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1.
Behav Brain Res ; 459: 114796, 2024 02 29.
Artigo em Inglês | MEDLINE | ID: mdl-38048911

RESUMO

Exposure by women to stressors before pregnancy increases their risk of contracting prenatal depression, a condition which typically may require antidepressant treatment. And even though such perinatal antidepressant treatment is generally considered to be safe. For the mother, its effects on the development and functioning of the offspring`s brain remain unknown. In this study, we aimed to investigate the effects of pregestational chronic unpredictable stress (CUS) and perinatal bupropion on the anxiety behavior and firing activity of the dorsal raphe nucleus (DRN) serotonin (5-HT) neurons. Female rats underwent CUS for three weeks before mating. Bupropion was administered to them from gestation day ten until their offspring were weaned. Behavioral (elevated plus maze or EPM test) and neurophysiological (single-unit in vivo electrophysiology) assessments were performed on offspring who reached the age of 48-56 days. We found that maternal CUS and perinatal bupropion, as separate factors on their own, did not change offspring behavior. There was, however, an interaction between their effects on the number of entries to the open arms and time spent in the intersection: maternal CUS tended to decrease these values, and perinatal bupropion tended to diminish CUS effect. Maternal CUS increased the firing activity of 5-HT neurons in males, but not females. Perinatal bupropion did not alter the firing activity of 5-HT neurons but tended to potentiate the maternal CUS-induced increase in 5-HT neuronal firing activity. The CUS-induced increase in firing activity of 5-HT neurons might be a compensatory mechanism that diminishes the negative effects of maternal stress. Perinatal bupropion does not alter the offspring`s anxiety and firing activity of 5-HT, but it does intervene in the effects of maternal stress.


Assuntos
Bupropiona , Neurônios Serotoninérgicos , Humanos , Gravidez , Masculino , Ratos , Feminino , Animais , Lactente , Bupropiona/farmacologia , Serotonina/fisiologia , Ratos Sprague-Dawley , Núcleo Dorsal da Rafe , Ansiedade , Antidepressivos
2.
Drug Alcohol Depend ; 248: 109920, 2023 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-37224676

RESUMO

Fibroblast growth factor 2 (FGF2) is involved in the development and maintenance of the brain dopamine system. We previously showed that alcohol exposure alters the expression of FGF2 and its receptor, FGF receptor 1 (FGFR1) in mesolimbic and nigrostriatal brain regions, and that FGF2 is a positive regulator of alcohol drinking. Here, we determined the effects of FGF2 and of FGFR1 inhibition on alcohol consumption, seeking and relapse, using a rat operant self-administration paradigm. In addition, we characterized the effects of FGF2-FGFR1 activation and inhibition on mesolimbic and nigrostriatal dopamine neuron activation using in vivo electrophysiology. We found that recombinant FGF2 (rFGF2) increased the firing rate and burst firing activity of dopaminergic neurons in the mesolimbic and nigrostriatal systems and led to increased operant alcohol self-administration. In contrast, the FGFR1 inhibitor PD173074 suppressed the firing rate of these dopaminergic neurons, and reduced operant alcohol self-administration. Alcohol seeking behavior was not affected by PD173074, but this FGFR1 inhibitor reduced post-abstinence relapse to alcohol consumption, albeit only in male rats. The latter was paralleled by the increased potency and efficacy of PD173074 in inhibiting dopamine neuron firing. Together, our findings suggest that targeting the FGF2-FGFR1 pathway can reduce alcohol consumption, possibly via altering mesolimbic and nigrostriatal neuronal activity.


Assuntos
Dopamina , Fator 2 de Crescimento de Fibroblastos , Ratos , Masculino , Animais , Dopamina/metabolismo , Fator 2 de Crescimento de Fibroblastos/farmacologia , Etanol/farmacologia , Etanol/metabolismo , Consumo de Bebidas Alcoólicas/genética , Recidiva , Área Tegmentar Ventral
3.
Drug Discov Today ; 28(2): 103467, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36528281

RESUMO

Perinatal depression is the most common psychiatric complication of pregnancy, with its detrimental effects on maternal and infant health widely underrated. There is a pressing need for specific molecular biomarkers, with pregnancy-related decline in brain-derived neurotrophic factor (BDNF) in the blood and downregulation of TrkB receptor in the brain reported in clinical and preclinical studies. In this review, we explore the emerging role of BDNF in reproductive biology and discuss evidence suggesting its deficiency as a risk factor for perinatal depression. With the increasing evidence for restoration of serum BDNF levels by antidepressant therapy, the strengthening association of perinatal depression with deficiency of BDNF supports its potential as a surrogate endpoint for preclinical and clinical studies.


Assuntos
Depressão , Transtorno Depressivo , Gravidez , Feminino , Humanos , Depressão/tratamento farmacológico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Transtorno Depressivo/tratamento farmacológico , Encéfalo/metabolismo , Biomarcadores
4.
Gen Physiol Biophys ; 41(3): 255-262, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35616005

RESUMO

The concentrations of circulating glucocorticoids are regulated by their synthesis and metabolism. Cytochrome P450 (CYP), primarily expressed in the liver, is one of the main metabolizers of glucocorticoids. Since glucocorticoids, as well as monoamines, are fundamental in stress, the link between hepatic glucocorticoid metabolism and central monoamine transmission might be important in pathophysiology of stress-related disorders. We had previously reported that CYP inhibition by proadifen (SKF525) led to the inhibition of central serotonin (5-HT) neurons. The aim of this study was to investigate the effect of SKF525 on the excitability of central catecholamine neurons. Adult male Wistar rats were administered SKF525 forty-eight, twenty-four, and one hour before electrophysiological assessments. Control animals were injected saline. Rats were anesthetized with chloral hydrate and glass electrodes were inserted into the locus coeruleus (LC) or ventral tegmental area (VTA). Noradrenaline neurons of the LC and dopamine of the VTA neurons were identified, and their firing activity was recorded. It was found that the SKF525 enhanced the excitability of noradrenaline and reduced the excitability of dopamine neurons. We suggest that corticosterone-induced inhibition of 5-HT neurons underlines, at least in part, the ability of SKF525 to stimulate noradrenaline neurons. The inhibitory effect of SKF525 on dopamine neurons might be in turn secondary to the stimulatory effect of this compound on noradrenaline neurons.


Assuntos
Catecolaminas , Proadifeno , Serotonina , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Catecolaminas/metabolismo , Inibidores das Enzimas do Citocromo P-450/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Glucocorticoides/metabolismo , Masculino , Neurônios/efeitos dos fármacos , Norepinefrina/metabolismo , Proadifeno/farmacologia , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Serotonina/metabolismo
5.
Int J Mol Sci ; 22(24)2021 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-34948423

RESUMO

Depression associated with poor general medical condition, such as post-stroke (PSD) or post-myocardial infarction (PMID) depression, is characterized by resistance to classical antidepressants. Special treatment strategies should thus be developed for these conditions. Our study aims to investigate the mechanism of action of 2-morpholino-5-phenyl-6H-1,3,4-thiadiazine, hydrobromide (L-17), a recently designed thiadiazine derivative with putative neuro- and cardioprotective and antidepressant-like effects, using combined in silico (for prediction of the molecular binding mechanisms), ex vivo (for assessment of the neural excitability using c-Fos immunocytochemistry), and in vivo (for direct examination of the neuronal excitability) methodological approaches. We found that the predicted binding affinities of L-17 to serotonin (5-HT) transporter (SERT) and 5-HT3 and 5-HT1A receptors are compatible with selective 5-HT serotonin reuptake inhibitors (SSRIs) and antagonists of 5-HT3 and 5-HT1A receptors, respectively. L-17 robustly increased c-Fos immunoreactivity in the amygdala and decreased it in the hippocampus. L-17 dose-dependently inhibited 5-HT neurons of the dorsal raphe nucleus; this inhibition was partially reversed by the 5-HT1A antagonist WAY100135. We suggest that L-17 is a potent 5-HT reuptake inhibitor and partial antagonist of 5-HT3 and 5-HT1A receptors; the effects of L-17 on amygdaloid and hippocampal excitability might be mediated via 5-HT, and putatively mediate the antidepressant-like effects of this drug. Since L-17 also possesses neuro- and cardioprotective properties, it can be beneficial in PSD and PMID. Combined in silico predictions with ex vivo neurochemical and in vivo electrophysiological assessments might be a useful strategy for early assessment of the efficacy and neural mechanism of action of novel CNS drugs.


Assuntos
Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Hidrazinas/farmacologia , Infarto do Miocárdio/complicações , Acidente Vascular Cerebral/complicações , Animais , Antidepressivos/uso terapêutico , Simulação por Computador , Depressão/etiologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hidrazinas/uso terapêutico , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico , Ratos , Ratos Wistar , Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Receptores 5-HT3 de Serotonina/efeitos dos fármacos , Antagonistas do Receptor 5-HT1 de Serotonina , Antagonistas do Receptor 5-HT3 de Serotonina , Proteínas da Membrana Plasmática de Transporte de Serotonina/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia
6.
Eur Neuropsychopharmacol ; 43: 82-91, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33341344

RESUMO

Higher risk of depression and schizophrenia in descendants of mothers experienced acute infection during the pregnancy has been reported. Since monoamines are fundamental in mentioned psychopathologies, it is possible that maternal immune activation leads to impaired functioning of serotonin (5-HT), noradrenaline, and dopamine neurons in offspring. To test this hypothesis, we examined the effect of maternal immune activation by lipopolysaccharide (LPS) in rats on the excitability of monoamine-secreting neurons in the offspring. LPS was administered during days 15-19 of the gestation in the rising doses of 20-80 µg/kg; control dams received vehicle. During days 53-63 postpartum, rats were anesthetized and electrodes were inserted into the dorsal raphe nucleus, locus coeruleus, and ventral tegmental area for in vivo excitability assessment of 5-HT, noradrenaline, and dopamine neurons. Maternal immune activation suppressed the firing rate of 5-HT neurons in both sexes and stimulated the firing rate of dopamine neurons in males. Decrease in the firing rate of 5-HT neurons was accompanied with an increase, and increase in the firing rate of dopamine neurons with a decrease, in the density of spontaneously active cells. Maternal immune activation also decreased the variability of interspike intervals in 5-HT and dopamine neurons. It is possible that the alteration of excitability of 5-HT and dopamine neurons by maternal immune activation is involved in the psychopathologies induced by infectious disease during the pregnancy. Stimulation of dopamine excitability in males might be a compensatory mechanism secondary to the maternal immune challenge-induced suppression of 5-HT neurons.


Assuntos
Locus Cerúleo , Norepinefrina , Potenciais de Ação , Animais , Neurônios Dopaminérgicos , Feminino , Masculino , Gravidez , Ratos , Ratos Sprague-Dawley
7.
Gen Physiol Biophys ; 37(6): 711-713, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30431437

RESUMO

The aim of this study was to investigate the effect an inhibitor of cytochrome-P450, proadifen hydrochloride (SKF525), on the excitability of serotonin neurons. Adult male Wistar rats were administered SKF525 forty-eight, twenty-four, and one hour before electrophysiological assessments. Control animals were injected saline. Rats were anesthetized with chloral hydrate and glass electrodes were stereotaxically inserted into the dorsal raphe nucleus (DRN). Serotonin neurons were identified and their firing activity was recorded. It was found that the SKF525 inhibits the excitability of 5-HT neurons. We suggest that corticosterone might play a key role in the SKF525-induced inhibition of 5-HT neurons.


Assuntos
Encéfalo , Animais , Sistema Enzimático do Citocromo P-450 , Masculino , Neurônios , Proadifeno , Ratos , Ratos Wistar , Serotonina
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