5-HT1A Receptor Gene Expression Research Articles

Effect of Subchronic Alcoholization on the Behavior and Monoaminergic Systems of the Brain of Mice with a Predisposition to Depression-Like Behavior

Depressive disorders and alcohol dependence are among the most common psychopathologies. It is known that disorders in the serotonergic and dopaminergic brain systems functioning lie in the pathogenesis of alcoholism and affective disorders. In this work, we studied the effects of prolonged administration of ethanol (1.5 g/kg, 20%, 10 days, i.p.) on behavior, functional activity of 5-HT1A and 5-HT2A receptors and expression of genes encoding serotonin (Htr1a, Htr2a) and dopamine (Drd1, Drd2) receptors in brain structures in mice of ASC strain (with the genetic predisposition to depressive-like behavior) and mice of the parental (“non-depressive”) CBA strain. It has been shown that alcoholization leads to an increase in motor activity in animals of both lines and an increase in the level of exploratory behavior in ASC mice. No significant effect of ethanol on social and depression-like behavior was found. The functional activities of 5-HT1A and 5-HT2A receptors (determined by the response to the administration of corresponding receptor agonists) were reduced by ethanol only in ASC animals. A decrease in 5-HT2A receptor gene expression was found in the frontal cortex of CBA mice treated with alcohol. At the same time, ethanol led to an increase in the mRNA levels of the 5-HT1A receptor gene in the striatum and the DRD1 receptor gene in the hypothalamus, as well as a decrease in the expression of the DRD2 receptor gene in the hippocampus of ASC mice. Thus, changes in the serotonergic and dopaminergic brain systems induced by chronic ethanol were more significant in ASC mice with a genetic predisposition to depression-like behavior.

Pensamientos Negativos y Estrés asociados al Receptor de Serotonina 5HT1a en Mujeres con Fibromialgia

La fibromialgia (FM) es una enfermedad crónica no degenerativa que se caracteriza por presentar dolor generalizado en todo el cuerpo, fatiga y alteraciones cognitivas. El 5HT1a es un receptor asociado a ansiedad, miedo y estrés. Son pocos los estudios que relacionan la expresión génica del receptor 5HT1a con pensamientos negativos y estrés en fibromialgia. Por lo tanto, el objetivo fue evaluar la correlación entre el receptor 5HT1a con estrés y pensamientos negativos en mujeres con fibromialgia. En el estudio participaron 49 mujeres con fibromialgia del Hospital General de México “Eduardo Liceaga” del servicio de Reumatología. El estrés y pensamientos negativos se evaluaron a partir de la aplicación de los instrumentos psicológicos: Cuestionario de Pensamientos Automáticos Negativos (ATQ-30) y Escala de Estrés Percibido (PSS). La expresión génica de 5HT1a se evaluó mediante PCR en tiempo real a partir de la extracción de RNA, por medio de sangre periférica. La evaluación psicológica y extracción de sangre se realizaron en dos momentos diferentes en un lapso no mayor de un día. Se identificó niveles altos de estrés y de pensamientos negativos específicamente autorreproche, ambos factores mostraron una correlación negativa con 5HT1a, en el cual percepción de estrés es un modelo predictor de la expresión de 5HT1a al igual que el estilo de pensamiento de indefensión. Se puede concluir que la percepción alta de estrés y tener pensamientos de autorreproche e indefensión produce posiblemente cambios en la reducción de la expresión génica del receptor 5HT1a en fibromialgia, estos resultados apoyan la idea de que el manejo de estrés y la modificación de pensamientos negativos son factores potenciales para un tratamiento psicológico en esta población por el impacto que podría tener a nivel psicológico y biológico.

5-HT2A receptor-mediated PKCδ phosphorylation is critical for serotonergic impairments induced by p-chloroamphetamine in mice

p-Chloroamphetamine (PCA), an amphetamine derivative, has been shown to induce serotonergic toxicity. However, the precise mechanism of serotonergic toxicity induced by PCA remains unclear. In this study, PCA treatment (20 mg/kg, i.p.) did not significantly change 5-HT1A receptor gene expression, but significantly increased 5-HT2A receptor gene expression. Furthermore, 5-HT2A receptor antagonist MDL11939, but not 5-HT1A receptor antagonist WAY100635, significantly attenuated PCA-induced serotonergic impairments. We investigated whether PCA activated a specific isoform of protein kinase C (PKC), since previous evidence indicated the involvement of PKC in neurotoxicity induced by amphetamines. We observed that PCA treatment significantly increased the expression levels of PKCδ among all PKC isoforms. MDL11939 treatment significantly attenuated PCA-induced phosphorylation of PKCδ. However, PCA-induced increase in 5-HT2A receptor gene expression was not altered by rottlerin (a pharmacological inhibitor of PKCδ) in mice, suggesting that 5-HT2A receptor is an upstream molecule for the activation of PKCδ. Rottlerin or PKCδ knockout significantly attenuated serotonergic behaviors. However, MDL11939 did not show any additional effects against the attenuation caused by PKCδ knockout in mice, suggesting that PKCδ gene is a molecular target for 5-HT2A receptor-mediated serotonergic effects. Our results suggest that 5-HT2A receptor mediates PCA-induced serotonergic impairments via activation of PKC.δ.

Intrahippocampal 5-HT1A receptor antagonist inhibits the improving effect of low-frequency stimulation on memory impairment in kindled rats

In addition to its anticonvulsant effect, low frequency stimulation (LFS) improves learning and memory in kindled animals. In the present study, the role of 5-HT1A receptors in mediating LFS’ improving effect on spatial learning and memory was investigated in amygdala-kindled rats. Amygdala kindling was conducted in a semi-rapid kindling stimulations (12 stimulations per day) in male Wistar rats. LFS (4 trains of 0.1 ms pulse duration at 1 Hz, 200 pulses, 50–150 μA, at 5 min intervals) was applied after termination of kindling stimulations. NAD-299 (a selective 5-HT1A receptor antagonist; 2.5 and 5 μg/μl) was microinjected into the hippocampal CA1 before applying LFS. The Morris water maze, and novel object recognition tests were conducted after the last kindling stimulation. Hippocampal samples were also prepared, and 5-HT1A receptor gene expression levels were assessed using quantitative RT-PCR. In kindled animals, LFS reduced impairments in spatial learning and memory in the Morris water maze and novel object recognition tests. Microinjection of NAD doses of 5 μg/μl reduced the effects of LFS on learning and memory. The gene expression level of 5-HT1A receptors increased significantly in the hippocampus of amygdala-kindled rats. However, LFS applied after kindling stimulations inhibited this effect. It seems that activation of 5-HT1A receptors in the CA1 field is necessary for LFS’ improving effects on spatial learning and memory in kindled animals; although surprisingly, LFS application prevented the elevation in gene expression of 5-HT1A receptors in kindled animals.

PKCδ Knockout Mice Are Protected from Dextromethorphan-Induced Serotonergic Behaviors in Mice: Involvements of Downregulation of 5-HT1A Receptor and Upregulation of Nrf2-Dependent GSH Synthesis.

We investigated whether a specific serotonin (5-HT) receptor-mediated mechanism was involved in dextromethorphan (DM)-induced serotonergic behaviors. We firstly observed that the activation of 5-HT1A receptor, but not 5-HT2A receptor, contributed to DM-induced serotonergic behaviors in mice. We aimed to determine whether the upregulation of 5-HT1A receptor induced by DM facilitates the specific induction of certain PKC isoform, because previous reports suggested that 5-HT1A receptor activates protein kinase C (PKC). A high dose of DM (80mg/kg, i.p.) induced a selective induction of PKCδ out of PKCα, PKCβI, PKCβII, PKCξ, and PKCδ in the hypothalamus of wild-type (WT) mice. More importantly, 5-HT1A receptor co-immunoprecipitated PKCδ in the presence of DM. Consistently, rottlerin, a pharmacological inhibitor of PKCδ, or PKCδ knockout significantly protected against increases in 5-HT1A receptor gene expression, 5-HT turnover rate, and serotonergic behaviors induced by DM. Treatment with DM resulted in an initial increase in nuclear factor erythroid-2-related factor 2 (Nrf2) nuclear translocation and DNA-binding activity, γ-glutamylcysteine (GCL) mRNA expression, and glutathione (GSH) level. This compensative induction was further potentiated by rottlerin or PKCδ knockout. However, GCL mRNA and GSH/GSSG levels were decreased 6 and 12h post-DM. These decreases were attenuated by PKCδ inhibition. Our results suggest that interaction between 5-HT1A receptor and PKCδ is critical for inducing DM-induced serotonergic behaviors and that inhibition of PKCδ attenuates the serotonergic behaviors via downregulation of 5-HT1A receptor and upregulation of Nrf2-dependent GSH synthesis.

Prenatal stress alters diazepam withdrawal syndrome and 5HT1A receptor expression in the raphe nuclei of adult rats

Early-life events have long-term effects on brain structures and cause behavioral alterations that persist into adulthood. The present experiments were designed to investigate the effects of prenatal stress on diazepam-induced withdrawal syndrome and serotonin-1A (5HT1A) receptor expression in the raphe nuclei of adult offspring.The results of the present study reveal that maternal exposure to chronic footshock stress increased the anxiety-like behavior in the prenatally stressed (PS) animals withdrawn from chronic diazepam (2.5mg/kg/day i.p for 1week). Moreover, prenatal stress induced a down-regulation of 5HT1A mRNA in the raphe nuclei of adult offspring. To our knowledge, this study is the first to demonstrate that maternal exposure to chronic footshock stress enhances diazepam withdrawal symptoms and alters 5HT1A receptor gene expression in the raphe nuclei of adult offspring. Thus, more studies are needed to clarify the mechanisms underlying the decrease of 5HT1A receptors expression in the raphe nuclei of PS rats.

5-HT1A receptor gene silencers Freud-1 and Freud-2 are differently expressed in the brain of rats with genetically determined high level of fear-induced aggression or its absence

Serotonin 5-HT1A receptor is known to play a crucial role in the mechanisms of genetically defined aggression. In its turn, 5-HT1A receptor functional state is under control of multiple factors. Among others, transcriptional factors Freud-1 and Freud-2 are known to be involved in the repression of 5-HT1A receptor gene expression. However, implication of these factors in the regulation of behavior is unclear. Here, we investigated the expression of 5-HT1A receptor and silencers Freud-1 and Freud-2 in the brain of rats selectively bred for 85 generations for either high level of fear-induced aggression or its absence. It was shown that Freud-1 and Freud-2 levels were different in aggressive and nonaggressive animals. Freud-1 protein level was decreased in the hippocampus, whereas Freud-2 protein level was increased in the frontal cortex of highly aggressive rats. There no differences in 5-HT1A receptor gene expression were found in the brains of highly aggressive and nonaggressive rats. However, 5-HT1A receptor protein level was decreased in the midbrain and increased in the hippocampus of highly aggressive rats.These data showed the involvement of Freud-1 and Freud-2 in the regulation of genetically defined fear-induced aggression. However, these silencers do not affect transcription of the 5-HT1A receptor gene in the investigated rats. Our data indicate the implication of posttranscriptional rather than transcriptional regulation of 5-HT1A receptor functional state in the mechanisms of genetically determined aggressive behavior. On the other hand, the implication of other transcriptional regulators for 5-HT1A receptor gene in the mechanisms of genetically defined aggression could be suggested.

Effect of central administration of the neurotrophic factors BDNF and GDNF on the functional activity and expression of 5-HT2A serotonin receptors in mice genetically predisposed to depressive-like behavior

Brain serotonin (5-HT) system plays an important role in the control of normal and pathological behavior. 5-HT2A receptors are widely implicated in the regulation both normal functions and psychopathologies, especially schizophrenia and depression. Here, we investigated implication of 5-HT2A receptor in mechanisms of neurotrophic factors BDNF and GDNF action. We found that the acute intracerebroventricular injection of BDNF produced considerable increase in 5-HT2A receptor functional activity in ASC mice. Moreover, BDNF injection led to the increasing of 5-HT2A receptor gene expression in the hippocampus and its decrease in the frontal cortex without any effects in the midbrain. On the contrary, GDNF injection failed to alter 5-HT2A receptor functional activity, but increased the 5-HT2A receptor gene expression in the frontal cortex without any effects in the hippocampus and midbrain. Thus, an effect of the central administration of the neurotrophic factors BDNF and GDNF on the 5-HT2A receptor functional activity and gene expression was shown. The results indicate the implication of 5-HT2A receptor in the mechanisms of BDNF and GDNF action.

Risk neurogenes for long-term spaceflight: dopamine and serotonin brain system.

Mice were exposed to 1month 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.

Effect of glial cell line‐derived neurotrophic factor on behavior and key members of the brain serotonin system in mouse strains genetically predisposed to behavioral disorders

The effect of glial cell line-derived neurotrophic factor (GDNF) on behavior and on the serotonin (5-HT) system of a mouse strain predisposed to depressive-like behavior, ASC/Icg (Antidepressant Sensitive Cataleptics), in comparison with the parental "nondepressive" CBA/Lac mice was studied. Within 7 days after acute administration, GDNF (800 ng, i.c.v.) decreased cataleptic immobility but increased depressive-like behavioral traits in both investigated mouse strains and produced anxiolytic effects in ASC mice. The expression of the gene encoding the key enzyme for 5-HT biosynthesis in the brain, tryptophan hydroxylase-2 (Tph-2), and 5-HT1A receptor gene in the midbrain as well as 5-HT2A receptor gene in the frontal cortex were increased in GDNF-treated ASC mice. At the same time, GDNF decreased 5-HT1A and 5-HT2A receptor gene expression in the hippocampus of ASC mice. GDNF failed to change Tph2, 5-HT1A , or 5-HT2A receptor mRNA levels in CBA mice as well as 5-HT transporter gene expression and 5-HT1A and 5-HT2A receptor functional activity in both investigated mouse strains. The results show 1) a GDNF-induced increase in the expression of key genes of the brain 5-HT system, Tph2, 5-HT1A , and 5-HT2A receptors, and 2) significant genotype-dependent differences in the 5-HT system response to GDNF treatment. The data suggest that genetically defined cross-talk between neurotrophic factors and the brain 5-HT system underlies the variability in behavioral response to GDNF.

Serotonin 5-HT1A receptor in infancy-onset aggression: Comparison with genetically defined aggression in adult rats

Antisocial aggressive behavior in adolescents represents growing clinical and social problem. Previously the implication of 5-HT1A receptor in the regulation of fear-induced aggression was shown. Here, the involvement of 5-HT1A receptor in infancy-onset genetically defined aggression was studied on Norway rats selectively bred for high level or for the lack of aggression toward man. The aggressive behavior and the expression of 5-HT1A receptor gene, 5-HT1A receptor density and functional activity were determined in infant (15-day-old) and adult rats. Considerable differences in aggressive response to man between infant rats of aggressive (A) and nonaggressive (NA) strains were found. In contrast to infant NA rats, A infants elicited marked aggressive response to handling, although its expression was less than in adult A rats. 5-HT1A receptor agonist 8-OH-DPAT (0.2 and 0.5mg/kg) decreased aggressive behavior in both A infant and adult rats. The desensitization of 5-HT1A receptors in the brain of A infant and adult rats was revealed. In contrast to decreased 5-HT1A gene expression in the midbrain of A adult rats, the 5-HT1A gene expression in the midbrain of infant rats did not differ between A and NA strains. There was no difference in 5-HT1A receptor density in infant rats. The data showed (1) the implication of 5-HT1A receptor in genetically defined infancy-onset fear-induced aggression, (2) the desensitization of 5-HT1A receptors as essential factor in infancy-onset aggression, and (3) the increased complexity of 5-HT-ergic control of aggressive behavior in adult rats with the involvement of 5-HT1A gene and the density of 5-HT1A receptors.

Administration of clomipramine to neonatal mice alters stress response behavior and serotonergic gene expressions in adult mice

Early life exposure to antidepressants frequently occurs when pregnant mothers take the medication during late pregnancy. Previous studies in animal models have shown that early exposure to certain antidepressants can alter some behaviors in adulthood. We examined whether the administration of clomipramine, a serotonin reuptake inhibitor, to neonatal mice could result in depression-related behavioral alterations in adult mice. In addition, in an attempt to uncover the mechanism underlying these behavioral changes, we examined the expression of candidate genes in different areas of the brain. Here we show that mice chronically injected with clomipramine specifically during early postnatal development demonstrated depression-like behavior as well as altered stress responses in adulthood. An analysis of the expression of serotonergic genes after exposure to social defeat stress revealed small but significant changes in the expression of 5-HT1A receptor gene (Htr1a) and 5-HTT gene (Slc6a4) in the mice treated with clomipramine compared with the mice injected with saline. We concluded that antidepressant exposure in early days of life could alter stress-related behavior in adulthood and that the behavioral alterations are accompanied by altered serotonergic gene expressions.

Cannabidiol blocks long-lasting behavioral consequences of predator threat stress: Possible involvement of 5HT1A receptors

Posttraumatic stress disorder (PTSD) is an incapacitating syndrome that follows a traumatic experience. Predator exposure promotes long-lasting anxiogenic effect in rodents, an effect related to symptoms found in PTSD patients. Cannabidiol (CBD) is a non-psychotomimetic component of Cannabis sativa with anxiolytic effects. The present study investigated the anti-anxiety actions of CBD administration in a model of PTSD. Male Wistar rats exposed to a predator (cat) received, 1 h later, singled or repeated i.p. administration of vehicle or CBD. Seven days after the stress animals were submitted to the elevated plus maze. To investigate the involvement of 5HT1A receptors in CBD effects animals were pre-treated with WAY100635, a 5HT1A receptor antagonist. To explore possible neurobiological mechanisms involved in these effects, 5HT1A receptor mRNA and BDNF protein expression were measured in the hippocampus, frontal cortex, amygdaloid complex and dorsal periaqueductal gray. Repeated administration of CBD prevented long-lasting anxiogenic effects promoted by a single predator exposure. Pretreatment with WAY100635 attenuated CBD effects. Seven days after predator exposure 5HT1A mRNA expression was up regulated in the frontal cortex and hippocampus. CBD and paroxetine failed to prevent this effect. No change in BDNF expression was found. In conclusion, predator exposure promotes long-lasting up-regulation of 5HT1A receptor gene expression in the hippocampus and frontal cortex. Repeated CBD administration prevents the long-lasting anxiogenic effects observed after predator exposure probably by facilitating 5HT1A receptors neurotransmission. Our results suggest that CBD has beneficial potential for PTSD treatment and that 5HT1A receptors could be a therapeutic target in this disorder.

Effect of brain-derived neurotrophic factor on behavior and key members of the brain serotonin system in genetically predisposed to behavioral disorders mouse strains

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-HT1A receptor gene expression but not 5-HT1A functional activity in ASC mice. Increased tryptophan hydroxylase-2 (Tph-2) and 5-HT2A receptor genes expression accompanied by 5-HT2A 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-HT1A and 5-HT2A genes expression and 5-HT2A receptor functional activity in animal model of hereditary behavior disorders.

Effects of swim stress and fluoxetine on 5-HT1A receptor gene expression and monoamine metabolism in the rat brain regions.

Changes in gene expression of the brain serotonin (5-HT) 1A receptors may be important for the development and ameliorating depression, however identification of specific stimuli that activate or reduce the receptor transcriptional activity is far from complete. In the present study, the forced swim test (FST) exposure, the first stress session of which is already sufficient to induce behavioral despair in rats, significantly increased 5-HT1A receptor mRNA levels in the brainstem, frontal cortex, and hippocampus at 24h. In the brainstem and frontal cortex, the elevation in the receptor gene expression after the second forced swim session was not affected following chronic administration of fluoxetine, while in the cortex, both control and FST values were significantly reduced in fluoxetine-treated rats. In contrast to untreated rats, no increase in hippocampal 5-HT1A receptor mRNA was observed in response to FST in rats chronically treated with fluoxetine. Metabolism of 5-HT (5-HIAA/5-HT) in the brainstem was significantly decreased by fluoxetine and further reduced by swim stress, showing a certain degree of independence of these changes on 5-HT1A receptor gene expression that was increased in this brain region only after the FST, but not after fluoxetine. FST exposure also decreased the brainstem dopamine metabolism, which was unexpectedly positively correlated with 5-HT1A receptor mRNA levels in the frontal cortex. Together, these data suggest that the effects of the forced swim stress as well as fluoxetine involve brain region-dependent alterations in 5-HT1A receptor gene transcription, some of which may be interrelated with concomitant changes in catecholamine metabolism.

Erratum to: “On the role of the selective silencer freud-1 in the regulation of the brain 5-HT1A receptor gene expression” [Molecular Biology 44, 795 (2010)

Erratum to: “On the role of the selective silencer freud-1 in the regulation of the brain 5-HT1A receptor gene expression” [Molecular Biology 44, 795 (2010)

On the role of the selective silencer Freud-1 in the regulation of the brain 5-HT1A receptor gene expression

Selective 5-HT(1A) receptor silencer (Freud-1) is known to be one of the main factors for transcriptional regulation of brain serotonin 5-HT(1A) receptor. However, there is a lack of data on implication of Freud-1 in the mechanisms underlying genetically determined and experimentally altered 5-HT(1A) receptor system state in vivo. In the present study we have found a difference in the 5-HT(1A) gene expression in the midbrain of AKR and CBA inbred mouse strains. At the same time no distinction in Freud-1 expression was observed. We have revealed 90.3% of homology between mouse and rat 5-HT(1A) receptor DRE-element, whereas there was no difference in DRE-element sequence between AKR and CBA mice. This indicates the absence of differences in Freud-1 binding site in these mouse strains. In the model of 5-HT(1A) receptor desensitization produced by chronic 5-HT(1A) receptor agonist administration, a significant reduction of 5-HT(1A) receptor gene expression together with considerable increase of Freud-1 expression were found. These data allow us to conclude that the selective silencer of 5-HT(1A) receptor, Freud-1, is involved in the compensatory mechanisms that modulate the functional state of brain serotonin system, although it is not the only factor for 5-HT(1A) receptor transcriptional regulation.

Decreased cerebral cortex and liver 5-HT2A receptor gene expression and enhanced ALDH activity in ethanol-treated rats and hepatocyte cultures

Objective: In this work, we evaluated the differential binding of serotonin 2A (5-HT2A) receptor antagonist [3H](±)2,3-dimethoxyphenyl-1-[2-(4-piperidine)-methanol] ([3H] MDL 100907) to 5-HT2A receptors in cerebral cortex and liver.Methods: Wistar adult male rats of 180–200 g body weight were given free access to 15% (v/v; ∼ 7·5 g/kg body weight per day) ethanol for 15 days. Brain 5-HT and its metabolites were assayed by a high-performance liquid chromatography. 5-HT2A receptor binding assay was done with different concentrations of [3H] MDL 100907. Hepatocyte culture was done with 10−9–10−3M of 5-HT and ketanserin. The hepatocytes were incubated for 24 hours at 37°C in 5% CO2.Results: Decreased 5-HT content (p<0·05 and p<0·001) and decreased (p<0·001) 5-HT2A receptor binding in cerebral cortex and liver of ethanol-treated rats were observed when compared with control. 5-HT2A receptor mRNA in the cerebral cortex and liver showed an increase in crossing threshold value showing decrease in gene expression in ethanol-treated rats when compared with control. In 24-hour culture works, hepatocytes with 10% ethanol showed an increase in aldehyde dehydrogenase (ALDH) activity (p<0·001), and it decreased (p<0·001) to a near-control level in the case of hepatocytes in a medium with 10% ethanol + 10−5M 5-HT and 10% ethanol + 10−7M 5-HT when compared with the hepatocytes in the medium with 10% ethanol.Conclusion: Our results suggest that the decreased serotonin function mediated through 5-HT2A receptors have a regulatory role on ALDH activity. This will have clinical significance to correct alcoholics from addiction due to allergic aldehyde accumulation.

Modifying 5-HT1A receptor gene expression as a new target for antidepressant therapy

Major depression is the most common form of mental illness, and is treated with antidepressant compounds that increase serotonin (5-HT) neurotransmission. Increased 5-HT1A autoreceptor levels in the raphe nuclei act as a “brake” to inhibit the 5-HT system, leading to depression and resistance to antidepressants. Several 5-HT1A receptor agonists (buspirone, flesinoxan, ipsapirone) that preferentially desensitize 5-HT1A autoreceptors have been tested for augmentation of antidepressant drugs with mixed results. One explanation could be the presence of the C(−1019)G 5-HT1A promoter polymorphism that prevents gene repression of the 5-HT1A autoreceptor. Furthermore, down-regulation of 5-HT1A autoreceptor expression, not simply desensitization of receptor signaling, appears to be required to enhance and accelerate antidepressant action. The current review focuses on the transcriptional regulators of 5-HT1A autoreceptor expression, their roles in permitting response to 5-HT1A-targeted treatments and their potential as targets for new antidepressant compounds for treatment-resistant depression.

Different Behavioral and Physiological Responses in Two Genetic Lines of Laying Hens After Transportation

Physiological and behavioral responses to transportation stress were examined in a chicken strain selected for high group productivity and survivability (HGPS) resulting from reduced cannibalism and flightiness in colony cages and in chickens from Dekalb XL (DXL) commercial strain. At 13 wk of age, 96 pullets per strain were randomly assigned to 4-bird cages within the same strain. At 17 wk of age, half of the cages of each strain (n = 12) were randomly used as experimental group. The birds of the experimental group were crated by line, with a caution to ensure all the birds in the same cage were unfamiliar to each other, and then transported for 2 h on a country road. After transportation, the birds were recaged in groups of 4 within the same line. Behavioral data were collected immediately after the recaging of the birds. Physical parameters (BW and organ weight), plasma corticosterone levels, blood and brain serotonin (5-HT) concentrations, and 5-HT1A receptor mRNA expressions were measured at 1 d posttransportation. Results showed that, compared with the control birds of each strain, transportation stress-induced behavioral changes in eating, drinking, and preening were found in the birds from both strains, but the HGPS birds showed a greater increase in drinking and preening (P < 0.01). In addition, after transportation stress, the HGPS birds had heavier adrenal glands (P < 0.01) with higher concentrations of plasma corticosterone (P < 0.01) and a trend to higher central 5-HT levels (P = 0.09) with a downregulated 5-HT1A receptor gene expression (P < 0.05), whereas the DXL birds had a higher H:L ratio (P < 0.05). The data indicate that there are a genetic basis of variations in chickens in response to transportation stress. The HGPS birds may have a better coping capability to transportation stress than DXL birds.