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1.
Pharmacol Rep ; 72(2): 449-455, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32162182

RESUMO

BACKGROUND: Kynurenic acid (KYNA) is an L-tryptophan metabolite with neuromodulatory activities, regulating the release of neurotransmitters such as glutamate, dopamine (DA), and acetylcholine (Ach). Dysregulation of the kynurenine pathway has been associated with neurodegenerative, neurological, and psychological disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, major depressive disorder, and schizophrenia. METHODS: The antidepressant-like effects of KYNA were studied with a modified mouse forced swimming test (FST), and the potential involvement of the serotonin (SER), norepinephrine, DA, Ach, N-methyl-D-aspartate, or gamma-aminobutyric acid subunit A (GABAA) receptors in its antidepressant-like effect was assayed by modified combination mouse FST. In combination studies, the mice were pretreated with the respective receptor antagonist, cyproheptadine (CPH), phenoxybenzamine, yohimbine, propranolol, haloperidol (HPD), atropine, MK-801, or bicuculline (BCL). RESULTS: The FST revealed that KYNA reversed immobility, climbing, and swimming times, suggesting the antidepressant-like effects of KYNA. Furthermore, the combination studies showed that CPH prevented the antidepressant-like effects of KYNA on immobility, climbing, and swimming times, whereas HPD reduced climbing time and BCL influenced immobility and climbing times and prevented the effects of KYNA on swimming time. CONCLUSIONS: The results demonstrated, for the first time, the presence of antidepressant-like effects of KYNA in a modified mouse FST. Furthermore, modified combination FST showed that the antidepressant-like actions of KYNA strongly interacted with 5-hydroxytryptamine type 2 SER-ergic receptors, weakly interacted with D2, D3, D4 DA-ergic receptors, and interacted moderately with GABAA receptors.


Assuntos
Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Depressão/tratamento farmacológico , Ácido Cinurênico/farmacologia , Atividade Motora/efeitos dos fármacos , Natação , Animais , Antidepressivos/uso terapêutico , Depressão/metabolismo , Modelos Animais de Doenças , Ácido Cinurênico/uso terapêutico , Masculino , Camundongos Endogâmicos , Receptores Dopaminérgicos/metabolismo , Receptores de GABA-A/metabolismo , Receptores 5-HT2 de Serotonina/metabolismo
2.
Arch Pharm (Weinheim) ; 353(2): e1900218, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31782553

RESUMO

Four 2-(1H-indol-3-yl)ethylthiourea derivatives were prepared by condensation of 2-(1H-indol-3-yl)ethanamine with the corresponding aryl/alkylisothiocyanates in a medium-polarity solvent. Their structures were confirmed by spectral techniques, and the molecular structure of 3 was determined by X-ray crystal analysis. For all derivatives, the binding affinities at the 5-HT2A and 5-HT2C receptors, as well as their functional activities at the 5-HT1A and D2 receptors, were determined. The arylthioureas 1 and 4 were the most active at the 5-HT1A receptor, showing, at the same time, significant selectivity over the studied 5-HT2 and D2 receptor subtypes. The compounds were tested for their pharmacological activities within the central nervous system in relevant mouse models. The involvement of the serotonergic system in the activity of 1 and 4 was indicated. The antinociceptive action of 4 was linked to its anti-inflammatory activity.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Indóis/farmacologia , Tioureia/farmacologia , Anfetamina , Analgésicos/síntese química , Analgésicos/química , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Sítios de Ligação/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Hipercinese/induzido quimicamente , Hipercinese/tratamento farmacológico , Indóis/síntese química , Indóis/química , Masculino , Camundongos , Modelos Moleculares , Estrutura Molecular , Receptores de Dopamina D2/metabolismo , Receptores 5-HT1 de Serotonina/metabolismo , Receptores 5-HT2 de Serotonina/metabolismo , Relação Estrutura-Atividade , Tioureia/síntese química , Tioureia/química
3.
Life Sci ; 236: 116790, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31626791

RESUMO

AIMS: Although the bulk of research into the biology of serotonin 5-HT2A receptors has focused on its role in the CNS, selective activation of these receptors in peripheral tissues can produce profound anti-inflammatory effects. We previously demonstrated that the small molecule 5-HT2 receptor agonist (R)-2,5-dimethoxy-4-iodoamphetamine [(R)-DOI] inhibits TNF-α-mediated proinflammatory signaling cascades and inflammation via 5-HT2A receptor activation and prevents the development of, and inflammation associated with, acute allergic asthma in a mouse ovalbumin (OVA) model. Here, we investigated the ability of (R)-DOI to reverse inflammation and symptoms associated with established asthma in a newly developed model of chronic asthma. METHODS: An 18-week ovalbumin challenge period was performed to generate persistent, chronic asthma in BALB/c mice. Four once daily intranasal treatments of (R)-DOI were administered one week after allergen cessation, with respiratory parameters being measured by whole-body plethysmography (WBP). Cytokine and chemokine levels were measured by quantitative real-time polymerase chain reaction (qRT-PCR) in homogenized lung tissue, bronchoalveolar (BALF) fluid was analyzed for chemokine modulation by multiplex assays, and Periodic Acid-Schiff and Masson's Trichrome staining was performed to determine goblet cell infiltration and overall changes to lung morphology. KEY FINDINGS: 5-HT2 activation via (R)-DOI attenuates elevated airway hyperresponsiveness to methacholine, reduces pulmonary inflammation and mucus production, and reduces airway structural remodeling and collagen deposition by nearly 70%. SIGNIFICANCE: Overall, these data provide support for the therapeutic potential of (R)-DOI and 5-HT2 receptor activation for the treatment of asthma, and identifies (R)-DOI as a novel therapeutic compound against pulmonary fibrosis.


Assuntos
Remodelação das Vias Aéreas/efeitos dos fármacos , Anfetaminas/farmacologia , Asma/tratamento farmacológico , Pneumonia/prevenção & controle , Receptores 5-HT2 de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Remodelação das Vias Aéreas/imunologia , Animais , Asma/induzido quimicamente , Asma/imunologia , Asma/patologia , Doença Crônica , Feminino , Hipersensibilidade/imunologia , Hipersensibilidade/patologia , Hipersensibilidade/prevenção & controle , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/toxicidade , Pneumonia/imunologia , Pneumonia/patologia
4.
Neuropharmacology ; 158: 107747, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31445991

RESUMO

Alcoholics often experience hyperalgesia, especially during abstinence, yet the underlying cellular and molecular bases are unclear. Recent evidence suggests that 5-HT type 2 receptors (5-HT2Rs) at glutamatergic synapses on lateral habenula (LHb) neurons may play a critical role. We, therefore, measured paw withdrawal responses to thermal and mechanical stimuli, and alcohol intake in a rat model of intermittent drinking paradigm, as well as spontaneous glutamatergic transmission (sEPSCs), and firing of LHb neurons in brain slices. Here, we report that nociceptive sensitivity was higher in rats at 24 h withdrawal from chronic alcohol consumption than that of alcohol-naive counterparts. The basal frequency of sEPSCs and firings was higher in slices of withdrawn rats than that of Naïve rats, and 5-HT2R antagonists attenuated the enhancement. Also, an acute ethanol-induced increase of sEPSCs and firings was smaller in withdrawal than in Naïve rats; it was attenuated by 5-HT2R antagonists but mimicked by 5-HT2R agonists. Importantly, intra-LHb infusion of 5-HT2R agonists increased nociceptive sensitivity in Naïve rats, while antagonists or 5-HT reuptake blocker decreased nociceptive sensitivity and alcohol intake in withdrawn rats. Additionally, KN-62, a CaMKII inhibitor, attenuated the enhancement of EPSCs and firing induced by acute alcohol and by 5-HT2R agonist. Furthermore, intra-LHb KN-62 reduced nociceptive sensitivity and alcohol intake. Quantitative real-time PCR assay detected mRNA of 5-HT2A and 2C in the LHb. Thus adaptation in 5-HT2R-CaMKII signaling pathway contributes to the hyper-glutamatergic state, the hyperactivity of LHb neurons as well as the higher nociceptive sensitivity in rats withdrawn from chronic alcohol consumption.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Depressores do Sistema Nervoso Central/farmacologia , Etanol/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Habenula/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Nociceptividade/efeitos dos fármacos , Síndrome de Abstinência a Substâncias/metabolismo , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Depressores do Sistema Nervoso Central/efeitos adversos , Inibidores Enzimáticos/farmacologia , Etanol/efeitos adversos , Ácido Glutâmico/metabolismo , Habenula/citologia , Habenula/metabolismo , Neurônios/metabolismo , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Ratos , Receptor 5-HT2A de Serotonina/efeitos dos fármacos , Receptor 5-HT2A de Serotonina/genética , Receptor 5-HT2C de Serotonina/efeitos dos fármacos , Receptor 5-HT2C de Serotonina/genética , Receptores 5-HT2 de Serotonina/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Síndrome de Abstinência a Substâncias/etiologia
5.
J Neurochem ; 151(5): 642-655, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31325179

RESUMO

As selective serotonin reuptake inhibitors (SSRIs) are among the most commonly prescribed medications in autism, we aimed to determine whether targets for SSRIs are differentially affected in three cortical areas in children and adults with autism compared to neurotypical individuals. Utilizing a large cohort of postmortem brain tissue (n = 14-19 per group), saturation ligand binding assays were conducted on sections from the anterior cingulate cortex (ACC), posterior cingulate cortex, and fusiform gyrus (FG). Specific binding to the 5-HT transporter (5-HTT) as well as to 5-HT2 and 1A receptors (5-HT2, 5-HT1A ) was quantified in superficial and deep layers of each region using the ligands [3 H]-citalopram (5-HTT), [3 H]-ketanserin (5-HT2 ), and [3 H]-8-OH-DPAT (5-HT1A ). A Welch's t-test was utilized to compare receptor densities (Bmax ), revealing a statistically significant decrease in 5-HTT within the ACC of the entire autism cohort. There was also a decrease in 5-HT2 receptor density in the ACC in the adult cohort, but not in child postmortem autism cases as compared to controls. Comparing linear regression lines of Bmax values plotted against age, shows a significantly lower intercept for 5-HTT in autism (p = 0.025). 5-HT2 density increases with age in control cases, whereas in autism there is a decrease with age and significantly different slopes between regression lines (p = 0.032). This suggests a deficit in 5-HTT within the ACC in individuals with autism, while decreases in 5-HT2 density are age-dependent. There were no differences in receptor densities in the posterior cingulate cortex or FG in autism and no differences in ligand affinity (KD ) across all regions and ligands examined.


Assuntos
Transtorno do Espectro Autista/metabolismo , Encéfalo/metabolismo , Receptores 5-HT2 de Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores de Captação de Serotonina/farmacocinética , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Adulto Jovem
6.
Exp Gerontol ; 124: 110642, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31255734

RESUMO

INTRODUCTION: The involvement of serotonin (5-HT) in increased lower urinary tract symptoms in aging is unclear. We sought to compare voiding function and 5-HT induced detrusor contraction between young and aged rats. METHODS: This study used young (2- to 3-month-old) and aged (26- to 30-month-old) male Fischer 344 rats. 1. Rats were housed in individual metabolic cages, and then the total volume of urination, volume per micturition, voiding frequency, and voiding interval were analyzed. 2. Using urinary bladder body strips, developed tension was recorded after cumulative addition of 5-HT (1-100 nM) in the absence or presence of tetrodotoxin (1 µM), and in the presence of tetrodotoxin with ketanserin (0.3-3 µM) or naftopidil (1 and 3 µM). We examined the effects of atropine, ketanserin, and naftopidil on electrical field stimulation (EFS)-induced contraction. RESULTS: 1. Compared to young rats, aged rats exhibited decreased voiding frequency and increased volume per micturition, but total volume of urination (normalized to body weight) did not differ. Moreover, voiding interval was significantly prolonged in aged rats during the active period. 2. In the presence of tetrodotoxin, pEC50 of 5-HT were significantly lower in aged rats than in young rats (P < 0.01), but the maximal response to 5-HT was not altered in the aged bladder. Ketanserin inhibited 5-HT-induced contraction in both groups, while suppression by naftopidil was relatively limited, especially in aged rats. EFS induced neurogenic contraction in a frequency-dependent manner. Atropine-resistant contraction was not inhibited by naftopidil, but was potentiated by ketanserin. CONCLUSIONS: Urination intervals were extended in aged rats, indicating that urination rhythm changed. In the senescent rat bladder, 5-HT induced detrusor contraction, but the effect of 5-HT and the naftopidil-sensitive contractile force were weaker than those in young rats. Additionally, 5-HT did not contribute to the increase in atropine-resistant EFS-induced contractions in aged rats.


Assuntos
Contração Muscular/efeitos dos fármacos , Naftalenos/farmacologia , Piperazinas/farmacologia , Serotonina/farmacologia , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/fisiologia , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Atropina/farmacologia , Ketanserina/farmacologia , Masculino , Ratos , Ratos Endogâmicos F344 , Receptores 5-HT2 de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/farmacologia , Tetrodotoxina
7.
Diabetes ; 68(8): 1591-1603, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31127052

RESUMO

The BBSome, a complex of eight Bardet-Biedl syndrome (BBS) proteins involved in cilia function, has emerged as an important regulator of energy balance, but the underlying cellular and molecular mechanisms are not fully understood. Here, we show that the control of energy homeostasis by the anorexigenic proopiomelanocortin (POMC) neurons and orexigenic agouti-related peptide (AgRP) neurons require intact BBSome. Targeted disruption of the BBSome by Bbs1 gene deletion in POMC or AgRP neurons increases body weight and adiposity. We demonstrate that obesity in mice lacking the Bbs1 gene in POMC neurons is associated with hyperphagia. Mechanistically, we present evidence implicating the BBSome in the trafficking of G protein-coupled neuropeptide Y Y2 receptor (NPY2R) and serotonin 5-hydroxytryptamine (HT)2C receptor (5-HT2CR) to cilia and plasma membrane, respectively. Consistent with this, loss of the BBSome reduced cell surface expression of the 5-HT2CR, interfered with serotonin-evoked increase in intracellular calcium and membrane potential, and blunted the anorectic and weight-reducing responses evoked by the 5-HT2cR agonist, lorcaserin. Finally, we show that disruption of the BBSome causes the 5-HT2CR to be stalled in the late endosome. Our results demonstrate the significance of the hypothalamic BBSome for the control of energy balance through regulation of trafficking of important metabolic receptors.


Assuntos
Proteína Relacionada com Agouti/metabolismo , Peso Corporal/fisiologia , Hiperfagia/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Neurônios/metabolismo , Obesidade/metabolismo , Pró-Opiomelanocortina/metabolismo , Adiposidade/fisiologia , Animais , Cálcio/metabolismo , Linhagem Celular , Membrana Celular/metabolismo , Hiperfagia/genética , Hipotálamo/metabolismo , Camundongos , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/genética , Obesidade/genética , Transporte Proteico/fisiologia , Receptores de Neuropeptídeo Y/metabolismo , Receptores 5-HT2 de Serotonina/metabolismo
8.
Cell Rep ; 27(7): 1960-1966.e6, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31091436

RESUMO

JC polyomavirus (JCPyV) is a ubiquitous human pathogen that causes progressive multifocal leukoencephalopathy (PML). The entry receptors for JCPyV belong to the 5-hydroxytryptamine 2 receptor (5-HT2R) family, but how individual members of the family function to facilitate infection is not known. We used proximity ligation assay (PLA) to determine that JCPyV interacts with each of the 5-HT2 receptors (5-HT2Rs) in a narrow window of time during entry. We used CRISPR-Cas9 to randomly introduce stop codons in the gene for each receptor and discovered that the second intracellular loop of each was necessary for infection. This loop contains a motif possibly involved in receptor internalization by ß-arrestin. Mutation of this motif and small interfering RNA (siRNA) knockdown of ß-arrestin recapitulated the results of our CRISPR-Cas9 screen, showing that this motif is critical. Our results have implications for the role these receptors play in virus infection and for their normal functioning as receptors for serotonin.


Assuntos
Vírus JC/genética , Receptores 5-HT2 de Serotonina/genética , Receptores 5-HT2 de Serotonina/metabolismo , Receptores Virais/genética , Receptores Virais/metabolismo , Internalização do Vírus , Células HEK293 , Interações Hospedeiro-Patógeno/genética , Humanos , Vírus JC/patogenicidade , beta-Arrestinas/genética , beta-Arrestinas/metabolismo
9.
Neuropsychopharmacology ; 44(13): 2163-2173, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-30952156

RESUMO

Addiction is regarded as a disorder of inflexible choice with behavior dominated by immediate positive rewards over longer-term negative outcomes. However, the psychological mechanisms underlying the effects of self-administered drugs on behavioral flexibility are not well understood. To investigate whether drug exposure causes asymmetric effects on positive and negative outcomes we used a reversal learning procedure to assess how reward contingencies are utilized to guide behavior in rats previously exposed to intravenous cocaine self-administration (SA). Twenty-four rats were screened for anxiety in an open field prior to acquisition of cocaine SA over six daily sessions with subsequent long-access cocaine SA for 7 days. Control rats (n = 24) were trained to lever-press for food under a yoked schedule of reinforcement. Higher rates of cocaine SA were predicted by increased anxiety and preceded impaired reversal learning, expressed by a decrease in lose-shift as opposed to win-stay probability. A model-free reinforcement learning algorithm revealed that rats with high, but not low cocaine escalation failed to exploit previous reward learning and were more likely to repeat the same response as the previous trial. Eight-day withdrawal from high cocaine escalation was associated, respectively, with increased and decreased dopamine receptor D2 (DRD2) and serotonin receptor 2C (HTR2C) expression in the ventral striatum compared with controls. Dopamine receptor D1 (DRD1) expression was also significantly reduced in the orbitofrontal cortex of high cocaine-escalating rats. These findings indicate that withdrawal from escalated cocaine SA disrupts how negative feedback is used to guide goal-directed behavior for natural reinforcers and that trait anxiety may be a latent variable underlying this interaction.


Assuntos
Cocaína/administração & dosagem , Comportamento de Procura de Droga/fisiologia , Reversão de Aprendizagem/efeitos dos fármacos , Reversão de Aprendizagem/fisiologia , Recompensa , Animais , Condicionamento Operante/efeitos dos fármacos , Masculino , Modelos Neurológicos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ratos , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores 5-HT2 de Serotonina/metabolismo , Estriado Ventral/efeitos dos fármacos , Estriado Ventral/metabolismo
10.
Brain Res ; 1715: 21-26, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-30880116

RESUMO

Lower urinary tract (LUT) dysfunction is the most common complication of diabetes mellitus (DM). An involvement of the 5-HT2A receptor in spinal micturition control has been demonstrated in urethane anaesthetized DM rats in which i.v. administration of the 5-HT2A/2C receptor agonist 2,5-methoxy-4-iodoamphetamine (DOI), stimulated high frequency oscillations (HFOs) and improved micturition. However, the mechanisms involved in these effects are not completely understood. The present work showed that 5-HT2A and -2C receptors were upregulated in lumbosacral cord motoneurons, and the number of serotonergic paraneurons were downregulated in the urethra in DM group. The importance of the downregulation of urethral paraneurons in DM remains to be elucidated but may be related to the reduced urethral sensation caused by the disease. We suggest that targets of 5-HT receptor agonists for improvement of voiding function may be found both in the LUT and lumbosacral spinal cord.


Assuntos
Diabetes Mellitus Experimental/fisiopatologia , Receptores 5-HT2 de Serotonina/metabolismo , Animais , Diabetes Mellitus Experimental/metabolismo , Feminino , Região Lombossacral/fisiopatologia , Neurônios Motores/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT2C de Serotonina/metabolismo , Receptores 5-HT2 de Serotonina/genética , Neurônios Serotoninérgicos/metabolismo , Serotonina/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Medula Espinal/efeitos dos fármacos , Estreptozocina/farmacologia , Ativação Transcricional/efeitos dos fármacos , Uretra/fisiopatologia , Bexiga Urinária/fisiopatologia
11.
PLoS One ; 14(1): e0209804, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30629611

RESUMO

The last fifteen years have seen the emergence and overflow into the drug scene of "superpotent" N-benzylated phenethylamines belonging to the "NBOMe" series, accompanied by numerous research articles. Although N-benzyl substitution of 5-methoxytryptamine is known to increase its affinity and potency at 5-HT2 receptors associated with psychedelic activity, N-benzylated tryptamines have been studied much less than their phenethylamine analogs. To further our knowledge of the activity of N-benzyltryptamines, we have synthesized a family of tryptamine derivatives and, for comparison, a few 5-methoxytryptamine analogs with many different substitution patterns on the benzyl moiety, and subjected them to in vitro affinity and functional activity assays vs. the human 5-HT2 receptor subtypes. In the binding (radioligand displacement) studies some of these compounds exhibited only modest selectivity for either 5-HT2A or 5-HT2C receptors suggesting that a few of them, with affinities in the 10-100 nanomolar range for 5-HT2A receptors, might presumably be psychedelic. Unexpectedly, their functional (calcium mobilization) assays reflected very different trends. All of these compounds proved to be 5-HT2C receptor full agonists while most of them showed low efficacy at the 5-HT2A subtype. Furthermore, several showed moderate-to-strong preferences for activation of the 5-HT2C subtype at nanomolar concentrations. Thus, although some N-benzyltryptamines might be abuse-liable, others might represent new leads for the development of therapeutics for weight loss, erectile dysfunction, drug abuse, or schizophrenia.


Assuntos
Receptores 5-HT2 de Serotonina/metabolismo , Triptaminas/farmacologia , 5-Metoxitriptamina/análogos & derivados , 5-Metoxitriptamina/farmacologia , Animais , Compostos de Benzil/farmacologia , Células CHO , Cricetulus , Células HeLa , Humanos , Estrutura Molecular , Fenetilaminas , Ensaio Radioligante , Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT2C de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Triptaminas/síntese química
12.
PLoS One ; 14(1): e0203980, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30695038

RESUMO

Despite the conserved function of aggression across taxa in obtaining critical resources such as food and mates, serotonin's (5-HT) modulatory role on aggressive behavior appears to be largely inhibitory for vertebrates but stimulatory for invertebrates. However, critical gaps exist in our knowledge of invertebrates that need to be addressed before definitively stating opposing roles for 5-HT and aggression. Specifically, the role of 5-HT receptor subtypes are largely unknown, as is the potential interactive role of 5-HT with other neurochemical systems known to play a critical role in aggression. Similarly, the influence of these systems in driving sex differences in aggressive behavior of invertebrates is not well understood. Here, we investigated these questions by employing complementary approaches in a novel invertebrate model of aggression, the stalk-eyed fly. A combination of altered social conditions, pharmacological manipulation and 5-HT2 receptor knockdown by siRNA revealed an inhibitory role of this receptor subtype on aggression. Additionally, we provide evidence for 5-HT2's involvement in regulating neuropeptide F activity, a suspected inhibitor of aggression. However, this function appears to be stage-specific, altering only the initiation stage of aggressive conflicts. Alternatively, pharmacologically increasing systemic concentrations of 5-HT significantly elevated the expression of the neuropeptide tachykinin, which did not affect contest initiation but instead promoted escalation via production of high intensity aggressive behaviors. Notably, these effects were limited solely to males, with female aggression and neuropeptide expression remaining unaltered by any manipulation that affected 5-HT. Together, these results demonstrate a more nuanced role for 5-HT in modulating aggression in invertebrates, revealing an important interactive role with neuropeptides that is more reminiscent of vertebrates. The sex-differences described here also provide valuable insight into the evolutionary contexts of this complex behavior.


Assuntos
Agressão/fisiologia , Comportamento Animal/fisiologia , Dípteros/fisiologia , Caracteres Sexuais , 5-Hidroxitriptofano/administração & dosagem , 5-Hidroxitriptofano/farmacologia , Agressão/efeitos dos fármacos , Animais , Técnicas de Observação do Comportamento/métodos , Comportamento Animal/efeitos dos fármacos , Feminino , Técnicas de Silenciamento de Genes , Masculino , Modelos Animais , Neuropeptídeos/metabolismo , RNA Interferente Pequeno/metabolismo , Receptores 5-HT2 de Serotonina/genética , Receptores 5-HT2 de Serotonina/metabolismo , Serotonina/metabolismo , Taquicininas/metabolismo
13.
Am J Physiol Endocrinol Metab ; 316(1): E1-E15, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29969315

RESUMO

Since the serendipitous discovery of the first antipsychotic (AP) drug in the 1950s, APs remain the cornerstone of treatment for schizophrenia. A shift over the past two decades away from first-generation, conventional APs to so-called "atypical" (or 2nd/3rd generation) APs parallels acknowledgment of serious metabolic side-effects associated in particular with these newer agents. As will be reviewed, AP drugs and type 2 diabetes are now inextricably linked, contributing to the three- to fivefold increased risk of type 2 diabetes observed in schizophrenia. However, this association is not straightforward. Biological and lifestyle-related illness factors contribute to the association between type 2 diabetes and metabolic disease independently of AP treatment. In addition, APs have a well-established weight gain propensity which could also account for elevated risk of insulin resistance and type 2 diabetes. However, compelling preclinical and clinical evidence now suggests that these drugs can rapidly and directly influence pathways of glucose metabolism independently of weight gain and even in absence of psychiatric illness. Mechanisms of these direct effects remain poorly elucidated but may involve central and peripheral antagonism of neurotransmitters implicated not only in the therapeutic effects of APs but also in glucose homeostasis, possibly via effects on the autonomic nervous system. The clinical relevance of studying "direct" effects of these drugs on glucose metabolism is underscored by the widespread use of these medications, both on and off label, for a growing number of mental illnesses, extending safety concerns well beyond schizophrenia.


Assuntos
Antipsicóticos/uso terapêutico , Diabetes Mellitus Tipo 2/metabolismo , Glucose/metabolismo , Esquizofrenia/tratamento farmacológico , Animais , Sistema Nervoso Autônomo/metabolismo , Clozapina/uso terapêutico , Diabetes Mellitus Tipo 2/epidemiologia , Técnica Clamp de Glucose , Humanos , Resistência à Insulina , Receptores de Dopamina D2/metabolismo , Receptores 5-HT2 de Serotonina/metabolismo , Ganho de Peso
14.
Drug Metab Dispos ; 47(2): 80-85, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30518657

RESUMO

Our recent study carried out after local injection of the serotonergic neurotoxin 5,7-dihydroxytryptamine into the arcuate nucleus (ARC) of the hypothalamus suggested a positive influence of the serotonergic innervation of the ARC on growth hormone (GH) secretion and GH-dependent expression of cytochrome P450. The aim of our present study was to determine the effect of the activation of the serotonin (5-HT)-type receptors, 5-HT1 or 5-HT2, in the ARC on the expression and activity of cytochrome P450 in the liver of male rats. The serotonergic agonist 5-carboxyamidotryptamine [(5-CT), a 5-HT1-type receptor agonist] or 2,5-dimethoxy-4-iodoamphetamine [(DOI), a 5-HT2-type receptor agonist] was injected into the ARC for 5 days. The activity and expression of cytochrome P450 isoenzymes and the levels of serum and pituitary hormones were estimated. DOI significantly increased the activity and expression (both mRNA and protein levels) of CYP2C11, CYP3A1/23, and CYP3A2, which positively correlated with an increase in the pituitary growth hormone-releasing hormone (GHRH) and serum GH level. The injection of 5-CT into the ARC did not affect the activity of liver P450 enzymes or hormone levels. The obtained results indicate that 5-HT2, but not the 5-HT1-type receptors in the ARC, are engaged in the positive neuroendocrine regulation of cytochrome P450, possibly by the stimulation of hypothalamic GHRH release and pituitary GH secretion, and an increase in the serum GH concentration. Further studies are going to identify which of the 5-HT2 receptor subtypes (5-HT2A, 5-HT2B, or 5-HT2C) is responsible for the observed neuroendocrine regulation of cytochrome P450.


Assuntos
Núcleo Arqueado do Hipotálamo/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Fígado/metabolismo , Receptores 5-HT2 de Serotonina/metabolismo , Transdução de Sinais/fisiologia , Animais , Sistema Enzimático do Citocromo P-450/genética , Hormônio do Crescimento/sangue , Hormônio do Crescimento/metabolismo , Hormônio Liberador de Hormônio do Crescimento/metabolismo , Sistema Hipotálamo-Hipofisário/fisiologia , Masculino , Hipófise/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Transdução de Sinais/efeitos dos fármacos
15.
Mol Brain ; 11(1): 65, 2018 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-30400993

RESUMO

Visual cortical areas show enhanced tactile responses in blind individuals, resulting in improved behavioral performance. Induction of unilateral vision loss in adult mice, by monocular enucleation (ME), is a validated model for such cross-modal brain plasticity. A delayed whisker-driven take-over of the medial monocular zone of the visual cortex is preceded by so-called unimodal plasticity, involving the potentiation of the spared-eye inputs in the binocular cortical territory. Full reactivation of the sensory-deprived contralateral visual cortex is accomplished by 7 weeks post-injury. Serotonin (5-HT) is known to modulate sensory information processing and integration, but its impact on cortical reorganization after sensory loss, remains largely unexplored. To address this issue, we assessed the involvement of 5-HT in ME-induced cross-modal plasticity and the 5-HT receptor (5-HTR) subtype used. We first focused on establishing the impact of ME on the total 5-HT concentration measured in the visual cortex and in the somatosensory barrel field. Next, the changes in expression as a function of post-ME recovery time of the monoamine transporter 2 (vMAT2), which loads 5-HT into presynaptic vesicles, and of the 5-HTR1A and 5-HTR3A were assessed, in order to link these temporal expression profiles to the different types of cortical plasticity induced by ME. In order to accurately pinpoint which 5-HTR exactly mediates ME-induced cross-modal plasticity, we pharmacologically antagonized the 5-HTR1A, 5-HTR2A and 5-HTR3A subtypes. This study reveals brain region-specific alterations in total 5-HT concentration, time-dependent modulations in vMAT2, 5-HTR1A and 5-HTR3A protein expression and 5-HTR antagonist-specific effects on the post-ME plasticity phenomena. Together, our results confirm a role for 5-HTR1A in the early phase of binocular visual cortex plasticity and suggest an involvement of 5-HTR2A and 5-HTR3A but not 5-HTR1A during the late cross-modal recruitment of the medial monocular visual cortex. These insights contribute to the general understanding of 5-HT function in cortical plasticity and may encourage the search for improved rehabilitation strategies to compensate for sensory loss.


Assuntos
Envelhecimento/fisiologia , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Córtex Visual/fisiopatologia , Animais , Modelos Animais de Doenças , Enucleação Ocular , Feminino , Masculino , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/efeitos dos fármacos , Receptor 5-HT1A de Serotonina/metabolismo , Receptores 5-HT2 de Serotonina/metabolismo , Receptores 5-HT3 de Serotonina/metabolismo , Serotonina/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Fatores de Tempo , Proteínas Vesiculares de Transporte de Monoamina/metabolismo , Córtex Visual/efeitos dos fármacos
16.
Proc Natl Acad Sci U S A ; 115(43): E10245-E10254, 2018 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-30297392

RESUMO

Autism spectrum disorder (ASD) is a common neurobehavioral disorder with limited treatment options. Activation of p38 MAPK signaling networks has been identified in ASD, and p38 MAPK signaling elevates serotonin (5-HT) transporter (SERT) activity, effects mimicked by multiple, hyperfunctional SERT coding variants identified in ASD subjects. Mice expressing the most common of these variants (SERT Ala56) exhibit hyperserotonemia, a biomarker observed in ASD subjects, as well as p38 MAPK-dependent SERT hyperphosphorylation, elevated hippocampal 5-HT clearance, hypersensitivity of CNS 5-HT1A and 5-HT2A/2C receptors, and behavioral and gastrointestinal perturbations reminiscent of ASD. As the α-isoform of p38 MAPK drives SERT activation, we tested the hypothesis that CNS-penetrant, α-isoform-specific p38 MAPK inhibitors might normalize SERT Ala56 phenotypes. Strikingly, 1-week treatment of adult SERT Ala56 mice with MW150, a selective p38α MAPK inhibitor, normalized hippocampal 5-HT clearance, CNS 5-HT1A and 5-HT2A/2C receptor sensitivities, social interactions, and colonic motility. Conditional elimination of p38α MAPK in 5-HT neurons of SERT Ala56 mice restored 5-HT1A and 5-HT2A/2C receptor sensitivities as well as social interactions, mirroring effects of MW150. Our findings support ongoing p38α MAPK activity as an important determinant of the physiological and behavioral perturbations of SERT Ala56 mice and, more broadly, supports consideration of p38α MAPK inhibition as a potential treatment for core and comorbid phenotypes present in ASD subjects.


Assuntos
Encéfalo/metabolismo , Trato Gastrointestinal/metabolismo , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Receptores 5-HT2 de Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Serotonina/metabolismo , Animais , Transtorno do Espectro Autista/metabolismo , Masculino , Camundongos , Fenótipo , Transdução de Sinais/fisiologia
17.
Cell Physiol Biochem ; 48(6): 2409-2428, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30121645

RESUMO

BACKGROUND/AIMS: Previously, we confirmed that liver-synthesized 5-HT rather than non-liver 5-HT, acting on the 5-HT2 receptor (5-HT2R), modulates lipid-induced excessive lipid synthesis (ELS). Here, we further revealed the effects of the hepatocellular 5-HT system in diabetes-related disorders. METHODS: Studies were conducted in male ICR mice, human HepG2 cells, and primary mouse hepatocytes (PMHs) under gene or chemical inhibition of the 5-HT system, key lipid metabolism, and inflammation-related factors. Protein and messenger RNA expression and levels of the factors were determined via western blotting, reverse transcription PCR, and quantitative assay kits, respectively. Hepatic steatosis with inflammation and fibrosis, intracellular lipid droplet accumulation (LDA), and reactive oxygen species (ROS) location were determined via hematoxylin and eosin, Masson's trichrome, Oil red O, and fluorescent-specific staining, respectively. RESULTS: Palmitic acid induced the activation of the 5-HT system: the activation of 5-HT2R, primarily 5-HT2AR, in addition to upregulating monoamine oxidase A (MAO-A) expression and 5-HT synthesis, by activating the G protein/ phospholipase C pathway modulated PKCε activation, resulting in ELS with LDA; the activation of NF-κB, which mediates the generation of pro-inflammatory cytokines, was primarily due to ROS generation in the mitochondria induced by MAO-A-catalyzed 5-HT degradation, and secondarily due to the activation of PKCε. These effects of the 5-HT system were also detected in palmitic acid- or high glucose-treated PMHs and regulated multiple inflammatory signaling pathways. In diabetic mice, co-treatment with antagonists of both 5-HT synthesis and 5-HT2R significantly abolished hepatic steatosis, inflammation, and fibrosis as well as hyperglycemia and dyslipidemia. CONCLUSION: Activation of the hepatocellular 5-HT system plays a crucial role in inducing diabetes-related hepatic dysfunction and is a potential therapeutic target.


Assuntos
Citocinas/metabolismo , Receptores 5-HT2 de Serotonina/metabolismo , Serotonina/metabolismo , Animais , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/antagonistas & inibidores , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Células Hep G2 , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Monoaminoxidase/química , Monoaminoxidase/genética , Monoaminoxidase/metabolismo , Ácido Palmítico/farmacologia , Proteína Quinase C-épsilon/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores 5-HT2 de Serotonina/química , Receptores 5-HT2 de Serotonina/genética , Serotonina/farmacologia , Triptofano Hidroxilase/antagonistas & inibidores , Triptofano Hidroxilase/genética , Triptofano Hidroxilase/metabolismo
18.
eNeuro ; 5(4)2018.
Artigo em Inglês | MEDLINE | ID: mdl-30073196

RESUMO

A developing brain shows intense reorganization and heightened neuronal plasticity allowing for environmental modulation of its development. During early life, maternal care is a key factor of this environment and defects in this care can derail adaptive brain development and may result in susceptibility to neuropsychiatric disorders. Nevertheless, the mechanisms by which those maternal interactions immediately impact the offspring's brain activity to initiate the pathway to pathology are not well understood. We do know that multiple neurotransmitter systems are involved, including the serotonergic system, a key neuromodulator involved in brain development and emotional regulation. We tested the importance of the serotonergic system and pups' immediate neural response to maternal presence using wireless electrophysiological recordings, a novel approach allowing us to record neural activity during pups' interactions with their mother. We found that maternal contact modulates the P10-P12 rat pups' anterior cingulate cortex (ACC) activity by notably increasing local-field potential (LFP) power in low-frequency bands. We demonstrated, by blocking serotonergic receptors, that this increase is mediated through 5-HT2 receptors (5-HT2Rs). Finally, we showed in isolated pups that enhancing serotonergic transmission, using a selective-serotonin-reuptake-inhibitor, is sufficient to enhance LFP power in low-frequency bands in a pattern similar to that observed when the mother is in the nest. Our results highlight a significant contribution of the serotonergic system in mediating changes of cortical activity in pups related to maternal presence.


Assuntos
Comportamento Animal/fisiologia , Eletroencefalografia/métodos , Giro do Cíngulo/fisiologia , Comportamento Materno/fisiologia , Potenciais da Membrana/fisiologia , Plasticidade Neuronal/fisiologia , Córtex Pré-Frontal/fisiologia , Receptores 5-HT2 de Serotonina/metabolismo , Serotonina/metabolismo , Transdução de Sinais/fisiologia , Animais , Ondas Encefálicas/fisiologia , Feminino , Giro do Cíngulo/metabolismo , Masculino , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Long-Evans , Serotoninérgicos/farmacologia
19.
Eur Neuropsychopharmacol ; 28(9): 1035-1046, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30006253

RESUMO

One of the major challenges of cross-species translation in psychiatry is the identification of quantifiable brain phenotypes linked to drug efficacy and/or side effects. A measure that has received increasing interest is the effect of antipsychotic drugs on resting-state functional connectivity (FC) in magnetic resonance imaging. However, quantitative comparisons of antipsychotic drug-induced alterations of FC patterns are missing. Consideration of receptor binding affinities provides a means for the effects of antipsychotic drugs on extended brain networks to be related directly to their molecular mechanism of action. Therefore, we examined the relationship between the affinities of three second-generation antipsychotics (amisulpride, risperidone and olanzapine) to dopamine and serotonin receptors and FC patterns related to the prefrontal cortex (PFC) and striatum in Sprague-Dawley rats. FC of the relevant regions was quantified by correlation coefficients and local network properties. Each drug group (32 animals per group) was subdivided into three dose groups and a vehicle control group. A linear relationship was discovered for the mid-dose of antipsychotic compounds, with stronger affinity to serotonin 5-HT2A, 5-HT2C and 5-HT1A receptors and decreased affinity to D3 receptors associated with increased prefrontal-striatal FC (p = 0.0004, r²â€¯= 0.46; p = 0.004, r²â€¯= 0.33; p = 0.002, r²â€¯= 0.37; p = 0.02, r²â€¯= 0.22, respectively). Interestingly, no correlation was observed for the low and high dose groups, and for D2 receptors. Our results indicate that drug-induced FC patterns may be linked to antipsychotic mechanism of action on the molecular level and suggest the technique's value for drug development, especially if our results are extended to a larger number of antipsychotics.


Assuntos
Antipsicóticos/farmacologia , Corpo Estriado/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Receptores Dopaminérgicos/metabolismo , Receptores 5-HT2 de Serotonina/metabolismo , Amissulprida/farmacologia , Animais , Corpo Estriado/fisiologia , Relação Dose-Resposta a Droga , Imagem por Ressonância Magnética , Masculino , Vias Neurais/fisiologia , Neuroimagem , Olanzapina/farmacologia , Córtex Pré-Frontal/fisiologia , Ensaio Radioligante/estatística & dados numéricos , Ratos , Risperidona/farmacologia
20.
Pharmacol Biochem Behav ; 171: 74-84, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29944910

RESUMO

Appetitive aspect of rat maternal behavior, such as pup retrieval, is motivationally driven and sensitive to dopamine disturbances. Activation or blockade of dopamine D2 receptors causes a similar disruption of pup retrieval, which may also reflect an increase in maternal anxiety and/or a disruption of executive function. Recent work indicates that serotonin 5-HT2A receptors also play an important role in rat maternal behavior. Given the well-known modulation of 5-HT2A on the mesolimbic and mesocortical dopamine functions, the present study examined the extent to which blockade of 5-HT2A receptors on dopamine D2-mediated maternal effects using a pup retrieval on the elevated plus maze (EPM) test. Sprague-Dawley postpartum female rats were acutely injected with quinpirole (a D2 agonist, 0.10 and 0.25 mg/kg, sc), or haloperidol (a D2 antagonist, 0.1 or 0.2 mg/kg, sc), in combination of MDL100907 (a 5-HT2A receptor antagonist, 1.0 mg/kg, sc, 30 min before quinpirole or haloperidol injection) or saline and tested at 30, 90 and 240 min after quinpirole or haloperidol injection on postpartum days 3 and 7. Quinpirole and haloperidol decreased the number of pup retrieved (an index of maternal motivation) and sequential retrieval score (an index of executive function), prolonged the pup retrieval latencies, reduced the percentage of time spent on the open arms (an index of maternal anxiety), and decreased the distance travelled on the maze in a dose-dependent and time-dependent fashion. MDL100907 treatment by itself had no effect on pup retrieval, but it exacerbated the quinpirole-induced disruption of pup retrieval, but had no effect on the haloperidol-induced one. These findings suggest a complex interactive effect between 5-HT2A and D2 receptors on one or several maternal processes (maternal motivation, anxiety and executive function), and support the idea that one molecular mechanism by which 5-HT2A receptors mediate maternal behavior is through its modulation of D2 receptors.


Assuntos
Antagonistas dos Receptores de Dopamina D2/farmacologia , Comportamento Materno/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Receptores de Dopamina D2/agonistas , Receptores 5-HT2 de Serotonina/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Animais , Relação Dose-Resposta a Droga , Interações Medicamentosas , Feminino , Fluorbenzenos/farmacologia , Haloperidol/farmacologia , Masculino , Piperidinas/farmacologia , Quimpirol/farmacologia , Ratos , Fatores de Tempo
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