Several studies suggest profound effects on mood and cognition by neuroactive steroids. Estrogen alone or in combination with antidepressant drugs affecting the serotonin system has been used to treat mood disorders. On the other hand, progesterone is related to negative effects on mood and memory. A major part of the progesterone effects on the brain can be mediated by its metabolite allopregnanolone, which is also de novo synthesized in the brain, and affects the GABAA receptors. It would be of great importance to find a substance that antagonize allopregnanolone adverse effects. To investigate how long term supplementation of estradiol and progesterone, resembling postmenopausal hormone replacement therapy, affects serotonin receptors in different brain areas important for mood and memory functions, we used ovariectomized female rats. After 2 weeks of supplementation with 17β-estradiol alone or in combination with progesterone, or placebo pellets, estradiol alone decreases but estradiol supplemented together with progesterone increases 5HT1A mRNA expression in the hippocampus. Estradiol decreases the 5HT2C receptor gene expression, while estradiol in combination with progesterone increases the 5HT2A mRNA expression in the ventral hippocampus. Thus, estradiol alone has opposite effects compared to the estradiol/progesterone combination. To detect if acute tolerance develops to allopregnanolone, an EEG method was used where male rats by continuous allopregnanolone infusion were kept on anesthesia level of the silent second (SS). After different time intervals (first SS, 30 min or 90 min of anesthesia) several GABAA receptor subunit mRNAs were measured for detecting if changed expression of any GABAA receptor subunits is involved in development of acute tolerance. There is development of acute tolerance to allopregnanolone and brain regions of importance are hippocampus, thalamus and hypothalamus. The GABAA receptor alpha4 subunit in thalamus and alpha2 subunit in the dorsal hippocampus are related to development of acute tolerance. For assessing allopregnanolone behavioral effects, we studied how this neurosteroid affects spatial learning in the Morris water maze task Allopregnanolone inhibits spatial learning short after the injection and shows a specific behavioral pattern with swimming close to the pool wall. The steroid UC1011 can inhibit the increase in chloride ion uptake induced by allopregnanolone. UC1011 decreases allopregnanoloneinduced impairment of spatial learning in the water maze, as well as the specific behavioral swim pattern. In conclusion, the present work demonstrates that neuroactive steroids affect the 5HT and GABA systems in a brain region specific way. GABAA receptor subunit changes in hippocampus and thalamus are related to acute allopregnanolone tolerance. Allopregnanolone induces cognitive deficits, like spatial learning impairment and UC1011 can inhibit allopregnanolone-induced effects in vitro and in vivo. Key words: Estradiol, progesterone, HRT, allopregnanolone, UC1011, serotonin receptor, GABAA receptor, mRNA, Morris water maze, silent second, tolerance.

Serotonin receptor subtypes 5-HT1A, 5-HT2A and 5-HT2C are expressed in motoneurons and modulate motoneuron excitability. Serotonergic neurons, which increase their discharge with motor activity, make numerous contacts with motoneurons; however, little is known about the adaptability of motoneuron serotonin receptor expression in response to exercise. The purpose of this study was to determine the effect of a 7-day treadmill exercise protocol on 5-HT1A, 5-HT2A and 5-HT2C receptor mRNA levels in rat lumbar motoneurons. Lumbar motoneurons of exercised and sedentary animals were collected via laser capture microdissection. RNA was isolated from these samples and real-time reverse transcription polymerase chain reactions were performed to determine differences in receptor mRNA levels between exercised and sedentary animals. It appears that 5-HT1A, 5-HT2A and 5-HT2C receptor mRNA levels are unaltered following 7 days of treadmill exercise; however, future research must be done to determine if an exercise effect exists when motoneurons are differentiated by type.

Serotonin receptor subtypes 5-HT1A, 5-HT2A and 5-HT2C are expressed in motoneurons and modulate motoneuron excitability. Serotonergic neurons, which increase their discharge with motor activity, make numerous contacts with motoneurons; however, little is known about the adaptability of motoneuron serotonin receptor expression in response to exercise. The purpose of this study was to determine the effect of a 7-day treadmill exercise protocol on 5-HT1A, 5-HT2A and 5-HT2C receptor mRNA levels in rat lumbar motoneurons. Lumbar motoneurons of exercised and sedentary animals were collected via laser capture microdissection. RNA was isolated from these samples and real-time reverse transcription polymerase chain reactions were performed to determine differences in receptor mRNA levels between exercised and sedentary animals. It appears that 5-HT1A, 5-HT2A and 5-HT2C receptor mRNA levels are unaltered following 7 days of treadmill exercise; however, future research must be done to determine if an exercise effect exists when motoneurons are differentiated by type.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 6 uppsatser.

Sexually-selected communication signals can be used by competing males to settle contests without incurring the costs of fighting. The ability to dynamically regulate the signal in a context-dependent manner can further minimize the costs of male aggressive interactions. Such is the case in the gymnotiform fish Brachyhypopomus gauderio, which, by coupling its electric organ discharge (EOD) waveform to endocrine systems with circadian, seasonal, and behavioral drivers, can regulate its signal to derive the greatest reproductive benefit. My dissertation research examined the functional role of the EOD plasticity observed in male B. gauderio and the physiological mechanisms that regulate the enhanced male EOD. To evaluate whether social competition drives the EOD changes observed during male-male interactions, I manipulated the number of males in breeding groups to create conditions that exemplified low and high competition and measured their EOD and steroid hormone levels. My results showed that social competition drives the enhancement of the EOD amplitude of male B. gauderio. In addition, changes in the EOD of males due to changes in their social environment were paralleled by changes in the levels of androgens and cortisol. I also examined the relationship between body size asymmetry, EOD waveform parameters, and aggressive physical behaviors during male-male interactions in B. gauderio, in order to understand more fully the role of EOD waveforms as reliable signals. While body size was the best determinant of dominance in male B. gauderio, EOD amplitude reliably predicted body condition, a composite of length and weight, for fish in good body condition. To further characterize the mechanisms underlying the relationship between male-male interactions and EOD plasticity, I identified the expression of the serotonin receptor 1A, a key player in the regulation of aggressive behavior, in the brains of B. gauderio. I also identified putative regulatory regions in this receptor in B. gauderio and other teleost fish, highlighting the presence of additional plasticity. In conclusion, male-male competition seems to be a strong selective driver in the evolution of the male EOD plasticity in B. gauderio via the regulatory control of steroid hormones and the serotonergic system.

Made available in DSpace on 2016-08-10T10:38:40Z (GMT). No. of bitstreams: 1 FERNANDA APARECIDA VARGAS DE BRITO E ALVES.pdf: 1009586 bytes, checksum: 8dc12edf912fed637ebefe39ffdd52d4 (MD5) Previous issue date: 2012-06-30 / Introduction: Fibromyalgia is a syndrome characterized by widespread chronic pain. The syndrome is chronic with dubious possibility of healing. The prevalence in the world population varies from 0,66 to 4,4 %. It is believed that fibromyalgia is the result of abnormal changes in sensory processing of pain. In this context, are inserted gene polymorphisms T102C gene HTR2A serotonin receptor. The HTR2A gene T102C polymorphism is the presence of a thymine (T) or cytosine (C), defined by a transition from T to C at nucleotide position 102. It is a silent polymorphism receptor gene HTR2A, which determine the different levels of gene expression. Objectives: To determine and compare the allele frequency and genotype of the T102C polymorphism of the serotonin receptor gene HTR2A in a group of 48 women diagnosed with fibromyalgia and 50 healthy controls. Methodology: For this we used the PCR- RFLP , from DNA extracted from peripheral blood samples obtained from control and testing. The comparison of allele and genotype frequencies was performed by Chi -square test. Results: The results showed allele frequencies obtained for both groups were: T (46,9%) and C (53,1%). The TT genotype frequencies were found (22,9%), TC (47,9%) and CC (29,2%) for patients with fibromyalgia and TT (16%), TC (70%) and CC (14%) for controls. Conclusions: The FMS is composed of multiple characteristics that reflect a diversity of causes. Our results showed a significantly higher frequency for the CC genotype in patients with FMS, partially explaining the reduced serotoninergic response observed in such patients. / Introdução: A Fibromialgia é uma síndrome reumática caracterizada por dor difusa e crônica. A síndrome é crônica com duvidosa possibilidade de cura. A prevalência na população mundial varia de 0,66 a 4,4%. Acredita-se que a fibromialgia seja o resultado de mudanças anormais no processamento sensorial da dor. Neste contexto, inserem-se os polimorfismos do gene T102C do gene do receptor de serotonina HTR2A. O polimorfismo T102C do gene HTR2A consiste na presença de uma timina (T) ou citosina (C), definida por uma transição de um T para C na posição nucleotídica 102. Trata-se de um polimorfismo silencioso do gene do receptor HTR2A, que determinam níveis de expressão gênica diferentes. Objetivos: Determinar e comparar a freqüência alélica e genotípica do polimorfismo T102C do gene do receptor de serotonina HTR2A em um grupo de 48 mulheres diagnosticadas com fibromialgia e 50 controles saudáveis. Metodologia: Para isso foi utilizada a técnica de PCR-RFLP, a partir de DNA extraído de amostras de sangue periférico obtidas do grupo controle e testes. A comparação das freqüências alélicas e genotípicas foi feita por meio de teste Chi-quadrado. Resultados: Os resultados demonstraram as freqüências alélicas obtidas para os dois grupos foram: T (46,9%) e C (53,1%). As freqüências genotípicas encontradas foram TT (22,9%); TC (47,9%) e CC (29,2%) para os pacientes com fibromialgia e TT (16%); TC (70%) e CC (14%) para os controles. Conclusões: A SFM é composta por múltiplas características que refletem em uma diversidade de causas. Nossos resultados demonstraram que o genótipo CC foi significativamente mais comum nas pacientes com a SFM, justificando parcialmente a menor resposta serotononérgica observada nesse grupo.

The variability in caffeine consumption and inconsistencies among studies linking caffeine to heart disease may be explained by genetic variation. Caffeine antagonizes adenosine receptors with downstream effects on dopamine and serotonin. The objectives of this thesis were to determine whether the DRD2 957C>T or HTR2A 102C>T polymorphisms are associated with caffeine consumption or modify the association between coffee consumption and risk of myocardial infarction (MI). DRD2 genotype was associated with caffeine consumption among non-smokers and CYP1A2 -163C allele carriers. HTR2A genotype was associated with caffeine consumption among non-smokers and subjects with the ADORA2A TT genotype. Neither polymorphism modified the association between coffee consumption and risk of MI; however, a significant coffee x HTR2A interaction was seen among subjects with the CYP1A2 -163C allele. The results suggest caffeine’s reinforcing effects may be mediated by the dopamine and serotonin receptors and implicate serotonin in caffeine’s effect on risk of MI.

The variability in caffeine consumption and inconsistencies among studies linking caffeine to heart disease may be explained by genetic variation. Caffeine antagonizes adenosine receptors with downstream effects on dopamine and serotonin. The objectives of this thesis were to determine whether the DRD2 957C>T or HTR2A 102C>T polymorphisms are associated with caffeine consumption or modify the association between coffee consumption and risk of myocardial infarction (MI). DRD2 genotype was associated with caffeine consumption among non-smokers and CYP1A2 -163C allele carriers. HTR2A genotype was associated with caffeine consumption among non-smokers and subjects with the ADORA2A TT genotype. Neither polymorphism modified the association between coffee consumption and risk of MI; however, a significant coffee x HTR2A interaction was seen among subjects with the CYP1A2 -163C allele. The results suggest caffeine’s reinforcing effects may be mediated by the dopamine and serotonin receptors and implicate serotonin in caffeine’s effect on risk of MI.

Neonatal 6-hydroxydopamine (6-OHDA) treatment of rats is associated with concurrent supersensitization of dopamine (DA) D1 and serotonin 5-HT1C receptors, for agonist-induced oral activity. The present study was conducted to determine if graded reduction of striatal DA content and/or graded elevation of striatal 5-HT content by 6-OHDA would alter sensitivity of either receptor type, and thereby influence oral activity responses to DA and 5-HT agonists. At 3 days after birth, groups of rats were pretreated with desipramine (20 mg/kg i.p.), 1 h before administration of a range of doses of 6-OHDA HBr (15, 30, 60, 100, 150 and 200 μg, i.c.v., salt form; half in each lateral ventricle) or the vehicle, saline (0.85%)-ascorbic acid (0.1%). Between 2 and 4 months, a series of challenge doses of SKF 38393 HCl (0.30 to 3.0 mg/kg i.p.) and m-chlorophenylpiperazine 2HCl (0.30 to 6.0 mg/kg i.p.; m-CPP 2HCl) were administered to each group of rats and oral activity was observed. Oral activity was determined for 1 min every 10 min during a 60-min period, starting 10 min after injection of agonist or vehicle. SKF 38393 dose-response curves demonstrated enhanced oral activity responses in rats lesioned neonatally with 150 or 200 μg of 6-OHDA. m-CPP dose-response curves demonstrated enhanced oral activity responses in these 2 groups of rats, as well as those lesioned neonatally with 100 μg of 6-OHDA. Striatal DA content was reduced by > 97% in these 3 groups of rats. Striatal 5-HT content was elevated by > 80% in rats treated neonatally with 150- or 200-μg doses of 6-OHDA, and by 50% in rats treated neonatally with the 100-μg dose of 6-OHDA. Lower doses of 6-OHDA produced less of an effect on striatal DA and 5-HT content. Regression analysis determined that both SKF 38393- and m-CPP-induced oral activities were most closely correlated with the magnitude of change in striatal content of DA. These findings demonstrate that 5-HT agonist responses can be enhanced when DA agonist responses are not enhanced. Also, in neonatal 6-OHDA-lesioned rats the extent of DA depletion vs. the extent of 5-HT elevation seems to be a critical factor in the enhanced behavioral effects of DA and 5-HT agonists.

Tardive dyskinesia (TD), a movement disorder produced by long-term treatment with a classical antipsychotic drug, is generally considered to be a disorder of dopamine (DA) systems, since classical antipsychotics are potent DA D2 receptor blockers. Also, acute DA D1 agonist treatment of rats is known to produce vacuous chewing movements (VCMs), a behavioral feature resembling the oral dyskinesia that is so prominent in most instances of TD. In this paper we outline a series of studies in a new animal model of TD in which DA D1 receptor supersensitivity was produced by neonatal 6-hydroxydopamine (6-OHDA)-induced destruction of nigrostriatal DA fibers. In rats so-lesioned 5-HT receptor supersensitivity is additionally produced, and in fact 5-HT receptor antagonists attenuate enhanced DA D16-lesioned rats treated with haloperidol for one year, there is a 2-fold increase in numbers of VCMs (versus intact rats treated with haloperidol); and this high frequency of VCMs persists for more than 6 months after discontinuing haloperidol treatment. During this stage, 5-HT2 receptor antagonists, but not DA D1 receptor antagonists, attenuate the incidence of VCMs. This series of findings implicates the 5-HT neuronal phenotype in TD, and promotes 5-HT2 receptor antagonists, more specifically 5-HT2C receptor antagonists, as a rational treatment approach for TD in humans.