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1.
Mol Neurobiol ; 18(2): 87-123, 1998 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-10065876

RESUMO

The serotonin neural system originates from ten nuclei in the mid- and hindbrain regions. The cells of the rostral nuclei project to almost every area of the forebrain, including the hypothalamus, limbic regions, basal ganglia, thalamic nuclei, and cortex. The caudal nuclei project to the spinal cord and interact with numerous autonomic and sensory systems. This article reviews much of the available literature from basic research and relevant clinical research that indicates that ovarian steroid hormones, estrogens and progestins, affect the function of the serotonin neural system. Experimental results in nonhuman primates from this laboratory are contrasted with studies in rodents and humans. The sites of action of ovarian hormones on the serotonin neural system include effects within serotonin neurons as well as effects on serotonin afferent neurons and serotonin target neurons. Therefore, information on estrogen and progestin receptor-containing neurons was synthesized with information on serotonin afferent and efferent circuits. The ability of estrogens and progestins to alter the function of the serotonin neural system at various levels provides a cellular mechanism whereby ovarian hormones can impact mood, cognition, pain, and numerous other autonomic functions.


Assuntos
Encéfalo/fisiologia , Estrogênios/fisiologia , Neurônios/fisiologia , Ovário/fisiologia , Progesterona/fisiologia , Serotonina/fisiologia , Animais , Feminino , Humanos , Receptores de Estrogênio/fisiologia , Receptores de Progesterona/fisiologia
2.
Neuropharmacology ; 36(4-5): 475-82, 1997.
Artigo em Inglês | MEDLINE | ID: mdl-9225272

RESUMO

The effect of repeated administration of the reuptake inhibitor citalopram (10 mg/kg s.c., b.i.d. for 14 days) or saline on extracellular 5-hydroxytryptamine (5-HT) and autoreceptor sensitivity was assessed using microdialysis in the frontal cortex (FCx) and dorsal hippocampus (DH) of unanesthetized rats. Acute citalopram (5 mg/kg s.c.) challenge produced significant increases in DH and FCx 5-HT. The nonselective 5-HT1A/1B receptor antagonist (-)+penbutolol (8 mg/kg s.c.), administered 2 hr after citalopram challenge, significantly enhanced 5-HT in FCx and DH of both the chronic citalopram and saline pretreatment groups. Administration of the selective 5-HT1A receptor antagonist WAY 100635 (0.3 mg/kg s.c.) after citalopram challenge significantly enhanced 5-HT in FCx but not DH of both pretreatment groups. This suggests that there may be differences between DH and FCx in regulation of 5-HT release. Nevertheless, these results provide evidence that 5-HT autoreceptors are still active in restraining 5-HT release. Nevertheless, these results provide evidence that 5-HT autoreceptors are still active in restraining 5-HT release even after repeated administration of an antidepressant drug.


Assuntos
Autorreceptores/antagonistas & inibidores , Química Encefálica/efeitos dos fármacos , Citalopram/antagonistas & inibidores , Espaço Extracelular/metabolismo , Receptores de Serotonina/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/antagonistas & inibidores , Antagonistas da Serotonina/farmacologia , Serotonina/metabolismo , Animais , Cromatografia Líquida de Alta Pressão , Citalopram/farmacologia , Espaço Extracelular/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Microdiálise , Pembutolol/farmacologia , Piperazinas/farmacologia , Prosencéfalo/efeitos dos fármacos , Prosencéfalo/metabolismo , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacologia
3.
Novartis Found Symp ; 230: 112-30; discussion 130-3, 2000.
Artigo em Inglês | MEDLINE | ID: mdl-10965505

RESUMO

The serotonin neural system plays an important role in cognitive, emotional and endocrine processes. If the ovarian hormones, oestrogen and progesterone, alter serotonin neural transmission, then functional changes in all of these systems would follow. Therefore, information on the effects of oestrogen and progesterone at a molecular level in the serotonin neural system was sought using non-human primates. Serotonin neurons express nuclear oestrogen receptor beta (ER beta) and progesterone receptors (PRs) which are gene transcription factors. Within serotonin neurons, the regulation of three genes related to serotonin neurotransmission was examined. The mRNA for tryptophan hydroxylase (TPH), the committal enzyme in serotonin synthesis, increased significantly with oestrogen treatment and remained elevated when progesterone was added to the oestrogen regimen. Serotonin reuptake transporter (SERT) mRNA decreased significantly with oestrogen treatment and addition of progesterone had no further effect. 5-HT1A autoreceptor mRNA decreased significantly with oestrogen treatment and addition of progesterone caused a further decrease. Little or no regulation of postsynaptic 5-HT1A, 5-HT2A or 5-HT2C receptor mRNAs was observed in hypothalamic target neurons. TPH protein is increased by oestrogen treatment and remains elevated with addition of progesterone in a manner similar to TPH mRNA. Medroxyprogesterone (MPA) blocked the stimulatory effect of oestrogen on TPH protein and tamoxifen reduced TPH protein levels below that observed in spayed monkeys. Together these data indicate that ovarian hormones and their synthetic analogues could modify cognitive and autonomic neural functions by acting on the serotonin neural pathway.


Assuntos
Proteínas de Transporte/genética , Glicoproteínas de Membrana/genética , Proteínas de Membrana Transportadoras , Proteínas do Tecido Nervoso , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Receptores de Serotonina/genética , Serotonina/metabolismo , Triptofano Hidroxilase/genética , Animais , Receptor beta de Estrogênio , Feminino , Regulação da Expressão Gênica , Humanos , Macaca mulatta , Ovário/metabolismo , Receptores de Estrogênio/genética , Receptores 5-HT1 de Serotonina , Proteínas da Membrana Plasmática de Transporte de Serotonina , Esteroides/metabolismo
4.
Brain Res Mol Brain Res ; 63(2): 325-39, 1999 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-9878811

RESUMO

This study mapped the location of serotonin (5HT) 1A, 2A and 2C receptor mRNA expression in the female macaque hypothalamus and determined whether the expression was regulated by estrogen plus or minus progesterone treatment using in situ hybridization (ISH) and densitometric analysis of autoradiographic films. The experimental groups of pigtail macaques (Macaca nemestrina) were spayed controls (n=4), estrogen treated (28 days, n=4) and estrogen+progesterone-treated animals (14 days estrogen+14 days estrogen and progesterone, n=4). Monkey specific 5HT1A (432 bp), 2A (411 bp) and 2C (294 bp) receptor probes were generated with PCR. Moderate 5HT1A receptor hybridization signal was detected in the preoptic area and the ventromedial nuclei. Less intense 5HT1A receptor signal was detected in a contiguous area from the dorsomedial nuclei through the posterior hypothalamus and in the supramammillary area. There was no change in 5HT1A receptor hybridization signal in any area with ovarian steroid treatment. Dense 5HT2A receptor hybridization signal was morphologically confined to the paraventricular, supraoptic, and mammillary nuclei and the external capsule of the thalamus. Light 5HT2A mRNA signal was inconsistently observed in the ventromedial nuclei. There was no change in the 5HT2A receptor hybridization signal in any area with ovarian steroid treatment. The 5HT2C receptor mRNA was widely distributed in the macaque hypothalamus. The preoptic area and anterior hypothalamus were largely positive for 5HT2C mRNA with a more concentrated signal in a narrow periventricular area. Dense 5HT2C receptor signal was detected lateral to the ventromedial nuclei (capsule), in the tuberomammillary nuclei, arcuate nucleus, dorsomedial nuclei, infundibular area and choroid plexus. Moderate 5HT2C receptor signal was detected in the ventromedial nuclei, lateral hypothalamus and dorsal to posterior hypothalamus. There was a significant decrease in total 5HT2C mRNA hybridization signal with ovarian steroid treatment in the ventromedial nuclei, dorsal and posterior hypothalamus. In summary, macaque 5HT1A, 2A and 2C receptor mRNAs are located in distinct hypothalamic loci which play a role in a number of autonomic functions and behavior. Ovarian steroids decreased the expression of 5HT2C receptor mRNA in the ventromedial nuclei, dorsal and posterior hypothalamus. The expression of 5HT1A and 5HT2A receptor mRNA was not altered by treatment with ovarian steroids.


Assuntos
Estrogênios/farmacologia , Hipotálamo/efeitos dos fármacos , Progesterona/farmacologia , RNA Mensageiro/biossíntese , Receptores de Serotonina/genética , Animais , Autorradiografia , Sequência de Bases , Clonagem Molecular , Feminino , Hipotálamo/metabolismo , Hibridização In Situ , Macaca nemestrina , Dados de Sequência Molecular , Homologia de Sequência do Ácido Nucleico
5.
Brain Res Mol Brain Res ; 91(1-2): 14-22, 2001 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-11457488

RESUMO

This study used double in situ hybridization (ISH) to examine the colocalization of estrogen receptor beta (ERbeta) mRNA in serotonin neurons of rhesus macaques (Macaca mulatta). In addition, immunocytochemistry (ICC) was used to examine the expression and regulation of ERbeta protein in raphe neurons of the macaque midbrain. For double ISH, monkey specific riboprobes for ERbeta incorporating radiolabeled-UTP and a riboprobe for the human serotonin reuptake transporter (SERT) incorporating digoxigenin were applied to midbrain sections from spayed rhesus macaques. ERbeta mRNA hybridization signal was expressed in most cells containing SERT mRNA in the dorsal and median raphe and pons. There were also non-SERT neurons expressing ERbeta mRNA. In addition, ERbeta protein was detected with an affinity purified polyclonal antibody generated against a synthetic peptide corresponding to the D domain of human ERbeta conjugated to bovine serum albumin (provided by Dr. Philippa Saunders, MRC, Edinburgh). Midbrain sections containing the dorsal raphe from spayed rhesus macaques with and without hormone replacement therapy were processed for ERbeta immunostaining. ERbeta protein was detected at a similar intensity and in a similar number of cells in the dorsal raphe neurons in all treatment groups. Thus, the expression of ERbeta protein in the dorsal raphe was consistent with the expression of ERbeta mRNA. In conclusion, ERbeta mRNA is expressed by serotonin neurons and it is translated to protein. ERbeta protein, like ERbeta mRNA, is detected at similar levels in the presence or absence of ovarian hormones.


Assuntos
Neurônios/química , Neurônios/fisiologia , Receptores de Estrogênio/análise , Receptores de Estrogênio/genética , Serotonina/análise , Serotonina/genética , Afeto/fisiologia , Animais , DNA Complementar , Estradiol/sangue , Estradiol/farmacologia , Receptor beta de Estrogênio , Feminino , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/fisiologia , Hibridização In Situ , Macaca mulatta , Ovariectomia , Progesterona/sangue , Progesterona/farmacologia , Processamento de Proteína Pós-Traducional , RNA Mensageiro/análise , Núcleos da Rafe/citologia
6.
Brain Res Mol Brain Res ; 76(2): 191-204, 2000 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-10762694

RESUMO

This study used in situ hybridization (ISH) to examine the distribution of estrogen receptor beta (ERbeta) mRNA in hypothalamic, limbic, and midbrain regions of monkey brain and its regulation by estrogen (E) and progesterone (P). Monkey-specific ERbeta cDNAs were developed with human primers and reverse transcription and polymerase chain reaction (RT-PCR) using mRNA extracted from a rhesus monkey prostate gland. ERbeta 5' (262 bases) and 3' (205 bases) riboprobes were used in combination for ISH. Ovariectomized and hysterectomized (spayed) pigtail macaques (Macaca nemestrina; four per treatment group) were either untreated spayed-controls, treated with E (28 days), or treated with E plus P (14 days E+14 days E and P). Dense ERbeta hybridization signal was seen in the preoptic area, paraventricular nucleus, and ventromedial nucleus of the hypothalamus; the substantia nigra, caudal linear, dorsal raphe, and pontine nuclei of the midbrain; the dentate gyrus, CA1, CA2, CA3, CA4, and the prosubiculum/subiculum areas of the hippocampus. Expression in the suprachiasmatic region, supraoptic nucleus, arcuate nucleus, and amygdala was less intense. Image analysis of the dense areas showed no significant difference in the hybridization signal in individual regions of the hypothalamus, midbrain, or hippocampus between any of the treatment groups. However, P treatment decreased overall ERbeta signal in the hypothalamus and hippocampus when several different subregions were combined. The localization of ERbeta in monkey brain by ISH is in general agreement with that previously described in rodents. The presence of monkey ERbeta mRNA in brain regions that lack ERalpha should help to clarify the molecular mechanisms by which E acts in the central nervous system to influence hormone secretion, mood disorders, cognition, and neuroprotection.


Assuntos
Encéfalo/metabolismo , Estradiol/farmacologia , Terapia de Reposição de Estrogênios , Regulação da Expressão Gênica , Progesterona/farmacologia , Receptores de Estrogênio/genética , Tonsila do Cerebelo/metabolismo , Animais , Sequência de Bases , Encéfalo/efeitos dos fármacos , Receptor beta de Estrogênio , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Histerectomia , Macaca nemestrina , Masculino , Mesencéfalo/efeitos dos fármacos , Mesencéfalo/metabolismo , Camundongos , Dados de Sequência Molecular , Ovariectomia , Próstata/metabolismo , RNA Mensageiro/análise , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Alinhamento de Sequência , Homologia de Sequência do Ácido Nucleico , Lobo Temporal/efeitos dos fármacos , Lobo Temporal/metabolismo
7.
Brain Res ; 785(1): 91-6, 1998 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-9526054

RESUMO

The aim of the present study was to assess whether there are gender differences in (1) levels of extracellular serotonin (5-HT) in the forebrain, and (2) the effect on 5-HT of a reuptake inhibitor, paroxetine, or a releasing drug, fenfluramine. In vivo microdialysis was used to measure 5-HT in the hypothalamus of male and regularly cycling female rats. Hypothalamic 5-HT was significantly lower in estrous females (0.83 +/- 0.05 pg/sample, n=33) than in male rats (1.04 +/- 0.06 pg, n=38). Levels in diestrous females (0.98 +/- 0.09 pg, n=38) were not significantly different from males. Paroxetine (1 mg/kg) increased hypothalamic 5-HT in males, and diestrous and estrous females to approximately 2 pg/sample. However, the increase in hypothalamic 5-HT produced by a maximally effective dose of paroxetine (10 mg/kg) was significantly greater in male rats and during diestrous than during estrous. d,l-Fenfluramine (10 mg/kg) evoked an increase in extracellular 5-HT to approximately 15 pg/sample in all groups. A higher dose of d,l-fenfluramine (20 mg/kg) produced a significantly greater increase in hypothalamic 5-HT in males than in females during estrous or diestrous. These results are consistent with other evidence that during estrous, when rats are responding to peak levels of estrogen and progesterone, 5-HT release is decreased.


Assuntos
Estro/metabolismo , Hipotálamo/metabolismo , Serotonina/metabolismo , Animais , Diestro/efeitos dos fármacos , Diestro/metabolismo , Relação Dose-Resposta a Droga , Estro/efeitos dos fármacos , Espaço Extracelular , Feminino , Fenfluramina/farmacologia , Hipotálamo/efeitos dos fármacos , Masculino , Microdiálise/métodos , Paroxetina/farmacologia , Ratos , Ratos Sprague-Dawley , Caracteres Sexuais
8.
Neurosci Lett ; 171(1-2): 183-6, 1994 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-8084487

RESUMO

The effect of prolonged uptake inhibition with fluoxetine (10 mg/kg/day i.p. x 14 days) on extracellular serotonin (5-HT) in the rat diencephalon was monitored using in vivo microdialysis. The increase in extracellular 5-HT after repeated administration of fluoxetine was significantly greater than the increase produced by a single injection of this uptake blocker. This difference may have been due to a decrease in somatodendritic autoreceptor sensitivity, since the response to a low dose of the 5-HT1A agonist 8-OH-DPAT (25 micrograms/kg i.v.) was abolished in the chronic rats, while the response to a high dose (100 micrograms/kg i.v.) was attenuated as compared to animals injected once with fluoxetine.


Assuntos
Fluoxetina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Serotonina/metabolismo , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Animais , Diencéfalo/efeitos dos fármacos , Diencéfalo/metabolismo , Eletrofisiologia , Espaço Extracelular/efeitos dos fármacos , Espaço Extracelular/metabolismo , Masculino , Microdiálise , Ratos , Ratos Sprague-Dawley
9.
Neuropharmacology ; 63(6): 1051-63, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22796107

RESUMO

Estrogen acts through two molecularly distinct receptors termed estrogen receptor alpha (ERα) and estrogen receptor beta (ERß) which bind estradiol with similar affinities and mediate the effects of estrogen throughout the body. ERα plays a major role in reproductive physiology and behavior, and mediates classic estrogen signaling in such tissues as the uterus, mammary gland, and skeleton. ERß, however, modulates estrogen signaling in the ovary, the immune system, prostate, gastrointestinal tract, and hypothalamus, and there is some evidence that ERß can regulate ERα activity. Moreover, ERß knockout studies and receptor distribution analyses in the CNS suggest that this receptor may play a role in the modulation of mood and cognition. In recent years several ERß-specific compounds (selective estrogen receptor beta modulators; SERM-beta) have become available, and research suggests potential utility of these compounds in menopausal symptom relief, breast cancer prevention, diseases that have an inflammatory component, osteoporosis, cardiovascular disease, and inflammatory bowel disease, as well as modulation of mood, and anxiety. Here we demonstrate an antidepressant-like effect obtained using two SERM-beta compounds, SERM-beta1 and SERM-beta2. These compounds exhibit full agonist activity at ERß in a cell based estrogen response element (ERE) transactivation assay. SERM-beta1 and 2 are non-proliferative with respect to breast as determined using the MCF-7 breast cancer cell-based assay and non-proliferative in the uterus as determined by assessing the effects of SERM-beta compounds on immature rat uterine weight and murine uterine weight. In vivo SERM-beta1 and 2 are brain penetrant and display dose dependent efficacy in the murine dorsal raphe assays for induction of tryptophan hydroxylase mRNA and progesterone receptor protein. These compounds show activity in the murine forced swim test and promote hippocampal neurogenesis acutely in rats. Taken together these data suggest that ERß may play an important role in modulating mood and the ERß specific compounds described herein will be useful tools for probing the utility of an ERß agonist for treating neuroendocrine-related mood disturbance and menopausal symptoms.


Assuntos
Antidepressivos , Receptor beta de Estrogênio/efeitos dos fármacos , RNA Mensageiro/biossíntese , Núcleos da Rafe/enzimologia , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Natação/psicologia , Triptofano Hidroxilase/biossíntese , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA/genética , Relação Dose-Resposta a Droga , Receptor alfa de Estrogênio/efeitos dos fármacos , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/crescimento & desenvolvimento , Humanos , Imuno-Histoquímica , Hibridização In Situ , Neurogênese/efeitos dos fármacos , Tamanho do Órgão/efeitos dos fármacos , Plasmídeos/genética , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Receptores Androgênicos/metabolismo , Receptores de Progesterona/metabolismo , Ativação Transcricional/efeitos dos fármacos , Triptofano Hidroxilase/genética , Útero/anatomia & histologia , Útero/fisiologia
10.
Synapse ; 20(3): 225-33, 1995 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-7570354

RESUMO

In vivo microdialysis was used to examine the effects of peripheral uptake inhibition on extracellular serotonin (5-HT). Previous results from this lab indicated that systemic fluoxetine caused a decrease in 5-HT when terminal uptake was inhibited by local infusion of the uptake blocker. We hypothesized that the decrease in 5-HT levels in the terminal region was due to an increase in 5-HT in the vicinity of the inhibitory somatodendritic autoreceptors in the dorsal raphe nucleus (DRN). To test this prediction, rats were implanted with probes in both the basal diencephalon (a nerve terminal region) and the DRN (the cell body region). Fluoxetine (10 mg/kg i.p.) increased extracellular 5-HT, in a depolarization-dependent manner, by approximately 140% in both areas. In a separate experiment, fluoxetine was infused into the diencephalon overnight to block nerve terminal uptake sites. This pretreatment caused an eight- to 10-fold increase in 5-HT levels. Subsequent systemic fluoxetine, sertraline, or paroxetine, produced a 50% decrease in extracellular 5-HT in the diencephalon, presumably due to activation of the 5-HT1A somatodendritic autoreceptors. Consistent with this hypothesis, systemic administration of the 5-HT1 antagonists spiperone, penbutolol, or WAY100135 reversed the fluoxetine-induced decrease in 5-HT to approximately 85% of the pre-fluoxetine baseline levels. Likewise, pretreatment with penbutolol, but not selective beta-adrenergic antagonists, blocked the fluoxetine-induced decrease in release. These findings suggest that the ability of acute systemic 5-HT uptake inhibition to elevate nerve terminal 5-HT is limited by autoreceptor activation following elevation of 5-HT in the DRN.


Assuntos
Dendritos/metabolismo , Receptores de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Serotonina/metabolismo , Animais , Dendritos/efeitos dos fármacos , Diencéfalo/efeitos dos fármacos , Diencéfalo/metabolismo , Ácido Hidroxi-Indolacético/metabolismo , Masculino , Microdiálise , Núcleos da Rafe/efeitos dos fármacos , Núcleos da Rafe/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia
11.
J Pharmacol Exp Ther ; 283(2): 581-91, 1997 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-9353373

RESUMO

Because monoamine reuptake inhibitors and releasing agents both increase extracellular neurotransmitter levels, establishing in vivo experimental criteria for their classification has been difficult. Using microdialysis in the hypothalamus of unanesthetized rats, we provide evidence that serotonin- (5-HT) selective and nonselective reuptake inhibitors can be distinguished from the 5-HT-releasing agent fenfluramine by four criteria: 1) Systemic fenfluramine produces a much greater increase in 5-HT than the reuptake inhibitors. 2) The 5-HT somatodendritic autoreceptor agonist, (+/-)-8-hydroxy-(dipropylamino)tetralin (8-OH-DPAT), attenuates the increase in 5-HT produced by reuptake inhibitors, but not by fenfluramine. 3) The large increase in 5-HT produced by infusion of reuptake inhibitors into the hypothalamus is attenuated by their systemic administration. However, systemic injection of fenfluramine during its local infusion does not attenuate this increase. 4) Reuptake inhibitor pretreatment attenuates fenfluramine-induced increases in 5-HT. According to these criteria, the in vivo effects of the novel antiobesity drug sibutramine are consistent with its characterization as a 5-HT reuptake inhibitor and not a 5-HT releaser. Thus, sibutramine produced increases in hypothalamic 5-HT similar in magnitude to the effects of the known reuptake inhibitors, and the increase was attenuated by 8-OH-DPAT. Also, sibutramine attenuated fenfluramine-induced 5-HT release. Systemic administration of sibutramine failed to attenuate the increase in 5-HT produced by its local infusion, suggesting that this criterion is not applicable to compounds with low affinity for the 5-HT transporter.


Assuntos
Ciclobutanos/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Serotonina/metabolismo , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Animais , Fenfluramina/farmacologia , Fluoxetina/farmacologia , Masculino , Microdiálise , Paroxetina/farmacologia , Ratos , Ratos Sprague-Dawley
12.
Endocrine ; 11(3): 257-67, 1999 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-10786822

RESUMO

The effect of estrogen (E) and progesterone (P) on the protein expression of the rate-limiting enzyme in serotonin synthesis, tryptophan hydroxylase (TPH), and the level of serotonin in the hypothalamic terminal field was examined in guinea pigs. In addition, we questioned whether serotonin neurons of guinea pigs contain ovarian steroid receptors (estrogen receptoralpha[ERalpha], estrogen receptor beta[ERbeta], progestin receptors [PRs]) that could directly mediate the actions of E or P. Western blot and densitometric analysis for TPH were used on raphe extracts from untreated-ovariectomized (OVX), OVX-E-treated (28 d), and OVX-E+P-treated (14 d E+14 d E+P) guinea pigs. The medial basal hypothalami from the same animals were extracted and subjected to high-performance liquid chromatography analysis for serotonin, dopamine, 5-hydroxyindole acetic acid, and homovanillic acid. The brains from other animals treated in an identical manner were perfusion fixed and examined for the colocalization of ERalpha plus serotonin and PR plus serotonin with double immunohistochemistry or for expression of ERbeta mRNA with in situ hybridization. E and E+P treatment significantly increased TPH protein levels compared to the untreated control group (p < 0.05), but TPH levels were similar in the E and E+P-treated groups. By contrast, serotonin (nanogram/milligram of protein) in the hypothalamus was significantly increased by E+P treatment, but not by E alone. Neither ERalpha nor PR proteins were detected within serotonin neurons of the guinea pig raphe nucleus. However, ERbeta mRNA was expressed in the dorsal raphe. In summary, E alone increased TPH protein expression and the addition of P had no further effect, whereas E+P increased hypothalamic serotonin and E alone had no effect. The localization of ERbeta, but not ERalpha or PR, in the dorsal raphe nucleus suggests that E acting via ERbeta within serotonin neurons increases expression of TPH, but that P acting via other neurons and transsynaptic stimulation may effect changes in TPH enzymatic activity, which in turn, would lead to an increase in serotonin synthesis.


Assuntos
Estrogênios/farmacologia , Mesencéfalo/química , Progesterona/farmacologia , Receptores de Esteroides/análise , Serotonina/metabolismo , Triptofano Hidroxilase/metabolismo , Animais , Monoaminas Biogênicas/análise , Western Blotting , Receptor alfa de Estrogênio , Receptor beta de Estrogênio , Estrogênios/sangue , Feminino , Cobaias , Hipotálamo/química , Tamanho do Órgão , Ovariectomia , Hipófise/anatomia & histologia , Progesterona/sangue , RNA Mensageiro/análise , Núcleos da Rafe/química , Receptores de Estrogênio/análise , Receptores de Estrogênio/genética , Receptores de Estrogênio/fisiologia , Receptores de Progesterona/análise , Receptores de Progesterona/fisiologia
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