RESUMO
Testosterone is involved in many processes like aggression and mood disorders. As it may easily diffuse from blood into saliva, salivary testosterone is thought to reflect plasma free testosterone level. If so, it would provide a welcome noninvasive and less stressful alternative to blood sampling. Past research did not reveal consensus regarding the strength of the association, but sample sizes were small. This study aimed to analyse the association in a large cohort. In total, 2,048 participants (age range 18-65 years; 696 males and 1,352 females) were included and saliva (using cotton Salivettes) and plasma were collected for testosterone measurements. Levels were determined by enzyme-linked immunosorbent assay and radioimmunoassay respectively. Free testosterone was calculated by the Vermeulen algorithm. Associations were determined using linear regression analyses. Plasma total and free testosterone showed a significant association with salivary testosterone in men (adjusted ß = .09, p = .01; and ß = .15, p < .001, respectively) and in women (adjusted ß = .08, p = .004; and crude ß = .09, p = .002 respectively). The modest associations indicate that there are many influencing factors of both technical and biological origin.
Assuntos
Saliva/química , Testosterona/análise , Adolescente , Adulto , Idoso , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Radioimunoensaio , Testosterona/sangue , Adulto JovemRESUMO
BACKGROUND: Long-term neuroimmune activation is a common finding in major depressive disorder (MDD). Literature suggests a dual effect of electroconvulsive therapy (ECT), a highly effective treatment strategy for MDD, on neuroimmune parameters: while ECT acutely increases inflammatory parameters, such as serum levels of pro-inflammatory cytokines, there is evidence to suggest that repeated ECT sessions eventually result in downregulation of the inflammatory response. We hypothesized that this might be due to ECT-induced attenuation of microglial activity upon inflammatory stimuli in the brain. METHODS: Adult male C57Bl/6J mice received a series of ten electroconvulsive seizures (ECS) or sham shocks, followed by an intracerebroventricular (i.c.v.) lipopolysaccharide (LPS) or phosphate-buffered saline (PBS) injection. Brains were extracted and immunohistochemically stained for the microglial marker ionized calcium-binding adaptor molecule 1 (Iba1). In addition, a sucrose preference test and an open-field test were performed to quantify behavioral alterations. RESULTS: LPS induced a short-term reduction in sucrose preference, which normalized within 3 days. In addition, LPS reduced the distance walked in the open field and induced alterations in grooming and rearing behavior. ECS did not affect any of these parameters. Phenotypical analysis of microglia demonstrated an LPS-induced increase in microglial activity ranging from 84 to 213 % in different hippocampal regions (CA3 213 %; CA1 84 %; dentate gyrus 131 %; and hilus 123 %). ECS-induced alterations in microglial activity were insignificant, ranging from -2.6 to 14.3 % in PBS-injected mice and from -20.2 to 6.6 % in LPS-injected mice. CONCLUSIONS: We were unable to demonstrate an effect of ECS on LPS-induced microglial activity or behavioral alterations.
Assuntos
Eletrochoque/métodos , Comportamento Exploratório/fisiologia , Comportamento Alimentar/fisiologia , Lipopolissacarídeos/toxicidade , Microglia/metabolismo , Convulsões/metabolismo , Animais , Eletrochoque/efeitos adversos , Comportamento Exploratório/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Convulsões/etiologiaRESUMO
P-glycoprotein (P-gp), an ATP-driven efflux pump in the blood-brain barrier, has a major impact on the delivery of antidepressant drugs in the brain. Genetic variants in the gene ABCB1 encoding for P-gp have inconsistently been associated with adverse effects. In order to resolve these inconsistencies, we conducted a study in a large cohort of patients with major depressive disorder with the aim to unravel the association of ABCB1 variants with adverse effects of antidepressants and in particular with selective serotonin reuptake inhibitors (SSRIs), which display affinity as substrate for P-gp. The Netherlands Study of Depression and Anxiety (NESDA) study was used as a clinical sample. For 424 patients data were available on drug use, side effects. We selected six ABCB1 gene variants (1236T>C, 2677G>T/A, 3435T>C, rs2032583, rs2235040 and rs2235015) and analyzed them for association with adverse drug effects using multinomial regression analysis for both single variants and haplotypes. We found a significant association between the number of SSRI-related adverse drug effects and rs2032583 (P=0.001), rs2235040 (P=0.002) and a haplotype (P=0.002). Moreover, serotonergic effects (sleeplessness, gastrointestinal complaints and sexual effects) were significantly predicted by these variants and haplotype (P=0.002/0.003). We conclude that adverse drug effects with SSRI treatment, in particular serotonergic effects, are predicted by two common polymorphisms of the ABCB1 gene.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Subfamília B de Transportador de Cassetes de Ligação de ATP , Adulto , Antidepressivos/administração & dosagem , Transtorno Depressivo Maior/patologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Feminino , Estudos de Associação Genética , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , Polimorfismo de Nucleotídeo Único , Serotonina/metabolismoRESUMO
Data from the Genetic Association Information Network (GAIN) genome-wide association study (GWAS) in major depressive disorder (MDD) were used to explore previously reported candidate gene and single-nucleotide polymorphism (SNP) associations in MDD. A systematic literature search of candidate genes associated with MDD in case-control studies was performed before the results of the GAIN MDD study became available. Measured and imputed candidate SNPs and genes were tested in the GAIN MDD study encompassing 1738 cases and 1802 controls. Imputation was used to increase the number of SNPs from the GWAS and to improve coverage of SNPs in the candidate genes selected. Tests were carried out for individual SNPs and the entire gene using different statistical approaches, with permutation analysis as the final arbiter. In all, 78 papers reporting on 57 genes were identified, from which 92 SNPs could be mapped. In the GAIN MDD study, two SNPs were associated with MDD: C5orf20 (rs12520799; P=0.038; odds ratio (OR) AT=1.10, 95% CI 0.95-1.29; OR TT=1.21, 95% confidence interval (CI) 1.01-1.47) and NPY (rs16139; P=0.034; OR C allele=0.73, 95% CI 0.55-0.97), constituting a direct replication of previously identified SNPs. At the gene level, TNF (rs76917; OR T=1.35, 95% CI 1.13-1.63; P=0.0034) was identified as the only gene for which the association with MDD remained significant after correction for multiple testing. For SLC6A2 (norepinephrine transporter (NET)) significantly more SNPs (19 out of 100; P=0.039) than expected were associated while accounting for the linkage disequilibrium (LD) structure. Thus, we found support for involvement in MDD for only four genes. However, given the number of candidate SNPs and genes that were tested, even these significant may well be false positives. The poor replication may point to publication bias and false-positive findings in previous candidate gene studies, and may also be related to heterogeneity of the MDD phenotype as well as contextual genetic or environmental factors.
Assuntos
Transtorno Depressivo Maior/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Biologia Computacional , Frequência do Gene , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Desequilíbrio de Ligação , Proteínas do Tecido Nervoso/genética , Neuropeptídeo Y/genética , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/genética , Razão de Chances , Peptidil Dipeptidase A/genética , PubMed/estatística & dados numéricos , Fator de Necrose Tumoral alfa/genéticaRESUMO
BACKGROUND: Testosterone has been implicated in suicidality in cross-sectional studies. Stress that coincides with a suicide attempt may alter androgen levels, so prospective studies are needed to exclude reverse causation. We aimed to examine the associations of plasma androgens with concurrent and future suicidality, and if present, whether these associations were mediated by a behavioral trait like reactive aggression. METHODS: Baseline plasma levels of total testosterone, 5α-dihydrotestosterone, and androstenedione were determined with liquid chromatography-tandem mass spectrometry, and dehydroepiandrosterone-sulphate with a radioimmunoassay. Suicidality was assessed using the Suicidal Ideation Scale at baseline and after 2-, 4-, 6-, and 9-year follow-up. Men and women were analyzed separately, and potential confounders were considered. RESULTS: Participants (N = 2861; 66.3% women) had a mean age of 42.0 years (range 18-65) and almost half (46.9%) fulfilled criteria for a major depressive or anxiety disorder. At baseline 13.2% of men and 11.2% of women reported current suicidal ideation. In participants who were non-suicidal at baseline, slightly more men than women reported suicidal ideation during follow-up (14.7% vs. 12.5%), whereas the reverse pattern was observed for suicide attempts (3.6% vs. 4.2%). None of the associations between androgens and current and future suicidality were significant. LIMITATIONS: Androgens were determined once, which may have been insufficient to predict suicidality over longer periods. DISCUSSION: The lack of associations between plasma levels of androgens determined by 'gold-standard' laboratory methods with suicidality do not support previous cross-sectional and smaller studies in adult men and women with values within the physiological range.
Assuntos
Transtorno Depressivo Maior , Suicídio , Adolescente , Adulto , Idoso , Androgênios , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Plasma , Estudos Prospectivos , Fatores de Risco , Ideação Suicida , Adulto JovemRESUMO
OBJECTIVE: Assessment of the temporal interrelationship of neuropsychiatric parameters requires technologies allowing frequent biological measurements. We propose glucocorticoid receptor (GR) function of lymphocytes to assess the temporal relationship between glucocorticoid resistance and the course of major depressive disorder. METHOD: Dexamethasone suppression of lymphocyte proliferation was in vitro assessed via 5-bromo-2' deoxyuridine (BrdU) incorporation in DNA. Optimal conditions were determined using blood of healthy volunteers. Thereafter the relation between depression severity (Hamilton Depression Rating Scale, HDRS, scores), lymphocyte proliferation and morning cortisol levels in blood was studied in thirteen depressed patients, mostly with a history of treatment resistance. RESULTS: Recovery from depression was not directly associated with changes in lymphocyte glucocorticoid resistance. However, a negative correlation was observed between HDRS and BrdU incorporation and a positive correlation between morning cortisol and BrdU incorporation. No significant correlation was found between cortisol and HDRS. Regression analyses showed that HDRS was related to both suppression of BrdU incorporation (beta -0.508, p<0.001) and cortisol levels (beta 0.364, p=0.001) in a highly significant model (F2,60=14,244, p<0.001) Except for one case, such relation could not be found within patients. CONCLUSION: Our preliminary results suggest a mutual relation between lymphocyte GR function, morning cortisol levels and MDD symptom severity. A direct relation between glucocorticoids resistance and recovery may not exist, but glucocorticoid resistance might attenuate or prevent recovery. It is clear that additional studies using larger and more homogenous groups of MDD patients are required to support our findings.
Assuntos
Depressão/patologia , Linfócitos/fisiologia , Receptores de Glucocorticoides/fisiologia , Bromodesoxiuridina/metabolismo , Contagem de Células , Proliferação de Células/efeitos dos fármacos , Dexametasona/farmacologia , Relação Dose-Resposta a Droga , Feminino , Glucocorticoides/farmacologia , Humanos , Ativação Linfocitária , Linfócitos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Análise de RegressãoRESUMO
Despite the advances of recent decades, there is still an urgent need for antidepressants with improved efficacy, safety and tolerability. Agomelatine is a new antidepressant with an innovative pharmacological profile. It is the first melatonergic antidepressant, and is a potent agonist of melatonin receptors (MT1 and MT2) with 5-HT2C antagonist properties. The efficacy of 25 mg/day agomelatine in treating major depressive disorder (MDD) has been demonstrated in a number of placebo-controlled studies. Evidence of improvement in depressive symptoms was observed in a dose-ranging study in which 25 mg/day agomelatine was significantly better than placebo, whatever the rating scale used (Hamilton Rating Scale for Depression, Clinical Global Impression, and Montgomery-Asberg Depression Rating Scale). These results have been confirmed in two similarly designed placebo-controlled studies. Agomelatine also produces a significant improvement in anxiety compared to placebo, according to Hamilton Rating Scale for Anxiety scores. The efficacy of agomelatine has been studied in subpopulations with more severe depression, demonstrating its efficacy in these difficult-to-treat patients. In view of the available data on agomelatine, this antidepressant can be regarded as an innovative treatment for MDD patients, offering a new approach in the management of depressed patients.
Assuntos
Acetamidas/administração & dosagem , Antidepressivos/administração & dosagem , Transtorno Depressivo Maior/tratamento farmacológico , Drogas em Investigação/administração & dosagem , Acetamidas/efeitos adversos , Adolescente , Adulto , Idoso , Antidepressivos/efeitos adversos , Ensaios Clínicos Controlados como Assunto , Relação Dose-Resposta a Droga , Drogas em Investigação/efeitos adversos , Humanos , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Paroxetina/administração & dosagem , Paroxetina/efeitos adversos , Resultado do TratamentoRESUMO
Many fear conditioning studies use electric shock as the aversive stimulus. The intensity of shocks varies throughout the literature. In this study, shock intensities ranging from 0 to 1.5 mA were used, and the effects on the rats assessed by both behavioural and biochemical stress parameters. Results indicated a significant difference with respect to defaecation and freezing behaviour between controls and those animals that received a shock. Significant differences in corticosterone levels were also noted between controls and those groups that received a shock. No significant differences were found between the shock groups with regards to the stress parameters measured in our fear conditioning paradigm, indicating that the two shock groups were similarly stressed. Increased significance levels were noted for freezing behaviour as well as a lower standard error of means was found in the highest shock intensity group. We therefore recommend using the higher shock intensity (1.5 mA) as the rats in the higher shock intensity group were more homogeneously fear-conditioned and therefore the results should be more reproducible and robust than in the lower shock intensity group. This would allow for fewer rats to be used in order to gain an accurate impression of the conditioning paradigm employed.
Assuntos
Comportamento Animal/fisiologia , Condicionamento Clássico/fisiologia , Medo/psicologia , Ratos Sprague-Dawley/psicologia , Animais , Corticosterona/sangue , Defecação/fisiologia , Masculino , Ratos , Organismos Livres de Patógenos Específicos , Estatísticas não ParamétricasRESUMO
BACKGROUND: Mood disorders constitute a high burden for both patients and society. Notwithstanding the large arsenal of available treatment options, a considerable group of patients does not remit on current antidepressant treatment. There is an urgent need to develop alternative treatment strategies. Recently, low-strength transcranial pulsed electromagnetic field (tPEMF) stimulation has been purported as a promising strategy for such treatment-resistant depression (TRD). The mode of action of this new technique is however largely unknown. METHODS: We searched PubMed for literature reports on the effects of tPEMF and for information regarding its working mechanism and biological substrate. RESULTS: Most studies more or less connect with the major hypotheses of depression and concern the effects of tPEMF on brain metabolism, neuronal connectivity, brain plasticity, and the immune system. Relatively few studies paid attention to the possible chronobiologic effects of electromagnetic fields. LIMITATIONS: We reviewed the literature of a new and still developing field. Some of the reports involved translational studies, which inevitably limits the reach of the conclusions. CONCLUSION: Weak magnetic fields influence divergent neurobiological processes. The antidepressant effect of tPEMF may be specifically attributable to its effects on local brain activity and connectivity.
Assuntos
Encéfalo/metabolismo , Depressão/terapia , Estimulação Magnética Transcraniana/métodos , Humanos , PubMed/estatística & dados numéricosRESUMO
A low-grade inflammatory response is commonly seen in the peripheral blood of major depressive disorder (MDD) patients, especially those with refractory and chronic disease courses. However, electroconvulsive therapy (ECT), the most drastic intervention reserved for these patients, is closely associated with an enhanced haematogenous as well as neuroinflammatory immune response, as evidenced by both human and animal studies. A related line of experimental evidence further shows that inflammatory stimulation reinforces neurotrophin expression and may even mediate dramatic neurogenic and antidepressant-like effects following exposure to chronic stress. The current review therefore attempts a synthesis of our knowledge on the neurotrophic and immunological aspects of ECT and other electrically based treatments in psychiatry. Perhaps contrary to contemporary views, we conclude that targeted potentiation, rather than suppression, of inflammatory responses may be of therapeutic relevance to chronically depressed patients or a subgroup thereof.
Assuntos
Transtorno Depressivo Maior/terapia , Eletroconvulsoterapia , Inflamação/fisiopatologia , Fatores de Crescimento Neural/fisiologia , Transtorno Depressivo Maior/imunologia , Humanos , Resultado do TratamentoRESUMO
BACKGROUND: We investigated the combination of selective serotonin reuptake inhibitors (SSRIs) with the beta-adrenoceptor/serotonin 1A (5-HT(1A)) antagonist pindolol, based on the concept that 5-HT(1A) receptor blockade would eliminate the need for desensitization of presynaptic 5-HT(1A) receptors and therefore hasten the onset of action and improve the efficacy of SSRIs. However, since pindolol plasma levels after 2.5 mg three times a day are about 60 nmol/L, and the K(i) for the 5-HT(1A) receptor is 30 nmol/L, it is questionable whether pindolol levels in the brain would be sufficient to antagonize 5-HT(1A) receptors. Using microdialysis in the guinea pig, we correlated brain and plasma levels of pindolol with its capability of augmenting paroxetine-induced increases in brain 5-HT levels. In addition, central beta-receptor antagonism of pindolol was studied by investigating blockade of beta-agonist-induced increases in brain cyclic adenosine monophosphate (cAMP) formation. METHODS: Using microdialysis and jugular vein catheterization, we studied the ability of systemically administered pindolol to antagonize central 5-HT(1A) and beta-adrenoceptors, while simultaneously monitoring pindolol plasma and brain concentrations. RESULTS: Augmentation of paroxetine-induced increases in extracellular 5-HT levels in the ventral hippocampus was only observed at steady state plasma levels exceeding 7000 nmol/L (concurrent brain levels 600 nmol/L). In contrast, antagonism of beta-agonist-induced increases of brain cAMP levels was already observed at pindolol plasma levels of 70 nmol/L (concurrent brain levels < 3 nmol/L). CONCLUSIONS: At plasma levels that are observed in patients after 2.5 mg three times a day ( approximately 60 nmol/L), pindolol produces only a partial blockade of presynaptic 5-HT(1A) autoreceptors and does not augment the SSRI-induced 5-HT increase in the guinea pig brain. It is therefore very unlikely that the favorable effects of combining pindolol with SSRIs, as reported in a number of clinical studies, are due to 5-HT(1A) antagonism. Since pindolol completely blocks central beta-adrenoreceptors at clinically relevant plasma levels, it is possible that beta-adrenoceptor antagonism is involved in mediating pindolol's beneficial effects.
Assuntos
Antidepressivos/farmacologia , Autorreceptores/antagonistas & inibidores , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Pindolol/farmacologia , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Animais , AMP Cíclico/metabolismo , Cobaias , Hipocampo/efeitos dos fármacos , Imageamento por Ressonância Magnética , Masculino , Paroxetina/metabolismo , Paroxetina/farmacocinética , Pindolol/sangue , Pindolol/farmacocinética , Receptores 5-HT1 de Serotonina , Antagonistas da Serotonina/farmacocinética , Inibidores Seletivos de Recaptação de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacocinética , Fatores de Tempo , Tomografia Computadorizada de EmissãoRESUMO
The hearts of 9 to 12-weeks-old Sprague-Dawley rats were locally irradiated with a single dose of 20 Gy. The effects on myocardial norepinephrine concentrations and on alpha-adrenergic and beta-adrenergic receptor densities was examined up to 16 months post-treatment. Myocardial norepinephrine concentrations were reduced (to 50% of control values between 8 and 16 months) after irradiation. Receptor binding studies using radioactive ligands demonstrated that alpha-adrenergic receptor density was increased to maximally 210% of control values and that beta-adrenergic receptor density was increased to maximally 150% of control values, both measured at 8 months posttreatment. The affinities of both receptor types were not changed after irradiation. An inverse correlation was found between the myocardial norepinephrine concentration and the alpha-adrenergic receptor density. Myocardial norepinephrine concentration was not correlated to the beta-adrenergic receptor density. The changes in myocardial norepinephrine concentration and receptor density observed after irradiation suggest that even 16 months after irradiation overt cardiac failure was not occurring as the radiation-induced alterations differ considerably from those reported for failing hearts.
Assuntos
Coração/efeitos da radiação , Miocárdio/metabolismo , Norepinefrina/metabolismo , Receptores Adrenérgicos alfa/metabolismo , Receptores Adrenérgicos beta/metabolismo , Animais , Feminino , Ventrículos do Coração , Camundongos , Concentração Osmolar , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos alfa/efeitos da radiação , Receptores Adrenérgicos beta/efeitos da radiação , Valores de Referência , Análise de Regressão , Fatores de TempoRESUMO
The delay in clinical effects of selective serotonin reuptake inhibitors (SSRIs) suggest the existence of adaptive phenomena, such as receptor sensitivity changes. To examine the effects of repeated administration of SSRIs on serotonin neurotransmission, we investigated the effects of acute and chronic administration of the SSRI fluvoxamine on the extracellular levels of 5-HT in the median raphe nucleus and dorsal hippocampus of conscious rats by means of brain microdialysis. A single oral dose of fluvoxamine (30 mg/kg) augmented extracellular 5-HT in the median raphe and dorsal hippocampus to 270 and 191% of baseline level, respectively. Administration of fluvoxamine (30 mg/kg) or vehicle for 14 days did not affect 5-HT baseline levels. Moreover, the increase in extracellular 5-HT in the median raphe nucleus and dorsal hippocampus after an oral dose of fluvoxamine (30 mg/kg) in rats chronically treated with fluvoxamine was not different from rats treated with vehicle. Using RU 24969 as a probe for the sensitivity of the 5-HT1B autoreceptors in the dorsal hippocampus, no change in receptor sensitivity could be observed. These results demonstrate that repeated oral treatment with fluvoxamine does not affect extracellular 5-HT in the median raphe and dorsal hippocampus, suggesting that presynaptic functional changes of 5-HT in the brain areas tested are not implicated in the observed delayed onset of action of this SSRI in humans.
Assuntos
Fluvoxamina/farmacologia , Hipocampo/efeitos dos fármacos , Núcleos da Rafe/efeitos dos fármacos , Serotonina/metabolismo , Administração Oral , Animais , Cinética , Masculino , Microdiálise , Ratos , Ratos Wistar , Inibidores Seletivos de Recaptação de Serotonina/farmacologiaRESUMO
This study investigated the alterations of the 5-HT1A and 5-HT1B autoreceptor function following chronic treatment with fluvoxamine using osmotic minipumps. The 5-HT1A and 5-HT1B autoreceptor function were studied using microdialysis in the dorsal hippocampus. The effect of the 5-HT1A receptor agonist 8-OH-DPAT (0.3 mg/kg, SC) and the 5-HT1B receptor agonist RU-24969 (100 nM through the dialysis probe for 30 min) on 5-HT release was compared with rats chronically treated with saline. 8-OH-DPAT decreased 5-HT release to 55% and 60% of baseline, while RU-24969 decreased 5-HT release to 66% and 70% of baseline value in the saline and fluvoxamine group, respectively. In both cases, differences between the saline and fluvoxamine groups were not statistically significant. Plasma levels of fluvoxamine after 21 days of treatment ranged from 3 to 5 ng/ml. Fluvoxamine concentration in rat brain during treatment was estimated between 100 and 200 nM, which approximates to the IC50 value of fluvoxamine on the 5-HT transporter in synaptosomes and is 50 times higher than the Kd value for the 5-HT reuptake site. In conclusion, no evidence was found for changes in 5-HT1A,B receptor function using 8-OH-DPAT and RU-24969 as probes after continuous treatment with fluvoxamine by means of osmotic minipumps.
Assuntos
Fluvoxamina/farmacologia , Hipocampo/metabolismo , Receptores de Serotonina/efeitos dos fármacos , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Animais , Encéfalo/metabolismo , Sistemas de Liberação de Medicamentos , Fluvoxamina/administração & dosagem , Fluvoxamina/farmacocinética , Hipocampo/efeitos dos fármacos , Indóis/farmacologia , Injeções Subcutâneas , Masculino , Microdiálise , Ratos , Ratos Wistar , Receptores de Serotonina/metabolismo , Serotonina/metabolismo , Agonistas do Receptor de Serotonina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologiaRESUMO
To investigate the effect of in vivo heart irradiation on myocardial energy metabolism, we measured myocardial adenosine nucleotide concentrations and mitochondrial oxygen consumption in left ventricular tissue of rats 0-16 months after local heart irradiation (20 Gy). At 24 h and 2 months no difference in myocardial adenosine nucleotide concentration was apparent between irradiated and control hearts. The total myocardial adenosine nucleotide concentrations in irradiated hearts compared to those of nonirradiated controls tended to be lower from 4 months onward. The rate of oxidative energy production (state 3 respiration) in irradiated hearts was significantly reduced compared with that of age-matched controls from 2 months onward. Moreover, as a result of aging, a time-dependent decrease in the rate of oxidative energy production was observed in both irradiated and control hearts (P < 0.001). The respiratory control index (RCI = oxygen consumption in state 3/oxygen consumption in state 4) in irradiated hearts was not different from the RCI measured in age-matched control animals. During the period of study the RCI diminished significantly with age in both groups (P < 0.005). The number of oxygen atoms used per molecule of ADP phosphorylated (P/O ratio) was not influenced by the irradiation. The P/O ratio for the NAD(+)-linked substrates remained unchanged at a value of about 3 during the period studied. At 6 months after irradiation activities of myocardial enzymes such as lactate dehydrogenase, creatine kinase, citrate synthase, and cytochrome c oxidase were reduced. The reduction in myocardial energy production and the changes in energy supplies provide a mechanism to explain impaired contractility after local heart irradiation.
Assuntos
Metabolismo Energético/efeitos da radiação , Coração/efeitos da radiação , Miocárdio/metabolismo , Nucleotídeos de Adenina/análise , Animais , Feminino , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/efeitos da radiação , Consumo de Oxigênio/efeitos da radiação , Ratos , Ratos Sprague-DawleyRESUMO
Using brain microdialysis, it was demonstrated that the release of 5-hydroxytryptamine (5-HT) in the central nucleus of the amygdala is under inhibitory control of somatodendritic and postsynaptic 5-HT1A receptors. Systemic administration of flesinoxan, a selective 5-HT1A receptor agonist, significantly reduced the extracellular levels of 5-HT in the central nucleus of the amygdala. This effect could be completely antagonized by the 5-HT1A receptor antagonist N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)-N-(2-pyridyl)cyclohexane carboxamine trihydrochloride (WAY 100635). Local administration of these compounds by reversed microdialysis into the raphe nuclei revealed that extracellular 5-HT levels in the central nucleus of the amygdala can be regulated through 5-HT1A receptors in the caudal linear raphe nucleus, but not in the dorsal and median raphe nuclei. Interestingly, administration of flesinoxan into the central nucleus of the amygdala also decreased dialysate 5-HT levels both locally and in the caudal linear raphe nucleus. The former effect could be blocked by pretreatment with WAY 100635 when applied into the central nucleus of the amygdala, but not when applied into the caudal linear raphe nucleus. These data provide circumstantial evidence for the existence of a 5-HT1A receptor mediated feedback loop from the central nucleus of the amygdala to the caudal linear raphe nucleus.
Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Núcleos da Rafe/efeitos dos fármacos , Receptores de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/farmacologia , Serotonina/metabolismo , Tonsila do Cerebelo/metabolismo , Animais , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Piperazinas/administração & dosagem , Piperazinas/antagonistas & inibidores , Piperazinas/farmacologia , Piridinas/administração & dosagem , Núcleos da Rafe/metabolismo , Ratos , Ratos Wistar , Receptores de Serotonina/efeitos dos fármacos , Receptores 5-HT1 de Serotonina , Serotonina/análise , Antagonistas da Serotonina/administração & dosagem , Transmissão Sináptica/efeitos dos fármacos , Núcleo Inferior Caudal do Nervo Trigêmeo/efeitos dos fármacos , Núcleo Inferior Caudal do Nervo Trigêmeo/metabolismoRESUMO
Pharmacokinetic and pharmacodynamic parameters of the selective serotonin reuptake inhibitor 1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-5-phtalancarbonitril (citalopram) were determined in order to find optimal conditions for augmentation of its effect on extracellular serotonin [5-hydroxytryptamine (5-HT)] through blockade of 5-HT(1A) and 5-HT(1B) autoreceptors. Citalopram dose-dependently (0.3-10 micromol/kg s.c.) increased serotonin levels in ventral hippocampus of conscious rats. At plasma levels above approximately 0.15 microM, the effect of citalopram on extracellular 5-HT was augmented by both a 5-HT(1A) [N-[2-[4-(2-mehoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridil) cyclohexa necarboxamide trihydrochloride (Way 100635), 1 micromol/kg s.c.] and a 5-HT(1B) receptor antagonist (2'-methyl-4'-(5-methyl-[1,2, 4]oxadiazol-3-yl)biphenyl-4-carboxylic acid [4-methoxy]-3-(4-methylpiperazin-1-yl)phenyl]amide (GR 127935), 1 micromol/kg s.c.). However, at plasma levels of the selective serotonin reuptake inhibitor below 0.15 microM, the effects of the antagonists diverged viz. the 5-HT(1B) receptor antagonist was still able to potentiate citalopram's effect on extracellular 5-HT, while the 5-HT(1A) receptor antagonist was no longer effective. These results suggest that in contrast to 5-HT(1B) autoreceptors, indirect activation of 5-HT(1A) autoreceptors by citalopram is critically related to the dose of selective serotonin reuptake inhibitor administered. The latter may have consequences for selective serotonin reuptake inhibitor augmentation strategies with 5-HT(1A) receptor antagonists in the therapy of depression and anxiety disorders.
Assuntos
Citalopram/farmacologia , Oxidiazóis/farmacologia , Piperazinas/farmacologia , Piridinas/farmacologia , Receptores de Serotonina/efeitos dos fármacos , Serotoninérgicos/farmacologia , Animais , Autorreceptores/efeitos dos fármacos , Citalopram/sangue , Citalopram/farmacocinética , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Injeções Subcutâneas , Masculino , Ratos , Ratos Wistar , Receptor 5-HT1B de Serotonina , Receptores 5-HT1 de Serotonina , Serotonina/metabolismo , Fatores de TempoRESUMO
Rats were chronically treated with the selective serotonin re-uptake inhibitor citalopram [1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-5-phtalancarbonitril ], by means of osmotic minipumps. Using an infusion concentration of 50 mg/ml citalopram, steady-state plasma concentrations of approximately 0.3 mcM citalopram were maintained for 15 days. Citalopram plasma levels dropped below pharmacologically active concentrations 48 h after removal of the minipumps. Although chronic treatment with citalopram did induce an attenuated response by extracellular levels of 5-hydroxytryptamine (5-HT) after systemic administration of the 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), no effect of chronic citalopram treatment was observed when 5-HT(1B) receptor function was evaluated with a local infusion of 5-HT(1B/D) receptor agonist, sumatriptan (3-[2-dimethylamino]ethyl-N-methyl-1H-indole-5methane sulphonamide). Controversially, no augmentation of the increase of 5-HT levels was observed upon systemic administration of citalopram. It is concluded that, although chronic treatment with citalopram does induce desensitisation of 5-HT(1A) receptors, the absence of augmented effects of citalopram on 5-HT levels indicates that other mechanisms compensate for the loss of autoreceptor control.
Assuntos
Autorreceptores/efeitos dos fármacos , Citalopram/farmacocinética , Receptores de Serotonina/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/farmacocinética , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Animais , Citalopram/sangue , Bombas de Infusão , Masculino , Ratos , Ratos Wistar , Receptores 5-HT1 de Serotonina , Serotonina/metabolismo , Agonistas do Receptor de Serotonina/farmacologia , Sumatriptana/farmacologia , Fatores de TempoRESUMO
Partial purification of the dopamine D-2 receptor from bovine striatum, solubilized in the presence of 1% digitonin, was obtained by chromatography on wheat germ lectin agarose. The preparation was purified approximately 10-fold. The stability of the receptor preparation was considerably improved and non-specific protein absorption on the affinity gel used later was decreased. Further purification was achieved on a column containing a D-2-selective agonist, N-0434. Approximately 90% of the receptor activity was bound to the gel and 20-40% of the activity could be eluted by pH shock. The total purification factor after one affinity chromatography step was estimated to be at least 1500. An active preparation of at least 20% purity was obtained after a second cycle of affinity chromatography. This corresponds to an enrichment of more than 5000 times compared to the solubilized receptor preparation.
Assuntos
Corpo Estriado/metabolismo , Dopaminérgicos , Fenetilaminas , Receptores Dopaminérgicos/efeitos dos fármacos , Animais , Bovinos , Cromatografia de Afinidade , Corpo Estriado/efeitos dos fármacos , Concentração de Íons de Hidrogênio , Técnicas In Vitro , Lectinas , Proteínas do Tecido Nervoso/metabolismo , Espiperona/metabolismoRESUMO
1. The aim of the present study was to investigate the origin and modulation of 5-hydroxytryptamine release in dorsal hippocampus of freely moving rats using brain microdialysis. 2. Basal release of 5-hydroxytryptamine and 5-hydroxyindole-acetic acid was 3.0 +/- 0.2 pg/15 min and 519 +/- 18 pg/15 min, respectively. Stimulation by 60 mM K+ increased 5-hydroxytryptamine release by 66%. Inclusion of 10 microM tetrodotoxin in the perfusion medium reduced 5-hydroxytryptamine release to approximately 5% of basal levels. 3. In addition, release could be modulated by the 5-hydroxytryptamine receptor agonist 8-hydroxy-2-(di-N-propylamino)-tetralin (50 % decrease) and this effect was completely blocked by the 5-hydroxytryptamine-1 receptor antagonist pindolol. 4. These data are in concordance with results from the ventral hippocampus and indicate that release of 5-hydroxytryptamine is predominantly of neuronal origin. In contrast with other studies, the authors found the non-selective 5-hydroxytryptamine-1 antagonist, pindolol, to increase 5-hydroxytryptamine release by 65% following systemic administration. This may hint at a different autoreceptor control in serotonergic fibers ascending from the median raphe as compared to the dorsal raphe nucleus.