Pro-cognitive effect of acute imipramine administration correlates with direct interaction of BDNF with its receptor, Trkβ.

Given the important role of brain-derived neurotrophic factor (BDNF)-mediated Trkβ signalling in the mechanism of action of antidepressants (ADs), we examined ligand-receptor interactions in the rat cingulate cortex using a proximity ligation assay (PLA) in response to acute and repeated administration of imipramine (IMI), followed by various drug-free periods. Both the acute and chronic administration of IMI increased the BDNF-Trkβ interaction observed 3 h after drug administration. Withdrawal of IMI for 72 h or 7 days did not alter BDNF-Trkβ interaction.

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.

Restraint Stress in Mice Alters Set of 25 miRNAs Which Regulate Stress- and Depression-Related mRNAs.

In the present study, we aim to identify the effect of restrain stress (RS) on the expression of miRNAs in mouse serum. We used three genotypes of animals (mice with knock-out of the gene-encoding norepinephrine transporter, ; , and ) which had previously been shown to display different sensitivity to RS, and focused on miRNAs which were altered by RS in the serum of all three genotypes. An analysis of miRNAs expression allowed for the identification of a set of 25 differentially expressed miRNAs; 10 were down-regulated compared to an appropriate control group of animals, while 15 were up-regulated.

Serum Level of miR-1 and miR-155 as Potential Biomarkers of Stress-Resilience of NET-KO and SWR/J Mice.

In the present study, we used three strains of mice with various susceptibility to stress: mice with knock-out of the gene encoding norepinephrine transporter (NET-KO), which are well characterized as displaying a stress-resistant phenotype, as well as two strains of mice displaying two different stress-coping strategies, i.e., C57BL/6J (WT in the present study) and SWR/J.

Genetic variants in dopamine receptors influence on heterodimerization in the context of antipsychotic drug action.

Human dopamine D2 receptor (DR) gene has polymorphic variants, three of them alter its amino acid sequence: Val96Ala, Pro310Ser and Ser311Cys. Their functional role never became the object of extensive studies, even though there are some evidence that they correlate with schizophrenia. The present work reviews data indicating that these mutations play a role in dimer formation with dopamine D1 receptor (DR), with the strongest effect observed for Ser311Cys variant.

Genomic Screening of Wistar and Wistar-Kyoto Rats Exposed to Chronic Mild Stress and Deep Brain Stimulation of Prefrontal Cortex.

Stress, a major precipitant of depression, and antidepressants have major impact on synaptic integrity and plasticity in brain areas, such as hippocampus (HPC) and prefrontal cortex (PFC). We have recently shown that, unlike Wistar rats, rats of the Wistar-Kyoto (WKY) strain fail to respond to chronic antidepressant treatment after exposure to chronic mild stress (CMS) procedure. However, deep brain stimulation (DBS) of PFC was effective in both strains.

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.

Reciprocal MicroRNA Expression in Mesocortical Circuit and Its Interplay with Serotonin Transporter Define Resilient Rats in the Chronic Mild Stress.

Prolonged stress perturbs physiological balance of a subject and thus can lead to depression. Nevertheless, some individuals are more resilient to stress than the others. Defining molecular factors underlying resilience to stress may contribute to the development of a new antidepressant strategy based on the restoration of resilient phenotype in depressed subjects.

Time-dependent miR-16 serum fluctuations together with reciprocal changes in the expression level of miR-16 in mesocortical circuit contribute to stress resilient phenotype in chronic mild stress - An animal model of depression.

MicroRNAs (miRNAs) are involved in stress-related pathologies. However, the molecular mechanisms underlying stress resilience are elusive. Using chronic mild stress (CMS), an animal model of depression, we identified animals exhibiting a resilient phenotype.

Discovering the mechanisms underlying serotonin (5-HT)2A and 5-HT2C receptor regulation following nicotine withdrawal in rats.

We have previously demonstrated that nicotine withdrawal produces depression-like behavior and that serotonin (5-HT)2A/2C receptor ligands modulate that mood-like state. In the present study we aimed to identify the mechanisms (changes in radioligand binding, transcription or RNA-editing) related to such a behavioral outcome. Rats received vehicle or nicotine (0.

Life-long norepinephrine transporter (NET) knock-out leads to the increase in the NET mRNA in brain regions rich in norepinephrine terminals.

These studies aimed to identify the genes differentially expressed in the frontal cortex of mice bearing a life-long norepinephrine transporter knock-out (NET-KO) and wild-type animals (WT). Differences in gene expression in the mouse frontal cortex were studied using a whole-genome microarray approach. Using an alternative approach, i.

Effect of desipramine on gene expression in the mouse frontal cortex - microarray study.

Background: These studies aimed to identify the genes differentially expressed in the frontal cortex of mice treated repeatedly with either saline or desipramine (DMI).

Methods: Differences in gene expression in the mouse frontal cortex were studied using a whole-genome microarray approach.

Results: The analyses revealed a group of 88 transcripts (18 genes) that were differentially expressed between the mice treated with saline and those treated with DMI.

Norepinephrine transporter knock-out alters expression of the genes connected with antidepressant drugs action.

Norepinephrine transporter knock-out mice (NET-KO) exhibit depression-resistant phenotypes. They manifest significantly shorter immobility times in both the forced swim test and the tail suspension test. Moreover, biochemical studies have revealed the up-regulation of other monoamine transporters (dopamine and serotonin) in the brains of NET-KO mice, similar to the phenomenon observed after the chronic pharmacological blockade of norepinephrine transporter by desipramine in wild-type (WT) animals.

Differential stress response in rats subjected to chronic mild stress is accompanied by changes in CRH-family gene expression at the pituitary level.

The purpose of this study was to examine molecular markers of the stress response at the pituitary and peripheral levels in animals that responded differently to chronic mild stress (CMS). Rats were subjected to 2-weeks CMS and symptoms of anhedonia was measured by the consumption of 1% sucrose solution. mRNA levels of CRH-family neuropeptides (Crh-corticotropin-releasing hormone, Ucn1-urocortin 1, Ucn2-urocortin 2, Ucn3-urocortin 3), CRH receptors (Crhr1-corticotropin-releasing hormone receptor 1, Crhr2-corticotropin-releasing hormone receptor 2) and Crhbp (corticotropin-releasing factor binding protein) in the pituitaries of rats were determined with real-time PCR.

Involvement of prolactin and somatostatin in depression and the mechanism of action of antidepressant drugs.

Neuropeptides have been implicated in the physiology and pathophysiology of stress responses and therefore may play an important role in the pathogenesis of affective disorders such as Major Depression Disorder (MDD). The data presented in this mini-review demonstrate the role of prolactin (PRL) and somatostatin (STT) in the pathology and pharmacotherapy of MDD, focusing particularly on the response to antidepressant treatment, and compare the available data with the results obtained in our laboratory using the well-validated chronic mild stress (CMS) animal model of MDD. Despite the availability of many pharmacological therapies for depression, ca.

Potential role of G protein-coupled receptor (GPCR) heterodimerization in neuropsychiatric disorders: a focus on depression.

G protein-coupled receptors (GPCRs) represent the largest family of membrane proteins in the human genome and are the target of approximately half of all therapeutic drugs. For many years, GPCRs were thought to exist and function as monomeric units. However, during the past two decades, substantial biochemical, structural and functional evidence have indicated that GPCRs can associate and form heteromers that exhibit functional properties distinct from the corresponding monomers.

Mesolimbic dopamine D₂ receptor plasticity contributes to stress resilience in rats subjected to chronic mild stress.

Rationale: Few studies have investigated neurobiological and biochemical differences between stress-resilient and stress-vulnerable experimental animals.

Objectives: We investigated alterations in mesolimbic dopamine D2 receptor density and mRNA expression level in stressed rats at two time points, i.e.

Antidepressant drugs promote the heterodimerization of the dopamine D2 and somatostatin Sst5 receptors--fluorescence in vitro studies.

Background: The interaction between the dopaminergic and somatostatinergic systems and their role in mood regulation have been well-documented. Therefore, we decided to investigate the effect of antidepressant drugs on the heterodimerization of the dopamine D2 and somatostatin Sst5 receptors.

Methods: The human receptor proteins were tagged with fluorescent proteins, expressed in the HEK 293 cells and incubated with antidepressant drugs: desipramine and citalopram.