RESUMO
Neurotrophic factors play a key role in development, differentiation, synaptogenesis, and survival of neurons in the brain as well as in the process of their adaptation to external influences. The serotonergic (5-HT) system is another major factor in the development and neuroplasticity of the brain. In the present review, the results of our own research as well as data provided in the corresponding literature on the interaction of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) with the 5-HT-system of the brain are considered. Attention is given to comparison of BDNF and GDNF, the latter belonging to a different family of neurotrophic factors and being mainly considered as a dopaminergic system controller. Data cited in this review show that: (i) BDNF and GDNF interact with the 5-HT-system of the brain through feedback mechanisms engaged in autoregulation of the complex involving 5-HT-system and neurotrophic factors; (ii) GDNF, as well as BDNF, stimulates the growth of 5-HT neurons and affects the expression of key genes of the brain 5-HT-system - those coding tryptophan hydroxylase-2 and 5-HT1A and 5-HT2A receptors. In turn, 5-HT affects the expression of genes that control BDNF and GDNF in brain structures; (iii) the difference between BDNF and GDNF is manifested in different levels and relative distribution of expression of these factors in brain structures (BDNF expression is highest in hippocampus and cortex, GDNF expression in the striatum), in varying reaction of 5-HT2A receptors on BDNF and GDNF administration, and in different effects on certain types of behavior.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Encéfalo/metabolismo , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Serotonina/metabolismo , Animais , Humanos , Receptor 5-HT1A de Serotonina/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Neurônios Serotoninérgicos/metabolismoRESUMO
The study of spaceflight effects on the brain is technically complex concern; complicated by the problem of applying an adequate ground model. The most-widely used experimental model to study the effect of microgravity is the tail-suspension hindlimb unloading model; however, its compliance with the effect of actual spaceflight on the brain is still unclear. We evaluated the effect of one month hindlimb unloading on the expression of genes related to the brain neuroplasticity-brain neutotrophic factors (Gdnf, Cdnf), apoptotic factors (Bcl-xl, Bax), serotonin- and dopaminergic systems (5-HT2A, Maoa, Maob, Th, D1r, Comt), and compared the results with the data obtained on mice that spent one month in spaceflight on Russian biosatellite Bion-M1. No effect of hindlimb unloading was observed on the expression of most genes, which were considered as risk neurogenes for long-term actual spaceflight. The opposite effect of hindlimb unloading and spaceflight was found on the level of mRNA of D1 dopamine receptor and catechol-O-methyltransferase in the striatum. At the same time, the expression of Maob in the midbrain decreased, and the expression of Bcl-xl genes increased in the hippocampus, which corresponds to the effect of spaceflight. However, the hindlimb unloading model failed to reproduce the majority of effects of long-term spaceflight on serotonin-, dopaminergic systems and some apoptotic factors.
Assuntos
Apoptose , Encéfalo/metabolismo , Dopamina/metabolismo , Serotonina/metabolismo , Ausência de Peso , Animais , Dopamina/genética , Elevação dos Membros Posteriores , Masculino , Camundongos Endogâmicos C57BL , Monoaminoxidase/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Serotonina/genética , Voo Espacial , Fatores de TempoRESUMO
Domestication of wild animals alters the aggression towards humans, brain monoamines and coat pigmentation. Our aim is the interplay between aggression, brain monoamines and depigmentation. The Hedlund white mutation in the American mink is an extreme case of depigmentation observed in domesticated animals. The aggressive (-2.06 ± 0.03) and tame (+3.5 ± 0.1) populations of wild-type dark brown color (standard) minks were bred during 17 successive generations for aggressive or tame reaction towards humans, respectively. The Hedlund mutation was transferred to the aggressive and tame backgrounds to generate aggressive (-1.2 ± 0.1) and tame (+3.0 ± 0.2) Hedlund minks. Four groups of 10 males with equal expression of aggressive (-2) or tame (+5) behavior, standard or with the Hedlund mutation, were selected to study biogenic amines in the brain. Decreased levels of noradrenaline in the hypothalamus, but increased concentrations of the serotonin metabolite, 5-hydroxyindoleacetic acid and dopamine metabolite, homovanillic acid, in the striatum were measured in the tame compared with the aggressive standard minks. The Hedlund mutation increased noradrenaline level in the hypothalamus and substantia nigra, serotonin level in the substantia nigra and striatum and decreased dopamine concentration in the hypothalamus and striatum. Significant interaction effects were found between the Hedlund mutation and aggressive behavior on serotonin metabolism in the substantia nigra (P < 0.001), dopamine level in the midbrain (P < 0.01) and its metabolism in the striatum (P < 0.05). These results provide the first experimental evidence of the interplay between aggression, brain monoamines and the Hedlund mutation in the American minks.
Assuntos
Agressão/fisiologia , Monoaminas Biogênicas/metabolismo , Encéfalo/metabolismo , Vison/fisiologia , Agressão/psicologia , Animais , Animais Domésticos , Comportamento Animal/fisiologia , Química Encefálica , Dopamina/metabolismo , Feminino , Cabelo/fisiologia , Ácido Hidroxi-Indolacético/metabolismo , Masculino , Mesencéfalo/metabolismo , Vison/genética , Vison/metabolismo , Mutação , Pigmentação/genética , Pigmentação/fisiologia , Serotonina/metabolismoRESUMO
UNLABELLED: Mice were exposed to 1 month of space flight on the Russian biosatellite BION-M1 to determine its effect on the expression of genes involved in the maintenance of the mouse brain dopamine system. The current article focuses on the genes encoding glial cell line-derived neurotrophic factor (GDNF) and cerebral dopamine neurotrophic factor (CDNF). Space flight reduced expression of the GDNF gene in the striatum and hypothalamus but increased it in the frontal cortex and raphe nuclei area. At the same time, actual space flight reduced expression of the gene encoding CDNF in the substantia nigra but increased it in the raphe nuclei area. To separate the effects of space flight from environmental stress contribution, we analyzed expression of the investigated genes in mice housed for 1 month on Earth in the same shuttle cabins that were used for space flight and in mice of the vivarium control group. Shuttle cabin housing failed to alter the expression of the GDNF and CDNF genes in the brain structures investigated. Thus, actual long-term space flight produced dysregulation in genetic control of GDNF and CDNF genes. These changes may be related to downregulation of the dopamine system after space flight, which we have shown earlier. © 2015 Wiley Periodicals, Inc. SIGNIFICANCE: Our results provide the first evidence of microgravity effects on expression of the GDNF and CDNF neurotrophic factor genes. A considerable decrease in mRNA level of GDNF and CDNF in the nigrostriatal dopamine system was found. Because both GDNF and CDNF play a significant role in maintenance and survival of brain dopaminergic neurons, we can assume that this dysregulation in genetic control of GDNF and CDNF genes in substantia nigra could be among the reasons for the deleterious effects of space flight on the dopamine system.
Assuntos
Encéfalo/metabolismo , Regulação da Expressão Gênica/fisiologia , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Fatores de Crescimento Neural/metabolismo , Ausência de Peso , Animais , Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Crescimento Neural/genética , RNA Mensageiro/metabolismo , Voo Espacial , Fatores de TempoRESUMO
Behavioral effects of classic antidepressants, fluoxetine and imipramine, and new psychotropic benzopentathiepin TC-2153 (20 mg/kg, per os) were studied on mice differing in the predisposition to catalepsy-noncataleptic AKR strain and cataleptic strains CBA and AKR.CBA-D13Mit76 (D13). Mice of D13 strain was created by transferring the CBA-allele of major locus of catalepsy to AKR genome. In the forced swim test (FST) fluoxetine showed antidepressant effect on mice of all three strains, imipramine was effective only in D13 mice, while TC-2153 produced antidepressant effect on AKR and D13 mice. Unlike to imipramine and fluoxetine, TC-2153 did not produce negative side effects in the open field and elevated plus-maze tests. Thus, TC-2153 produces antidepressant effects similar to imipramine and fluoxetine, without any visible negative side effect on locomotory activity and anxiety. The D13 mice in the FST showed high sensitivity to the studied drugs in comparison to the parent strains and can be used as new genetic model for investigation of the mechanism of antidepressant effects.
Assuntos
Antidepressivos/administração & dosagem , Ansiedade/tratamento farmacológico , Catalepsia/tratamento farmacológico , Predisposição Genética para Doença , Animais , Ansiedade/genética , Ansiedade/fisiopatologia , Benzotiepinas/administração & dosagem , Catalepsia/genética , Catalepsia/fisiopatologia , Fluoxetina/administração & dosagem , Genótipo , Humanos , Imipramina/administração & dosagem , CamundongosRESUMO
Recent studies considerably extended our knowledge of the mechanisms and physiological role of the interaction between different receptors in the brain. Current review summarizes data on the formation of receptor complexes and the role of such complexes in the autoregulation of the brain serotonin system, behavioral abnormalities and mechanism of antidepressants action. Particular attention is paid to 5-HT1A and 5-HT7 receptor heterodimers. The results described in the present review indicate that: i) dimerization and formation of mobile receptor complexes is a common feature for the members of G-protein coupled receptor superfamily; ii) 5-HT7 receptor appears to be a modulator for 5-HT1A receptor - the key autoregulator of the brain serotonin system; iii) 5-HT1A/5-HT7 receptor complexes formation is one of the mechanisms for inactivation and desensitization of the 5-HTIA receptors in the brain; iv) differences in the 5-HT7 receptor and 5-HTIA/5-HT7 heterodimers density define different sensitivity of pre- and postsynaptic 5-HTlA receptors to chronic treatment with selective serotonin reuptake inhibitors.
Assuntos
Antidepressivos/metabolismo , Multimerização Proteica/efeitos dos fármacos , Receptor 5-HT1A de Serotonina/metabolismo , Receptores de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Serotonina/metabolismo , Animais , HumanosRESUMO
Mice of C57BL/6J strain were exposed to 1-month spaceflight on Russian biosatellite Bion-M1 to determine the effect of long-term actual spaceflight on the expression of genes involved in the processes of neurogenesis and apoptosis. Specifically, we focused on the genes encoding proapoptotic factor BAX, antiapoptotic factor BCL-XL, brain-derived neurotrophic factor (BDNF) and BDNF receptors TrkB and p75. Spaceflight reduced the expression of the antiapoptotic BCL-XL gene in the striatum and hypothalamus, but increased it in the hippocampus. To estimate environmental stress contribution into spaceflight effects we analyzed spaceflight-responsive genes in mice housed for 1 month on Earth in the same shuttle cabins that were used for spaceflight, and in mice of the laboratory control group. It was shown that 1-month shuttle cabin housing decreased BCL-XL gene expression in the striatum but failed to alter BCL-XL mRNA levels in the hippocampus or hypothalamus. Spaceflight failed to alter the expression of the proapoptotic BAX gene in all investigated brain structures, although the insignificant increase of the BAX mRNA level in the hippocampus of spaceflight mice was found. At the same time, shuttle cabin housing produced insignificant decrease in BAX gene expression in the hippocampus. In contrast to the BCL-XL gene, genes encoding BAX, BDNF as well as TrkB and p75 receptors did not respond to 30-day spaceflight. Thus, long-term spaceflight (1) did not affect the expression of genes encoding BDNF as well as TrkB and p75 receptors, (2) produced dysregulation in genetic control of the neuronal apoptosis, (3) implicated BCL-XL as the risk factor for spaceflight-induced behavioral abnormalities.
Assuntos
Encéfalo/metabolismo , Voo Espacial , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Expressão Gênica , Abrigo para Animais , Masculino , Camundongos Endogâmicos C57BL , RNA Mensageiro/metabolismo , Receptor trkB/metabolismo , Receptores de Fator de Crescimento Neural/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estresse Fisiológico/fisiologia , Proteína X Associada a bcl-2/metabolismo , Proteína bcl-X/metabolismoRESUMO
Mice were exposed to 1 month of spaceflight on Russian biosatellite BION-M1 to determine its effect on the expression of key genes in the brain dopamine (DA) and serotonin (5-HT) systems. Spaceflight decreased the expression of crucial genes involved in DA synthesis and degradation, as well as the D1 receptor. However, spaceflight failed to alter the expression of tryptophan hydroxylase-2, 5-HT transporter, 5-HT1A, and 5-HT3 receptor genes, though it reduced 5-HT2A receptor gene expression in the hypothalamus. We revealed risk DA and 5-HT neurogenes for long-term spaceflight for the first time, as well as microgravity-responsive genes (tyrosine hydroxylase, catechol-O-methyltransferase, and D1 receptor in the nigrostriatal system; D1 and 5-HT2A receptors in the hypothalamus; and monoamine oxidase A (MAO A) in the frontal cortex). Decreased genetic control of the DA system may contribute to the spaceflight-induced locomotor impairment and dyskinesia described for both humans and rats.
Assuntos
Comportamento Animal/fisiologia , Encéfalo/metabolismo , Dopamina/metabolismo , Serotonina/metabolismo , Voo Espacial , Animais , Regulação da Expressão Gênica/fisiologia , Humanos , Masculino , Camundongos Endogâmicos C57BL , Receptor 5-HT2A de Serotonina/metabolismo , TempoRESUMO
Glycoprotein gp130 is involved in the intracellular transduction of signals from receptors ofinterleukin-6--related cytokines. The linkage between Il6st gene encoding gp130 and predisposition to excessive freezing (catalepsy) in mice was shown. The aim of present study was to investigate the Il6st mRNA concentration, the level and the rate of glycosilation of gp130 in five brain structures in catalepsy-resistant AKR/J mice strain and in catalepsy-prone CBA/LacJ, AKR.CBA-D13Mit76 with the CBA-derived Il6st gene variant in the AKR/J genome, and ASC created by selection of back-crosses between CBA and AKR strains on catalepsy. Highest concentrations of the nonglycosilated and the glycosilated gp130 protein levels were detected in the midbrain. High levels of Il6st mRNA were discovered in the midbrain, the striatum and the hypothalamus in all mouse strains. The level of Il6st mRNA in the striatum of AKR.CBA-D13Mit76 mice was significantly higher compared with AKR/J. An association between hereditary catalepsy and Il6st expression in the striatum in mice was suggested.
Assuntos
Encéfalo/metabolismo , Catalepsia/metabolismo , Receptor gp130 de Citocina/biossíntese , Reação de Congelamento Cataléptica , Regulação da Expressão Gênica , Proteínas do Tecido Nervoso/biossíntese , RNA Mensageiro/biossíntese , Animais , Encéfalo/patologia , Catalepsia/genética , Catalepsia/patologia , Predisposição Genética para Doença , Camundongos , Especificidade da EspécieRESUMO
Recent investigations have widened the knowledge concerning the brain derived neurotrophic factor (BDNF). The review concentrates on the data of literature and original data of authors on BDNF effects on genetically and epigenetically defined behavioral disorders. Specifically it describes the implication of the brain serotonergic system and the role of genotype in the neuroprotective effects of BDNF. The review provides evidence that: 1) genes encoding key elements of the brain serotonergic system (tryptophan hydroxylase-2, 5-HT1A and 5-HT2A receptors) are implicated in the effect ofBDNF; 2) acute central administration of BDNF produced long-term ameliorative effects on some animal models of genetically defined behavior disorders; 3) BDNF decreased behavioral disorders induced by prenatal stress and ethanol exposure and may play an important role in the treatment of epigenetically defined pathological behavior.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Epigênese Genética , Transtornos Mentais/genética , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/uso terapêutico , Transtornos do Espectro Alcoólico Fetal/tratamento farmacológico , Transtornos do Espectro Alcoólico Fetal/genética , Transtornos do Espectro Alcoólico Fetal/metabolismo , Humanos , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/metabolismo , Receptores de Serotonina/genética , Receptores de Serotonina/metabolismoRESUMO
ASC mice, which were selected for high predisposition to catalepsy, are convenient genetic model for research of central mechanisms related to disorder of motor regulation. The aim of the work was to study the effect of glial cell line-derived neurotrophic factor (GDNF) on catalepsy, locomotor activity, stereotyping behavior in the marble burying test and on the dopamine level in striatum of ASC mice. It was shown that GDNF increased the locomotor activity in the open field, reduced catalepsy expression and stimulated the stereotyping obsessive-compulsive behavior. These changes in behavior were accompanied by increasing dopamine level in striatum.
Assuntos
Catalepsia/fisiopatologia , Predisposição Genética para Doença , Fator Neurotrófico Derivado de Linhagem de Célula Glial/biossíntese , Animais , Catalepsia/genética , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Genótipo , Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Humanos , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Atividade Motora/genética , Comportamento Estereotipado/efeitos dos fármacos , Comportamento Estereotipado/fisiologiaRESUMO
The aim of the current study was to investigate the association between expression of acoustic startle response and fear-induced aggression. The intensity of aggressive response towards man and acoustic startle response in adult and 15-day old Norway rats selectively bred for 70 generation for high level or the lack of fear-induced aggression was studied. Adult rats of aggressive strain demonstrated high aggression and increased amplitude of acoustic startle response compared to rats selectively bred for the lack of fear-induced aggression. It was found that, in contrast to infant rats of tame strain, 15-day old rat pups of aggressive strain demonstrated distinct aggressive response towards man, although this response was not as intensive as in adult rats of this strain. There was no considerable difference between aggressive and tame infants in amplitude of acoustic startle response. Significant habituation of startle response was shown in adult rats of aggressive strain, whereas in 15-day old rat pups of aggressive rat strain amplitude of startle response remained unaltered. Both adult and infant rats of tame strain demonstrated considerable habituation of startle response. Thus, defensive aggression in rats with genetic predisposition to fear-induced aggression appears quite early--at eyes opening they demonstrate a pronounced aggressive response toward man. The acoustic startle reflex is one of the elements of complex behavior--fear-induced aggression, and this element is involved in the enhancement of aggressive response towards man in adult rats but does not play any essential role in infant aggressiveness.
Assuntos
Agressão/fisiologia , Medo/fisiologia , Reflexo de Sobressalto/fisiologia , Estimulação Acústica , Animais , Habituação Psicofisiológica , Humanos , Masculino , RatosRESUMO
Brain serotonin (5-HT) system has been implicated in pathophysiology of anxiety, depression, drug addiction, and schizophrenia. 5-HT2A receptor is involved in the mechanisms of stress-induced psychopathology and impulsive behavior. Here, we investigated the role of 5-HT2A receptor in the autoregulation of the brain 5-HT system. The chronic treatment with agonist of 5-HT2A receptor DOI (1.0 mg/kg, i.p./14 days) produced considerable decrease of 5-HT2A receptor-mediated "head-twitches" in AKR/J mice indicating desensitization of 5-HT2A receptors. Chronic DOI treatment failed to alter 5-HT2A receptor gene expression in the midbrain, hippocampus and frontal cortex. At the same time, the increase in the expression of the gene encoding key enzyme of 5-HT synthesis, tryptophan hydroxylase 2 (TPH2), the increase in TPH2 activity and 5-HT levels and decreased expression of serotonin transporter (5-HTT) gene was found in the midbrain of DOI-treated mice. The results provide new evidence of receptor-gene cross-talk in the brain 5-HT system and the implication of 5-HT2A receptor in the autoregulation of the brain 5-HT system.
Assuntos
Homeostase/genética , Receptor 5-HT2A de Serotonina/metabolismo , Serotonina/metabolismo , Transdução de Sinais/genética , Anfetaminas/administração & dosagem , Animais , Comportamento Animal/efeitos dos fármacos , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Homeostase/efeitos dos fármacos , Masculino , Mesencéfalo/efeitos dos fármacos , Mesencéfalo/metabolismo , Camundongos , Camundongos Endogâmicos AKR , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Triptofano Hidroxilase/genética , Triptofano Hidroxilase/metabolismoRESUMO
The neurotransmitter serotonin (5-HT) is involved in the regulation of mouse intermale aggression. Previously, it was shown that intensity of mouse intermale aggression was positively associated with activity of the key enzyme of 5-HT synthesis - tryptophan hydroxylase 2 (TPH2) in mouse brain. The aim of the present study was to investigate the effect of pharmacological activation or inhibition of 5-HT synthesis in the brain on intermale aggression in two mouse strains differing in the TPH2 activity: C57BL/6J (B6, high TPH2 activity, high aggressiveness) and CC57BR/Mv (BR, low TPH2 activity, low aggressiveness). Administration of 5-HT precursor L-tryptophan (300 mg/kg, i.p.) to BR mice significantly increased the 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels in the midbrain as well as the number of attacks and their duration in the resident-intruder test. And vice versa, administration of TPH2 inhibitor p-chlorophenylalanine (pCPA) (300 mg/kg, i.p., for 3 consecutive days) to B6 mice dramatically reduced the 5-HT and 5-HIAA contents in brain structures and attenuated the frequency and the duration of aggressive attacks. At the same time, L-tryptophan or pCPA did not influence the percentage of aggressive mice and the attack latency reflecting the threshold of aggressive reaction. This result indicated that the intensity of intermale aggression, but not the threshold of aggressive reaction is positively dependent on 5-HT metabolism in mouse brain.
Assuntos
Agressão/fisiologia , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Serotonina/metabolismo , Triptofano Hidroxilase/metabolismo , Agressão/efeitos dos fármacos , Animais , Encéfalo/anatomia & histologia , Eletroquímica , Inibidores Enzimáticos/efeitos adversos , Comportamento Exploratório/efeitos dos fármacos , Fenclonina/efeitos adversos , Ácido Hidroxi-Indolacético/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Polimorfismo Genético/genética , Triptofano/farmacologia , Triptofano Hidroxilase/genéticaRESUMO
The effect of brain-derived neurotrophic factor (BDNF) on depressive-like behavior and serotonin (5-HT) system in the brain of antidepressant sensitive cataleptics (ASC)/Icg mouse strain, characterized by depressive-like behavior, in comparison with the parental nondepressive CBA/Lac mouse strain was examined. Significant decrease of catalepsy and tail suspension test (TST) immobility was shown 17days after acute central BDNF administration (300ng i.c.v.) in ASC mice. In CBA mouse strain, BDNF moderately decreased catalepsy without any effect on TST immobility time. Significant difference between ASC and CBA mice in the effect of BDNF on 5-HT system was revealed. It was shown that central administration of BDNF led to increase of 5-HT(1A) receptor gene expression but not 5-HT(1A) functional activity in ASC mice. Increased tryptophan hydroxylase-2 (Tph-2) and 5-HT(2A) receptor genes expression accompanied by 5-HT(2A) receptor sensitization was shown in BDNF-treated ASC but not in CBA mouse strain, suggesting BDNF-induced increase of the brain 5-HT system functional activity and activation of neurogenesis in "depressive" ASC mice. There were no changes found in the 5-HT transporter mRNA level in BDNF-treated ASC and CBA mice. In conclusion, central administration of BDNF produced prolonged ameliorative effect on depressive-like behavior accompanied by increase of the Tph-2, 5-HT(1A) and 5-HT(2A) genes expression and 5-HT(2A) receptor functional activity in animal model of hereditary behavior disorders.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/administração & dosagem , Encéfalo/metabolismo , Transtorno Depressivo/metabolismo , Predisposição Genética para Doença , Receptor 5-HT1A de Serotonina/biossíntese , Receptor 5-HT2A de Serotonina/biossíntese , Serotonina/metabolismo , Animais , Encéfalo/fisiologia , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/genética , Predisposição Genética para Doença/genética , Injeções Intraventriculares , Masculino , Camundongos , Camundongos Endogâmicos CBA , Neurogênese/genética , Receptor 5-HT1A de Serotonina/genética , Receptor 5-HT2A de Serotonina/genética , Serotonina/biossíntese , Serotonina/genética , Resultado do Tratamento , Triptofano Hidroxilase/biossíntese , Triptofano Hidroxilase/genética , Regulação para Cima/genéticaRESUMO
Freezing or catalepsy is a passive-defensive reaction to stress. The participation of brain serotonin (5-HT) in the regulation of catalepsy was shown. The major gene of predisposition to catalepsy in CBA strain was localized in a 59-70 cM fragment of chromosome 13. This fragment was transferred from the CBA strain to genome of AKR non-cataleptic strain and created AKR. CBA-D13Mit76 (D13) congenic strain. The aim of the study was to compare the effects of acute stress (restriction, 1 h) on corticosterone level in plasma, the expression of c-Fos gene (neuromarker of stress) and serotonin metabolism in the brain in AKR catalepsy-resistant strain and congenic D13 catalepsy-prone strain. The level of corticosterone was significantly lower (p < 0.001) in the stressed D13 mice compared with the stressed AKR mice. Acute stress led to increased expression of c-Fos gene in the hypothalamus and midbrain in mice of both strains. Stress increased (p < 0.05) serotonin turnover in midbrain in D13 mice, but not in AKR. Thus, the fragment of chromosome 13, containing the major gene of catalepsy, participates in the regulation of hormonal response and serotonin turnover to acute stress.
Assuntos
Catalepsia/genética , Hipotálamo/metabolismo , Mesencéfalo/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Serotonina/metabolismo , Estresse Fisiológico , Animais , Catalepsia/etiologia , Catalepsia/metabolismo , Cromossomos de Mamíferos , Corticosterona/sangue , Expressão Gênica , Predisposição Genética para Doença , Hipotálamo/fisiopatologia , Masculino , Mesencéfalo/fisiopatologia , Camundongos , Camundongos Endogâmicos AKR , Camundongos Endogâmicos CBA , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-fos/genética , Restrição Física/efeitos adversosRESUMO
Study of molecular mechanisms of psychotropic drug action is the main aim of molecular psychopharmacology. New synthetic analog of variacin 8-(Trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine (TX-2153) was shown to produce anxiolytic and anticonvulsant effects on mice. Here the effect of chronic administration of TX-2153 on expression of some serotonin-related genes in mouse brain was investigated. The drug (10 mg/kg, per os, 16 days) was administered to adult males of ASC (Antidepressant Sensitive Catalepsy) mouse strain characterizing by alterations in behavior and brain serotonin system. The expression of genes encoding 1) the key enzyme of serotonin synthesis, tryptophan hydroxylase 2 (TPH2), 2) main enzyme of serotonin degradation, monoamine oxydase A (MAOA), 3) 5-HT transporter (SERT) and 4) 5-HT(1A) receptor was studied using quantitative RT-PCR. TX-2153 significantly reduced m-RNA level of 5-HT(1A) receptor and MAOA genes in the midbrain without any effect on expression of these genes in the frontal cortex and hippocampus. The drug failed to affect expression of TPH2 and SERT genes in the midbrain. The result indicates involvement of the brain 5-HT system in the molecular mechanism underlying the effect of TX-2153.
Assuntos
Benzotiepinas/farmacologia , Hipocampo/efeitos dos fármacos , Mesencéfalo/efeitos dos fármacos , Inibidores da Monoaminoxidase/farmacologia , Psicotrópicos/farmacologia , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia , Serotonina/genética , Animais , Bacteriocinas/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica , Hipocampo/metabolismo , Masculino , Mesencéfalo/metabolismo , Camundongos , Monoaminoxidase/efeitos dos fármacos , Monoaminoxidase/genética , Receptor 5-HT1A de Serotonina/genética , Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Triptofano Hidroxilase/efeitos dos fármacos , Triptofano Hidroxilase/genéticaRESUMO
Glycoprotein gp130 is involved in signaling out of significant cytokine receptors as interleukin-6 (IL-6), leukemia inhibitory factor and ciliary neurotrophic factor, which play critical role in immunity, inflammation and neurogenesis. IL-6 and brain neurotransmitter serotonin are involved in the mechanism of depression. The aim of this work was to investigat the role of protein gp130 in the regulation of expression of genes, coding the key enzyme of serotonin synthesis--tryptophan hydroxylase 2 (TPH2), 5-HT-transporter, 5-HT(1A)- and 5-HT(2A)-receptors of serotonin. The study was carried out on adult mouse males of AKR and congenic AKR.CBA-D13Mit76 strains, created by transfer of the fragment of chromosome 13 containing the gene coding gp130 protein from CBA/Lac strain to the genome of AKR/J strain. Decreased expression of 5-HT(1A) - 5-HT(2A)-receptor genes in hippocampus midbrain and TPH2 gene in midbrain in AKR.CBA-D13Mit76 mice compared with AKR mice were shown. Activation of nonspecific immunity by bacterial endotoxin lipopolysaccharide (LPS) administration did not affect the genes expression in AKR mice, but increased 5-HT(2A)-receptor expression in midbrain and decreased 5-HT(1A)-receptor expression in cortex in AKR.CBA-D13Mit76 mice. The results indicate: 1) the participation of gp130 in the regulation of TPH2, 5-HT(1A)- and 5-HT(2A)-receptor genes and 2) association of this protein in the genetically determined sensitivity to LPS.
Assuntos
Receptor gp130 de Citocina/biossíntese , Hipocampo/metabolismo , Neurotransmissores/metabolismo , Serotonina/metabolismo , Animais , Cromossomos de Mamíferos/metabolismo , Fator Neurotrófico Ciliar/metabolismo , Depressão/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/fisiologia , Interleucina-6/metabolismo , Fator Inibidor de Leucemia/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos AKR , Camundongos Endogâmicos CBA , Receptor 5-HT2A de Serotonina/biossíntese , Proteínas da Membrana Plasmática de Transporte de Serotonina/biossíntese , Triptofano Hidroxilase/biossínteseRESUMO
The review concentrates on the role of different types and subtypes of 5-HT receptors in physiological and behavioural effects of the brain neurotransmitter serotonin. Specifically it describes: 1) the effects of 5-HT1A and 5-HT1B receptors on aggressive behavior, sexual arousal, food and water consumption; 2) the data showing reciprocal effect of 5-HT2A, 5-HT2C receptor agonists; 3) interaction of 5-HT3 and 5-HT1A-receptors in 5-HT3-induced hypothermia. The review provides converging lines of evidence that: different types and subtypes of 5-HT receptors are involved in the regulation of various kinds of behavior as additive as well as opposite factors providing neuroplasticity, compensatory and adaptive mechanism.
Assuntos
Encéfalo/fisiologia , Polimorfismo Genético , Receptor Cross-Talk/fisiologia , Serotonina/metabolismo , Agressão/efeitos dos fármacos , Agressão/fisiologia , Animais , Encéfalo/efeitos dos fármacos , Ingestão de Líquidos/efeitos dos fármacos , Ingestão de Líquidos/fisiologia , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Expressão Gênica , Humanos , Receptor 5-HT1A de Serotonina/genética , Receptor 5-HT1A de Serotonina/metabolismo , Receptor 5-HT1B de Serotonina/genética , Receptor 5-HT1B de Serotonina/metabolismo , Receptor 5-HT2A de Serotonina/genética , Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT2C de Serotonina/genética , Receptor 5-HT2C de Serotonina/metabolismo , Receptores 5-HT3 de Serotonina/genética , Receptores 5-HT3 de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/farmacologia , Comportamento Sexual/efeitos dos fármacos , Comportamento Sexual/fisiologiaRESUMO
Glycoprotein gp130 is involved in the interleukin-6 (IL-6) and related cytokines' signaling. Linkage between the gp130 coding gene and freezing reaction (catalepsy) was shown. Here, we compared the expression and function of the gp130 in male mice of catalepsy-resistant AKR/J strain and catalepsy-prone congenic AKR.CBA-D13Mit76 strain created by transferring the gp130 gene allele from catalepsy-prone CBA/Lac to the genome of AKR/J strain. No difference in the gp130 expression in the frontal cortex, hippocampus and midbrain between AKR and AKR.CBA-D13Mit76 mice was found. However, AKR.CBA-D13Mit76 mice were more sensitive to bacterial lipopolysaccharide (LPS). The administration of LPS (50 µg/kg, ip) significantly increased mRNA level of the gene coding IL-6-regulated glial fibrillary acidic protein (GFAP) in the midbrain, induced catalepsy and decreased locomotion in the open field and social investigation tests in AKR.CBA-D13Mit76, but not in AKR mice. The result indicates (1) the association between gp130 and hereditary catalepsy, (2) increased functional activity rather than expression of gp130 in AKR.CBA-D13Mit76 mice and (3) the involvement of gp130 in the mechanism of LPS-induced alteration of behavior.