Effect of Repetitive Transcranial Magnetic Stimulation on Serum Levels of Steroid Adrenal Hormones in Parkinson's Disease: Sex Differences.

In a parallel placebo-controlled study, we examined the effect of repetitive transcranial magnetic stimulation (rTMS) on serum concentrations of cortisol and dehydroepiandrosteron sulfate (DHEAS), and their relationships with clinical symptoms in men and women with Parkinson's disease. A 20-day course of real rTMS reduced the UPDRS and UPDRS III scores in patients with Parkinson's disease in comparison with the basal parameters (before rTMS), regardless of their sex. The level of cortisol did not change in men and women; at the same time, the content of DHEAS in men increased and before rTMS negatively correlated with the UPDRS scores. Sham rTMS had no effects on clinical parameters or hormonal levels. Possible mechanisms of sex-dependent differences in the effect of rTMS on the level of the neurosteroid hormone DHEAS are discussed.

Peculiarities of the Composition of Peripheral Immune Cells and Cytokine Profile in Brain Structures in Mutant DISC1-L100P Mice.

Intact Disc1-L100P mice carrying a point mutation DISC1Rgsc1390 in the second exon of the DISC1 gene (genetic model of schizophrenia) differ from the parental C57BL/6NCrl strain by higher content of CD3+ T cells and reduced number of CD19+B cells in the peripheral blood and spleen. Analysis of T cell subpopulations revealed an increase in the number of CD3+CD4+ T helpers in the blood of mutant mice and a decrease in the level of CD3+CD8+ suppressor/cytotoxic T cells and CD3+CD4+CD25+ T-regulatory cells. The distribution pattern of inflammatory (IL-1ß, IL-2, IL-6, IL-17, IFNγ, and TNFα) and anti-inflammatory (IL-4, IL-10) cytokines specific for Disc1-L100P mice was revealed in the brain structures involved in the pathogenesis of schizophrenia. A possible implication of immune mechanisms in the development of schizophrenia-like endophenotype of Disc1-L100P mice is discussed.

Content of Peripheral Blood T- and B-Cell Subpopulations in Transgenic A53T Mice of Different Age (A Model of Parkinson's Disease).

We analyzed the behavior and peripheral blood T- and B-cell subpopulations in mice overexpressing the mutant form of human α-synuclein (A53T) in comparison with mice of the wild type (WT) parent C57BL/6J strain. Behavioral phenotype and the content of various cell subpopulations of A53T mice depended on animal age. Young (2-month-old mice) were characterized by low emotionality and the most pronounced changes in cell subpopulation composition (an increase in CD3+T cells and CD4+T helper cells, a decrease in CD19+B cells along with unchanged content of CD3+CD4+CD25+T-regulatory cells and CD19+CD25+B-regulatory cells). In old A53T mice (10-month-old), movement impairments appeared and increased numbers of CD4+T helper cells and CD3+CD4+CD25+T-regulatory cells were revealed.

Cytokine Content in the Hypothalamus and Hippocampus of C57Bl/6J Mice with Depressive-Like Behavior.

The content of pro- and anti-inflammatory cytokines in the hypothalamus, hippocampus, and blood serum of C57Bl/6J mice with depressive-like behavior induced by 20-day social stress was analyzed in 4 h after immune stimulation with LPS (250 µg/kg). These animals are characterized by a tendency to an increase in the blood content of IL-6 and a decrease in the level of IL-10. Changes in cytokine content in the brain of mice with depressive-like state developed under these conditions were observed only in the hippocampus: the levels of IL-1ß, IL-6, TNFα, and IL-10 increased and the content of IFNγ decreased in comparison the corresponding parameters in the controls (not exposed to social stress) and aggressive animals. No changes in the levels of IL-2, IL-4, and IL-17 were revealed in the hypothalamus and hippocampus.

Therapeutic Effects of Repetitive Transcranial Magnetic Stimulation (rTMS) on Neuroinflammation and Neuroplasticity in Patients with Parkinson's Disease: a Placebo-Controlled Study.

The parallel placebo-controlled study examined the therapeutic effects of dual-target repetitive transcranial magnetic stimulation (rTMS) of the motor cortex (bilaterally) and the left prefrontal cortex (dorsolaterally) on spontaneous and mitogen-stimulating synthesis of pro- and anti-inflammatory cytokines by the blood cells and the level of brain-derived neurotrophic factor (BDNF) in blood serum of patients with Parkinson's disease. The significantly steeper positive clinical dynamics (assessed by UPRSD scale) observed in rTMS group in comparison with the placebo group was accompanied by a significant drop in spontaneous production of proinflammatory cytokines IFNγ and IL-17A. rTMS produced no significant effect on serum BDNF. The possible mechanisms of rTMS therapeutic action on the level of cytokines associated with neuroinflammation in patients with Parkinson's disease are discussed.

Cytokine Production by Splenic Cells in C57BL/6J Mice with Depression-Like Behavior Depends on the Duration of Social Stress.

We studied the influence of depression-like behavior developed in C57BL/6J mice under conditions of social stress of different duration on cytokine production by splenic cells. Imbalance of the pro- and anti-inflammatory cytokines was detected at the early stage of depression-like behavior (10-day experience of defeats): increased production of proinflammatory IL-2 and IL-6 cytokines along with a decrease in anti-inflammatory IL-10 level; the levels of IL-1ß, TNFα, IFNγ, and IL-4 remained unaffected. At later terms (20 days of confrontations), we revealed more pronounced changes in spontaneous production of proinflammatory cytokines that were not detected after shorter social stress. These findings suggest that cytokine profile depends on duration of social stress. Possible mechanisms of cytokine production during formation of depression-like state are discussed.

Effect of Antidepressants on Immunological Reactivity in ASC Mice with Genetically Determined Depression-Like State.

The effect of chronic treatment with antidepressant drugs fluoxetine (20 mg/kg) and imipramine (25 mg/kg) on the number of antibody-producing cells and the main T cell subpopulations in ASC mice characterized by genetic predisposition to depression-like states was studied at the peak of the SE-induced immune response (5×10(8)). Fluoxetine produced an immunostimulatory effect manifested in an increase in the relative and absolute number of IgM antibody-producing cells in the spleen and index of immunoreactivity (CD4/CD8). Administration of fl uoxetine to parental mouse strains without depression (CBA and AKR) had no effect (CBA) or reduced the immune response. The CD4/CD8 ratio did not increase under these conditions. Imipramine was ineffective in the correction of immune reactions in a depression-like state.

[Involvement of the dopaminergic system in the mechanisms of immunomodulation].

This review considers functional organization of the brain dopaminergic (DAergic) system--DA-metabolism, major DA-pathways, classification and functions of DA-receptors. Involvement of the DAergic system including D1- and D2-receptors in the mechanisms of immunostimulation, ways of the realization and intraimmune mechanisms underlying DAergic immunomodulation also discussed.

[Effect of antipsychotic amisulpride on immune reactivity].

The effect of atypical antipsychotic solian (amisulpride), binding predominantly to dopamine D2/D3-receptors, on the immune reactivity has been studied in mice of the CBA strain with different psychoemotional states (aggressive and submissive behavior). In addition, the effect of solian on the expression of various CD-markers of lymphocytes in has been analyzed in vitro for patients with schizophrenia diagnosis. Chronic (10 days) administration of solian in mice at a dose of 5.0 mg/kg resulted in a significant suppression of the immune response to T-dependent antigen (sheep red blood cells). This effect was manifested in animals with both psychoemotional states, but was more expressed in aggressive animals. In the in vitro system, solian produced opposite effects on the expression of surface CD receptors in lymphocytes of patients with schizophrenia. It is suggested that solian does not only affects immune function through D2 receptors of the brain, but also directly influences immunocompetent cells.

[Effect of activation of serotonin 5-HT1A-receptors on the immune response in mice of the ASC strain with depressive-like behavior].

Selective activation of serotonin 5-HT(1A)-receptors produced different effects on immunological reactivity in mice of ASC strain with genetic predisposition to depressive-like behavior, and parental CBA and AKR strains displaying no depressive reactions. Administration of 5-HT(1A)-receptors agonist 8-OH-DPAT at low dose (0.1 mg/kg) affecting upon presynaptic receptors resulted in immunostimulation in CBA mice and did not change the immune response level in mice of ASC strain. Activation of postsynaptic 5-HT(1A)-receptors with higher dose of 8-OH-DPAT (1.0 mg/kg) caused immunosuppression in CBA and AKR strains while under the same conditions the immune response of ASC mice was increased. Decrease the immune reactions in ASC mice was observed only after application of 8-OHDPAT at dose of 5 mg/kg. The changes of functional activity of pre- and postsynaptic 5-HT(1A)-receptors under a high predisposition to depressive-like behavior providing different effects of this receptor activation on immune function are discussed.

[T-lymphocyte subpopulations and immune response in mice of the ASC strain with depressive-like behaviour].

Analysis of the content of CD16/32+, CD4+ and CD8+ -cells was perfomed in the peripheral blood and spleen ofmice of the ASC strain with high predisposition to depressive-like state in comparison with mice of parent CBA strain having no depressive behaviour. In both cases, ASC mice showed a decrease in the percentage of CD16/32+ and CD4+-cells along with an increase CD8 cells and lowering of immunoreactivity index (CD4+/CD8+). Changes in cellular subpopulations found in intact ASC mice was accompanied with animals' low capacity to respond to T-dependent antigen: sheep red blood cells at the dose of 5 x 10(8). In contrast to CBA mice the percentage and absolute number of IgM-antibody-forming cells were significantly decreased in the spleen of ASC mice on the 4th and 5th days after immunization as well as the numbers of IgG-antibody-forming cells on the 6th day of the immune response. Possible mechanisms underlying the immune reactivity inhibition under depressive-like state are discussed.

[Clinical and experimental research of immunomodulatory effect of amisulpride].

Study of immunomodulatory effect of atypical antipsychotic amisulpride has revealed a positive clinical effect after 6-week therapy of schizophrenic patients regarding both positive and negative symptoms. A decrease in activity of humoral immunity factors (B lymphocytes, immunoglobulins, HLADR(+)-cells) identified among schizophrenic patients in the process of amisulpride therapy can be attributed to a positive effect optimizing the ratio Th1/Th2. Amisulpride when used under experimental conditions produced a suppression of IgM-immune response in mice of the C57BL/6J strain. This effect was more expressed in animals with aggressive behavior pattern.

[Functional interplay of dopamine D1 and D2 receptors in the immune response control in different psychoemotional states].

It is established that preliminary blockade ofdopamine (DA) D2 receptors with haloperidol prevents immunostimulation observed upon the activation of D1 receptors with selective agonist SKF 38393 in mice of the CBA and C57BL/6J strains having no experience in social confrontations. These data are indicative of the functional interconnection between DA receptors of the D1 and D2 subtypes in the immune response control. Similar link between these DA receptor subtypes has been also found in C57BL/6J mice conditioned to display aggressive or submissive behaviors during 10-day social encounter testing. The data obtained give evidence that the interaction between D1 and D2 receptors is manifested in animals with various genotypes and psychoemotional states.

[Effects of chronic fluoxetine treatment on catalepsy and immune response in mice genetically predisposed to freezing reaction: the role of 5-HT1A and 5-HT2A receptors and tph2 and SERT genes].

ASC/Icg (Antidepressant Sensitive Catalepsy) mouse strain selected for high predisposition to pinch-induced catalepsy is characterized by depressive-like behavior and impaired immune response. Chronic treatment with SSRI fluoxetine attenuated catalepsy manifestation and normalized a decreased number of rosette-forming cells (RFC) in spleen in ASC mice. Chronic fluoxetine administration had no effect on catalepsy and RFC number in mice of parental cataleptic CBA/Lac strain. Fluoxetine failed to alter 5-HT1A receptor functional activity in mice of both strains and diminished 5-HT2A receptor functional activity in CBA but not in ASC mice. No effect on cortical 5-HT1A and 5-HT2A receptor mRNA levels and on 5-HT1A receptor, tph2 (tryptophan hydroxylase-2) and SERT (serotonin transporter) mesencephalic gene expression was observed in ASC mice. Other possible serotonergic mechanisms of fluoxetine effect on catalepsy and immune response in mice with depressive-like state are discussed.

Involvement of dopamine D1 and D2 receptors in the rat nucleus accumbens in immunostimulation.

Analysis of the nature of changes in the immune response in operated Wistar rats showed that electrolytic lesioning of the nucleus accumbens, the site of the greatest density of dopamine D1 and D2 receptors, led to suppression of the immune response in animals immunized with sheep erythrocytes. Administration of SKF 38393 (20 mg/kg) and quinpirol (1 mg/kg), selective agonists of dopamine D1 and D2 receptors respectively, to sham-operated rats induced significant increases in immune responses. However, no immunostimulation was seen on administration of the selective dopamine D2 agonist quinpirol to animals with lesions to the nucleus accumbens as compared with controls. At the same time, treatment of animals with nucleus accumbens lesions using the dopamine D1 receptor agonist SKF 38393 had no effect on the immune response as compared with that in sham-operated animals given the D1 receptor agonist. These data provide evidence that dopamine D2 receptors in the nucleus accumbens have a role in the mechanisms of immunostimulation, though D2 receptors in other brain structures may also make some contribution to this process; D1 receptors in the nucleus accumbens make no significant contribution to controlling the immune response.

Interaction between dopamine D1 and D2 receptors in modulation of the immune response.

The interaction between dopamine D1 and D2 receptors plays a role in immunomodulation. The results of thus interaction depends on the degree of receptor activation with selective agonists in different doses. Combined treatment with agonists of D1 and D2 receptors in high doses had a synergistic effect in the mechanisms of immunomodulation. Receptor agonists in low doses suppressed the immune response. Our results suggest that weak activation of one of these receptors is accompanied by inactivation of the other receptor type.

[The role of D1 and D2 dopamine receptors of the rat nucleus accumbens in immunostimulation].

The analysis of the immune response changes in Wistar rats has shown that bilateral electrolytic lesions of the nucleus accumbens characterized by a high density of D1 an D2 dopamine (DA) receptors resulted in a decrease of the immune response to SRBC. Administration of selective agonists of D1 and D2 DA receptors to sham-operated animal: 20 mg/kg of SKF 38393 or 1.0 mg/kg of quinpirol, respectively, produced significant enhancement of plaque- and rosette-formation. However, the immune response level in the damaged rats did not increase following quinpirol administration, but was maintained at control values, rather. At the same time, activation of D1 DA receptors in rats with destructed nucleus accumbens did not affect the immune response level as compared to that of sham-operated animals receiving SKF 38393. The data obtained give evidence of involvement of D2 DA receptors of the nucleus accumbens in immunomodulation, although D2 DA receptors of other brain structures may also contribute to this process. D1 DA receptors of this localization seem not to play any important role in the immune response control.

[Changes in the immune reaction of animals under conditions of drug-induced activation and blockade of D1 dopamine receptors]. / Izmenenie immunnoi reaktsii u zhivotnykh v usloviiakh aktivatsii i blokady D1 dofaminovykh retseptorov.

A highly selective dopamine D1 receptor agonist (compound SKF 38393) administered in a dose of 20 mg/kg produced a significant increase in the number of rosette-forming cells (RFCs) in the spleen of Wistar rats on the 5th day upon their immunization with goat erythrocytes (5 x 10(8)). At the same time, a specific blocker of these receptors (compound SCH 23390) in a dose of 0.5 or 1 mg/kg inhibited the immune response of rats. In C57BL/6J mice, SCH 23390 (0.25, 0.5, or 1 mg/kg) also significantly reduced the number of RFCs. Preliminary blockade of the D1 dopamine receptors with SCH 23390 (1 mg/kg) prevented the immunostimulating effect of SKF 38393. These data indicate that D1 dopamine receptors are involved in immunomodulation.

[Contribution of D2 dopamine receptors of the rat dorsolateral caudate nucleus to immunomodulation]. / Vklad v immunomoduliatsiiu dofaminobykh D2-retseptorov dorsolateral'noi zony khvostatogo iadra u krys.

The analysis of the immune response changes in Wistar rats under activation or blockade of D2 DA receptors has shown that electrolytic lesion of the dorsolateral caudate nucleus characterized by a high density of D2 DA receptors resulted in a decrease of the immune response to SRBC. At the same time, in rats with similar lesion stimulation of the immune reactions caused by a selective D2 agonist guinpirol (1.0 mg/kg) did not develop completely. Administration of haloperidol (2.0 mg/kg), the immune-inhibitory effect of which is associated with increasing serotoninergic system activity, to rats with impaired dorso-lateral caudate nucleus did not produce more expressed immunosuppression. However, the level of the immune response in sham-operated rats receiving haloperidol was significantly lower than that of animal with the destructed nucleus caudatus. Considering that qunmpirol-induced immunostimulation is related to the selective activation of the DA-ergic brain system, it is concluded that D2 DA receptors of the nucleus caudatus are involved in the mechanisms of immunostimulation, although D2 DA receptors of other brain structures may also impact this process.

Nature of the distribution of serotonin and a serotonin metabolite in brain structures and the development of immunosuppression in submissive mice.

Studies of C57BL/6J mice with acquired submissive behavior in a sensory contact model demonstrated increases in serotonin (5-HT) levels in the amygdaloid complex, hippocampus, the dopaminergic nuclei A11, A10, and A9, and in the caudate nucleus and hypothalamus, compared with controls, after 10 and 20 days of confrontations. Levels of the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) in most structures were significantly higher after 20 days of confrontations than after 10 days. Increases in the 5-HIAA/5-HT ratio in the cervical nuclei of the midbrain, nucleus accumbens, A9, and hypothalamus as compared with controls were seen in mice with 10 and 20 days of confrontations. Immunization of mice on days 10 and 20 of confrontations showed suppression of immune responses as compared with controls, while immune measures reached control values by 40 days of experience of defeat. Thus, experience of 10 days of defeat led to immunosuppression on a background of activation of the 5-HT system in a series of brain structures: the cervical nuclei of the midbrain, the nucleus accumbens, and A9. As confrontations continued, there were decreases in the 5-HIAA/5-HT ratio on these structures, along with a tendency for immune responses to increase.