Identification of Molecular Markers of Clozapine Action in Ketamine-Induced Cognitive Impairment: A GPCR Signaling PathwayFinder Study.

Background: Cognitive disorders associated with schizophrenia are closely linked to prefrontal cortex (PFC) dysfunction. Administration of the non-competitive NMDA receptor antagonist ketamine (KET) induces cognitive impairment in animals, producing effects similar to those observed in schizophrenic patients. In a previous study, we showed that KET (20 mg/kg) induces cognitive deficits in mice and that administration of clozapine (CLZ) reverses this effect.

Clozapine administered repeatedly following pretreatment with ketamine enhances dopamine D receptors in the dopamine mesolimbic pathway in mice brain.

The mechanisms underlying the beneficial effects of clozapine (CLZ) in the treatment of schizophrenia still remains far from clear. In the present work we studied the effect of CLZ on the dopamine D receptors (DR) in the mouse brain. CLZ was administered after ketamine (KET) in a paradigm strictly matching the one used in KET-induced attentional set-shifting task (ASST).

Understanding GPCR dimerization.

Initially G protein-coupled receptors, GPCRs, were thought to act as monomers, but recently strong evidence has been gathered indicating that they are capable of forming homo- and heterodimers or higher order oligomeric complexes, and that the dimerization phenomenon can modulate the pharmacological response and function of these receptors. In this chapter we point to the great potential of alternative therapeutic approach targeted at GPCR dimers, which is especially important in the field of neuropsychopharmacology. We also included a brief description of methods used for studying the phenomenon of GPCR oligomerization, with particular attention paid to the proximity ligation assay, PLA, the procedure which allows the study of interactions between receptors not only in vitro but also in vivo, with good anatomical resolution, what is especially important in the studies of various GPCRs involved in central neurotransmission.

Regulation of somatostatin receptor 2 in the context of antidepressant treatment response in chronic mild stress in rat.

Rationale: The role of somatostatin and its receptors for the stress-related neuropsychiatric disorders has been widely raised. Recently, we have also demonstrated the involvement of somatostatin receptor type 2-sst2R and dopamine receptor type 2-D2R in stress.

Objective: In this context, we decided to find if these receptors are involved in response to antidepressant treatment in animal model of depression-chronic mild stress (CMS).

Paroxetine and Low-dose Risperidone Induce Serotonin 5-HT and Dopamine D2 Receptor Heteromerization in the Mouse Prefrontal Cortex.

Recently, it has been shown that serotonin 5-HT receptor interacts with dopamine D2 receptor in vitro. However, the existence of 5-HT-D2 heteromers in native tissue remains unexplored. In the present study, we investigated 5-HT-D2 receptor heteromerization in mice treated acutely or chronically with paroxetine (10 mg/kg) or risperidone (0.

Effects on brain-derived neurotrophic factor signalling of chronic mild stress, chronic risperidone and acute intracranial dopamine receptor challenges.

We have previously reported the effects of intracranial injections of dopamine D1, D2 and D3 ligands in animals subjected to the Novel Object Recognition (NOR) test following exposure to chronic mild stress (CMS) and chronic treatment with risperidone (RSP). Here, we present some molecular biological data from the same animals. It was predicted that brain-derived neurotrophic factor (BDNF) signalling in the prefrontal cortex (PFC) would reflect behavioural performance, implying an increase following acute administration of a D2 agonist or a D3 antagonist, blockade of this effect by CMS and its restoration by chronic RSP.

Repeated Clozapine Increases the Level of Serotonin 5-HTR Heterodimerization with 5-HT or Dopamine D Receptors in the Mouse Cortex.

G-protein-coupled receptor (GPCR) heterodimers are new targets for the treatment of schizophrenia. Dopamine D receptors and serotonin 5-HT and 5-HT receptors play an important role in neurotransmission and have been implicated in many human psychiatric disorders, including schizophrenia. Therefore, in this study, we investigated whether antipsychotic drugs (clozapine (CLZ) and haloperidol (HAL)) affected the formation of heterodimers of D-5-HT receptors as well as 5-HT-5-HT receptors.

Antidepressants promote formation of heterocomplexes of dopamine D2 and somatostatin subtype 5 receptors in the mouse striatum.

The interaction between the dopaminergic and somatostatinergic systems is considered to play a potential role in mood regulation. Chronic administration of antidepressants influences release of both neurotransmitters. The molecular basis of the functional cooperation may stem from the physical interaction of somatostatin receptor subtypes and dopamine D2 receptors since they colocalize in striatal interneurons and were shown to undergo ligand-dependent heterodimerization in heterologous expression systems.