metabotropic receptors for glutamate, GABAB or muscarinic receptors were used, and the compounds were administered in several different combinations. Some combinations reversed all schizophrenia-related deficits in animal models, but others were active only in select models of schizophrenia symptoms (i.e., cognitive or negative symptoms).
Highlights
Schizophrenia is one of the most complicated mental disorders, and it is characterized by different symptoms that may enrich or disrupt normal behavior
GABAB and muscarinic M4 receptors are of particular importance in the pathophysiology of schizophrenia and antipsychotic drug discovery
The costimulation of GABAB-mGlu5 receptors exhibited clear and evident efficacy in models of the positive, negative and cognitive symptoms of schizophrenia, which were comparable to the effects of the active dose of each ligand administered alone [138]
Summary
Schizophrenia is one of the most complicated mental disorders, and it is characterized by different symptoms that may enrich or disrupt normal behavior. Sci. 2020, 21, 8811 cause of schizophrenia development and results from the hypofunction of NMDA receptors at critical sites in local circuits that modulate the function of a particular brain region or control projections from one region to another (e.g., hippocampal–cortical or thalamocortical projections) [25,26] This increased glutamate efflux under specific conditions or individual predisposition results in subsequent changes in other neurotransmitters, e.g., dopamine [15]. The formulation of this theory provided new possibilities in the search for treatment strategies based on the reduction of enhanced glutamatergic transmission. One possibility is as an add-on therapy based on the concomitant activation of other types of receptors involved in the regulation of the glutamatergic network
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