RESUMO
In the present studies, we assessed the effect of the 5-HT1A receptor (R) agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on motor and exploratory behaviors, object and place recognition and dopamine transporter (DAT) and serotonin transporter (SERT) binding in the rat brain. In Experiment I, motor/exploratory behaviors were assessed in an open field after injection of either 8-OH-DPAT (0.1 and 3 mg/kg) or vehicle for 30 min without previous habituation to the open field. In Experiment II, rats underwent a 5-min exploration trial in an open field with two identical objects. After injection of either 8-OH-DPAT (0.1 and 3 mg/kg) or vehicle, rats underwent a 5-min test trial with one of the objects replaced by a novel one and the other object transferred to a novel place. Subsequently, N-o-fluoropropyl-2b-carbomethoxy-3b-(4-[123I]iodophenyl)-nortropane ([123I]FP-CIT; 11 ± 4 MBq) was injected into the tail vein. Regional radioactivity accumulations were determined post mortem with a well counter. In both experiments, 8-OH-DPAT dose-dependently increased ambulation and exploratory head-shoulder motility, whereas rearing was dose-dependently decreased. In the test rial of Experiment II, there were no effects of 8-OH-DPAT on overall activity, sitting and grooming. 8-OH-DPAT dose-dependently impaired recognition of object and place. 8-OH-DPAT (3 mg/kg) increased DAT binding in the dorsal striatum relative to both vehicle and 0.1 mg/kg 8-OH-DPAT. Furthermore, in the ventral striatum, DAT binding was decreased after 3 mg/kg 8-OH-DPAT relative to vehicle. Findings indicate that motor/exploratory behaviors, memory for object and place and regional dopamine function may be modulated by the 5-HT1AR. Since, after 8-OH-DPAT, rats exhibited more horizontal and less (exploratory) vertical motor activity, while overall activity was not different between groups, it may be inferred, that the observed impairment of object recognition was not related to a decrease of motor activity as such, but to a decrease of intrinsic motivation, attention and/or awareness, which are relevant accessories of learning. Furthermore, the present findings on 8-OH-DPAT action indicate associations not only between motor/exploratory behavior and the recognition of object and place but also between the respective parameters and the levels of available DA in dorsal and ventral striatum.
Assuntos
Receptor 5-HT1A de Serotonina , Estriado Ventral , Ratos , Animais , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Dopamina , Agonistas do Receptor de Serotonina/farmacologiaRESUMO
Neuropathic pain is a well-documented phenomenon in experimental and clinical diabetes; however, current treatment is unsatisfactory. Serotoninergic-containing neurons are key components of the descending autoinhibitory pathway, and a decrease in their activity may contribute at least in part to diabetic neuropathic pain (DNP). A streptozotocin (STZ)-treated rat was used as a model for type 1 diabetes mellitus (T1DM). Pain transmission was evaluated using well-established nociceptive-based techniques, including the Hargreaves apparatus, cold plate and dynamic plantar aesthesiometer. Using qRT-PCR, Western blotting, immunohistochemistry, and HPLC-based techniques, we also measured in the central nervous system and peripheral nervous system of diabetic animals the expression and localization of 5-HT1A receptors (5-HT1AR), levels of key enzymes involved in the synthesis and degradation of tryptophan and 5-HT, including tryptophan hydroxylase-2 (Tph-2), tryptophan 2,3-dioxygenase (Tdo), indoleamine 2,3-dioxygenase 1 (Ido1) and Ido2. Moreover, spinal concentrations of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA, a metabolite of 5-HT) and quinolinic acid (QA, a metabolite of tryptophan) were also quantified. Diabetic rats developed thermal hyperalgesia and cold/mechanical allodynia, and these behavioral abnormalities appear to be associated with the upregulation in the levels of expression of critical molecules related to the serotoninergic nervous system, including presynaptic 5-HT1AR and the enzymes Tph-2, Tdo, Ido1 and Ido2. Interestingly, the level of postsynaptic 5-HT1AR remains unaltered in STZ-induced T1DM. Chronic treatment of diabetic animals with 8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT), a selective 5-HT1AR agonist, downregulated the upregulation of neuronal presynaptic 5-HT1AR, increased spinal release of 5-HT (↑ 5-HIAA/5-HT) and reduced the concentration of QA, decreased mRNA expression of Tdo, Ido1 and Ido2, arrested neuronal degeneration and ameliorated pain-related behavior as exemplified by thermal hyperalgesia and cold/mechanical allodynia. These data show that 8-OH-DPAT alleviates DNP and other components of the serotoninergic system, including the ratio of 5-HIAA/5-HT and 5-HT1AR, and could be a useful therapeutic agent for managing DNP.
Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Neuropatias Diabéticas , Neuralgia , Animais , Ratos , Hiperalgesia/etiologia , Diabetes Mellitus Tipo 1/complicações , Triptofano , 8-Hidroxi-2-(di-n-propilamino)tetralina , Ácido Hidroxi-Indolacético , Serotonina , Neuropatias Diabéticas/genética , Neuralgia/etiologia , Triptofano OxigenaseRESUMO
The effect of 5-HT1A receptor agonist 8-OH-DPAT (intraperitoneal injection in doses of 1, 2, and 4 mg/kg) on spontaneous alternation behavior of mice in Y-maze was studied without and with habituation procedure and food reward. In the first case, 8-OH-DPAT administration led to a decrease in spontaneous alternation and locomotor activity in mice. At the same time, 8-OH-DPAT treatment after habituation and food deprivation increased repeated choices of goal arms without affecting locomotor activity, which was consistent with perseverative behavior. 8-OH-DPAT-induced decrease in spontaneous alternation behavior in Y-maze in mice with habituation and food reward is the most suitable procedure for experimental modeling of the perseverative behavior and studying the anticompulsive activity of new substances.
Assuntos
Agonistas do Receptor de Serotonina , Camundongos , Animais , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Agonistas do Receptor de Serotonina/farmacologiaRESUMO
Understanding the neurobiological mechanisms of drug-related learning and memory formation may help the treatment of cognitive disorders. Dysfunction of the cannabinoid and serotonergic systems has been demonstrated in learning and memory disorders. The present paper investigates the phenomenon called state-dependent memory (SDM) induced by ACPA (a selective cannabinoid CB1 receptor agonist) and 8-OH-DPAT (a nonselective 5-HT1A receptor agonist) with special focus on the role of the 5-HT1A receptor in the effects of both ACPA and 8-OH-DPAT SDM and cross state-dependent memory retrieval between ACPA and 8-OH-DPAT in a step-down inhibitory avoidance task. The dorsal hippocampal CA1 regions of adult male NMRI mice were bilaterally cannulated, and all drugs were microinjected into the intended injection sites. A single-trial step-down inhibitory avoidance task was used to assess memory retrieval and state-dependence. Post-training and/or pre-test microinjections of ACPA (1 and 2 ng/mouse) and 8-OH-DPAT (0.5 and 1 µg/mouse) dose-dependently induced amnesia. Pre-test administration of the same doses of ACPA and 8-OH-DPAT reversed the post-training ACPA- and 8-OH-DPAT-induced amnesia, respectively. This phenomenon has been named SDM. 8-OH-DPAT (1 µg/mouse) reversed the amnesia induced by ACPA (0.5, 1, and 2 ng/mouse) and induced ACPA SDM. ACPA (2 ng/mouse) reversed the amnesia induced by 8-OH-DPAT (0.25, 0.5, and 1 µg/mouse) and induced 8-OH-DPAT SDM. Pre-test administration of a 5-HT1A receptor antagonist, (S)-WAY 100,135 (0.25 and 0.5 µg/mouse), 5 min before ACPA and 8-OH-DPAT dose-dependently inhibited ACPA- and 8-OH-DPAT-induced SDM, respectively. The present study results demonstrated ACPA- and 8-OH-DPAT- induced SDM. Overall, the data revealed that dorsal hippocampal 5-HT1A receptor mechanisms play a pivotal role in modulating cross state-dependent memory retrieval between ACPA and 8-OH-DPAT.
Assuntos
Canabinoides , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Amnésia/induzido quimicamente , Animais , Aprendizagem da Esquiva , Agonistas de Receptores de Canabinoides/farmacologia , Hipocampo , Masculino , Camundongos , Receptor CB1 de Canabinoide , Receptor 5-HT1A de SerotoninaRESUMO
Severe aggressive behavior of juvenile pufferfish affects economic efficiency and fish welfare in aquaculture. 5-HT plays an important role in regulating the aggressive behavior of fish in aquaculture environment. This study examined the effects of different concentrations (0, 0.25, 0.5, 1 mg/kg) of 8-OH-DPAT, a selective 5-HT1A receptor agonist, on the aggressive behavior of juvenile pufferfish. Forty-five minutes after drug injection, the aggressive behavior of juvenile fish was recorded for 20 min, including the latency to the first attack and the frequency of aggressive behaviors. The results showed no significant differences in the latency to the first attack of juvenile fish among treatment groups. During the first 10 min of the observation period, there was no significant difference in the total aggressive acts and locomotor activity among treatment groups. Total aggressive acts and locomotor activity were the least in the 1 mg/kg 8-OH-DPAT-treated during the 20 min observation period. Both aggressive behavior and locomotor activity were negatively correlated with 8-OH-DPAT treatment overall, respectively. The above results suggested that the serotonergic system activation had suppressive effects on aggressive behavior and locomotor activity in juvenile pufferfish.
Assuntos
Receptor 5-HT1A de Serotonina , Takifugu , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Agressão/fisiologia , Animais , Humanos , Agonistas do Receptor de Serotonina/farmacologiaRESUMO
The neurotransmitter serotonin (5-HT) reduces aggressive behaviour in a number of vertebrates, and the 5-HT1A receptor is known to be involved in this regulation. However, the role of this receptor in the modulation of sociopositive behaviour remains largely unknown. Here we investigated the role of the 5-HT1A receptor in the regulation of aggressive, submissive and affiliative behaviour in the cooperatively-breeding cichlid Neolamprologus pulcher. In two experiments, we performed intramuscular injections of a 5-HT1A agonist (8-OH-DPAT) and antagonist (Way-100635) followed by recordings of social behaviour of injected fish within their social groups. We determined the concentrations and post-injection times when the drugs had the greatest effect on social behaviour. We recorded spontaneous social behaviour in both experiments. In the second experiment we also recorded behaviour after social groups received a territorial challenge by live presentations of either conspecifics or egg predators. The 5-HT1A agonist caused an increase in aggression and a decrease in submission and affiliation, whereas the antagonist had the opposite effects. Thus, the 5-HT1A receptor plays an important regulatory role not only for aggressive but also sociopositive behaviour.
Assuntos
Ciclídeos , Receptor 5-HT1A de Serotonina , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Animais , Agonistas do Receptor de Serotonina/farmacologia , Comportamento SocialRESUMO
To determine the bioavailability and pharmacokinetic properties of the serotonin 5-HT1A receptor agonist R-8-OH-DPAT in goats, and 0.1 mg kg-1 R-8-OH-DPAT hydrobromide was administered intramuscularly (i.m.) and intravenously (i.v.) to six goats in a two-phase cross-over design experiment. Venous blood samples were collected from the jugular vein 2, 5, 10, 15, 20, 30, 40 and 60 min following treatment and analysed by liquid chromatography tandem mass spectrometry. Bioavailability and pharmacokinetic parameters were determined by a one-compartment analysis. Mean bioavailability of R-8-OH-DPAT when injected i.m. was 66%. The mean volume of distribution in the central compartment was 1.47 L kg-1 . The mean plasma body clearance was 0.056 L kg-1 min-1 . All goats injected i.v. and two of six goats injected i.m. showed signs of serotonin toxicity. In conclusion, R-8-OH-DPAT is well absorbed following i.m. injection and the observed pharmacokinetics suggest that administration via dart is feasible. Administration of R-8-OH-DPAT hydrobromide, at a dosage of 0.1 mg kg-1 , resulted in the observation of clinical signs of serotonin toxicity in the goats. It is suggested that dosages for the clinical use of the compound should be lower in order to achieve the desired clinical effect without causing serotonin toxicity.
Assuntos
8-Hidroxi-2-(di-n-propilamino)tetralina/farmacocinética , Agonistas do Receptor de Serotonina/farmacocinética , 8-Hidroxi-2-(di-n-propilamino)tetralina/administração & dosagem , 8-Hidroxi-2-(di-n-propilamino)tetralina/sangue , Animais , Disponibilidade Biológica , Feminino , Cabras/sangue , Cabras/metabolismo , Injeções Intramusculares/veterinária , Agonistas do Receptor de Serotonina/administração & dosagem , Agonistas do Receptor de Serotonina/sangueRESUMO
OBJECTIVE: To determine whether the R-enantiomer of 8-hydroxy-2-(di-n-propylamino) tetralin (R-8-OH-DPAT) alleviates respiratory depression in antelope species immobilized with etorphine. The experiment also aimed to establish the most clinically effective dose of this serotonin 5- HT1A receptor agonist. ANIMALS: A group of six female blesbok and six female impala. STUDY DESIGN: Each animal was subjected to four immobilization treatments in a prospective four-way crossover design-control treatment consisting of only etorphine at 0.09 mg kg-1 and three treatments consisting of etorphine at 0.09 mg kg-1 combined with 0.005, 0.02 and 0.07 mg kg-1 of R-8-OH-DPAT, respectively. Induction, quality of immobilization and recovery were monitored in each treatment. Physiological variables including heart rate, respiratory rate, arterial blood pressure and blood gases were measured for 35 minutes during immobilization. A linear mixed model was used to assess the effects of treatments over the recumbency period. RESULTS: R-8-OH-DPAT did not influence induction, immobilization or recovery scores. Respiratory rate in blesbok was increased in the medium- and high-dosage R-8-OH-DPAT treatment group. However, this increased respiratory rate did not translate into improvements of arterial partial pressure of oxygen (PaO2) values in the blesbok. The medium and higher dosages of R-8-OH-DPAT in impala led to an improved PaO2 as well as to decreased opioid-induced tachycardia during the first 10 minutes of immobilization. CONCLUSIONS AND CLINICAL RELEVANCE: Previous reports indicated that the racemic mixture of 8-OH-DPAT injected intravenously had a positive effect on blood-gas values in etorphine-treated hypoxemic goats. In this experiment, similar effects could be seen in impala at the higher dosage rates of R-8-OH-DPAT. However, failure to achieve an improvement of blood-gas values in blesbok was an unexpected result. It could be speculated that the dosage, species-specific differences of serotonin receptors or the use of the R-enantiomer of 8-OH-DPAT might play a role.
Assuntos
8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Analgésicos Opioides/efeitos adversos , Antílopes , Etorfina/efeitos adversos , Insuficiência Respiratória/veterinária , Agonistas do Receptor de Serotonina/farmacologia , 8-Hidroxi-2-(di-n-propilamino)tetralina/administração & dosagem , Analgésicos Opioides/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Estudos Cross-Over , Relação Dose-Resposta a Droga , Etorfina/farmacologia , Feminino , Frequência Cardíaca/efeitos dos fármacos , Oxigênio/sangue , Insuficiência Respiratória/induzido quimicamente , Insuficiência Respiratória/tratamento farmacológico , Agonistas do Receptor de Serotonina/administração & dosagemRESUMO
Chronic pain conditions such as low back pain and osteoarthritis are the most prominent causes of disability worldwide. Morphine and other opioid drugs are the gold standard treatment for severe pain, including surgical pain, but the use of these drugs for chronic pain is limited largely because long term use of these drugs is associated with drug abuse and hyperalgesia which produces a negative impact on the treatment. Non-addictive treatments for chronic pain are, therefore, highly needed. Commonly used opioid drugs activate mu opioid receptors, resulting in an inhibition of tonic activity of nociceptive neurons. The rewarding effects of opioid drugs are also mediated via activation of mu opioid receptors and inhibition of GABA mediated control of the activity of dopamineregic neurons. Enhanced glutamate release and greater activity of NMDA glutamate receptors is linked to the hyperalgesic effects of opioid drugs. Evidence suggests that activation of serotonin (5-hydroxytryptamine; 5-HT)-1â¯A receptors modulates dopamine neurotransmission to inhibit rewarding effects of drugs of abuse. Activation of these receptors inhibits glutamate release from the sensory neurons to reduce pain transmission. To help develop strategies for improving therapeutics in chronic pain, and draw research interest in the synthesis of non-addictive opioid drugs which do not predispose to hyperalgesia, the present article concerns the potential mechanism involved in 5-HT-1â¯A receptor mediated inhibition of pain and reward.
Assuntos
Analgésicos/uso terapêutico , Encéfalo/efeitos dos fármacos , Dor Crônica/tratamento farmacológico , Percepção da Dor/efeitos dos fármacos , Limiar da Dor/efeitos dos fármacos , Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Recompensa , Agonistas do Receptor 5-HT1 de Serotonina/uso terapêutico , Analgésicos/efeitos adversos , Analgésicos Opioides/efeitos adversos , Animais , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Dor Crônica/metabolismo , Dor Crônica/fisiopatologia , Dor Crônica/psicologia , Dopamina/metabolismo , Humanos , Transtornos Relacionados ao Uso de Opioides/metabolismo , Transtornos Relacionados ao Uso de Opioides/fisiopatologia , Transtornos Relacionados ao Uso de Opioides/psicologia , Receptor 5-HT1A de Serotonina/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina/efeitos adversos , Transdução de Sinais/efeitos dos fármacosRESUMO
The effects of chronic 5-HT1A receptor activation on the behavior, functional activity of 5-HT1A receptors, and expression of key genes of the brain 5-HT system were studied in mice of the catalepsy-prone CBA strain and the catalepsy-resistant C57BL/6 strain. Chronic treatment with 8-Hydroxy-2-(di-n-propyl-amino)tetralin (8-OH-DPAT) (1.0 mg/kg i.p., 14 days) led to a significant decrease in the hypothermic response to acute administration of 8-OH-DPAT in CBA and C57BL/6 mice, which indicates the desensiti-zation of 5-HT1A receptors in both strains. Pretreatment with the 5-HT7 receptor agonist SB 269970 did not affect the hypothermic response to the acute administration of 8-OH-DPAT, which suggests an independent functional response of 5-HT1A receptors. The treatment did not induce any changes in the behavior in the open field paradigm in CBA mice, but significantly increased the total path, the time spent in the center, and the number of rearings in C57BL/6 mice, which indicates the enhancement of locomotor and exploratory activity in C57BL/6 mice. The chronic activation of 5-HT1A receptor downregulated 5-HT1A gene expression, as well as the expression of the gene that encodes tryptophan hydroxylase 2, a key enzyme of 5-HT biosynthesis, in the midbrain and the expression of the gene that encodes the 5-HT2A receptor in the frontal cortex of CBA, but not C57BL/6 mice. The obtained data provide a new evidence on the receptor-gene cross talk in the brain 5-HT system that may underlie the loss of pharmacological efficacy of 5-HT1A receptor agonists. In turn, the loss of the behavioral response and compensatory alterations in key genes of the brain 5-HT system in CBA mice suggests that catalepsy-prone and -resistant genotypes demonstrate different sensibility to the effects of drugs.
Assuntos
8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Catalepsia , Predisposição Genética para Doença , Receptor 5-HT1A de Serotonina , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Animais , Catalepsia/induzido quimicamente , Catalepsia/genética , Catalepsia/metabolismo , Camundongos , Camundongos Endogâmicos CBA , Camundongos Mutantes , Receptor 5-HT1A de Serotonina/genética , Receptor 5-HT1A de Serotonina/metabolismoRESUMO
OBJECTIVE: To explore the feasibility and practicability of establishing a rat model of premature ejaculation (PE) by injection of 8-OH-DPAT into the subarachnoid space of the lumbosacral spinal cord segments. METHODS: Twenty-four male Wistar rats were equally randomized into a PE model and a blank control group. The PE model was established by injection of 8-OH-DPAT in 10 ml normal saline at 0.8 mg per kg of the body weight per day into the subarachnoid space of the lumbosacral spinal cord segments and the control rats were injected with the same volume of normal saline only, both for 4 weeks. Another 24 female Wistar rats were injected subcutaneously with benzoic acid estradiol at 20 µg to induce estrus at 36 hours before mated with the male animals. At 2 and 4 weeks, the male rats were mated with the female ones for 30 minutes each time and meanwhile observed for their mating behavior indicators, such as mount latency, intromission latency, ejaculation latency, mount frequency, intromission frequency, and ejaculation frequency. RESULTS: Compared with the controls, the PE model rats showed a significantly lower ejaculation latency (ï¼»712.35 ± 36.77ï¼½ vs ï¼»502.35 ± 46.72ï¼½ s, P<0.05), mount latency (ï¼»11.22 ± 3.60ï¼½ vs ï¼»8.69 ± 2.48ï¼½ s, P<0.05), mount frequency (13.28 ± 0.24 vs 7.53 ± 1.84, P<0.05), and intromission latency (ï¼»22.33 ± 2.45ï¼½ vs ï¼»12.08 ± 1.39ï¼½ s, P<0.05), but a remarkably higher ejaculation frequency (2.01 ± 0.48 vs 4.26 ± 0.89, P<0.05). No statistically significant difference was observed between the control and model animals in the intromission frequency (7.49 ± 2.21 vs 6.45 ± 1.89, P>0.05). CONCLUSIONS: A rat model of premature ejaculation was successfully established by injection of 8-OH-DPAT into the subarachnoid space of the lumbosacral spinal cord segments, which is of great significance for further study of the mechanism of premature ejaculation.
Assuntos
8-Hidroxi-2-(di-n-propilamino)tetralina/administração & dosagem , Modelos Animais de Doenças , Ejaculação Precoce/induzido quimicamente , Animais , Ácido Benzoico/administração & dosagem , Ejaculação , Estradiol/administração & dosagem , Estro , Estudos de Viabilidade , Feminino , Injeções Espinhais , Masculino , Ejaculação Precoce/fisiopatologia , Ratos , Ratos Wistar , Comportamento Sexual Animal , Medula Espinal , Espaço SubaracnóideoRESUMO
This study was designed to examine an anxiety-like behavior in the adult gonadectomized (GDX) male rats subjected to testosterone propionate (TP) treatment alone or in combination with 8-OH-DPAT, a 5-HT1A receptor agonist, or with NAN-190, 5-HT1A receptor antagonist. Two weeks after gonadectomy, GDX rats were subjected by treatments with the solvent, TP (0.5mg/kg, s.c.), 8-OH-DPAT (0.05mg/kg, s.c.), NAN-190 (0.1mg/kg, i.p.), TP in combination with 8-OH-DPAT or NAN-190 during 14days. Anxiety behavior was assessed in the elevated plus maze (EPM) and the open field test (OFT). 8-OH-DPAT treatment failed to modify the anxiety-like behavior of GDX rats in the EPM as compared to the GDX rats given with oil solvent. NAN-190 injected alone or in combination with TP to GDX rats resulted in a significant anxiolytic-like effect as compared to the GDX given with oil solvent or TP application. Our data indicate that the combination of NAN-190 and TP is more effective than TP alone in GDX rats inducing a more profound anxiolytic-like effect in the EPM. Thus, the results of this study suggest that effects of 5-HT1A receptor agonist/antagonist can modify anxiety level in opposite direction in male rats after gonadectomy.
Assuntos
Ansiedade/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Castração , Receptor 5-HT1A de Serotonina/metabolismo , Antagonistas do Receptor 5-HT1 de Serotonina/uso terapêutico , Testosterona/efeitos adversos , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , 8-Hidroxi-2-(di-n-propilamino)tetralina/uso terapêutico , Animais , Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , Ansiedade/patologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Ratos Wistar , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologiaRESUMO
The role of 5-HT1A receptors in regulating voiding functions remains unclear, particularly regarding the urine flow rate (UFR) during voiding. This study examined the effects of 5-HT1A receptors on regulating urethral functions in female rats and investigated underlying modulatory mechanisms. Intravesical pressure (IVP), external urethral sphincter-electromyography (EUS-EMG), and UFR were simultaneously recorded during continuous transvesical infusion to examine the effects of a 5-HT1A receptor agonist (8-OH-DPAT) and antagonist (WAY-100635) on bladder and urethral functions. In addition, this study evaluated the independent roles of urethral striated and smooth muscles in the UFR in rats after a neuromuscular blockade (NMB) treatment and bilateral hypogastric nerve transection. Our results revealed that 8-OH-DPAT significantly increased the maximal UFR but reduced the mean UFR. This discrepancy may be because 8-OH-DPAT markedly increased the maximal UFR during the initial segment of the flow duration and subsequently induced an approximately zero level of long oscillatory waves during the remaining flow duration. Thus the mean UFR was reduced because of the prolonged approximately zero level of the UFR. However, paralyzing the EUS with an NMB agent, 8-OH-DPAT, significantly increased the maximal and mean UFRs because the prolonged zero level of the oscillatory UFR did not continue. These results support the hypothesis that the increased UFR in female rats during voiding is due to the induction of urethral smooth muscle relaxation by 8-OH-DPAT. This paper provides a detailed understanding of the role of 5-HT1A receptors in controlling the UFR in female rats.
Assuntos
Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Agonistas do Receptor 5-HT1 de Serotonina/uso terapêutico , Urodinâmica/efeitos dos fármacos , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Animais , Denervação , Eletromiografia , Feminino , Plexo Hipogástrico/fisiologia , Bloqueadores Neuromusculares/farmacologia , Piperazinas/farmacologia , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia , Antagonistas da Serotonina/farmacologia , Uretra/fisiopatologia , Micção/efeitos dos fármacosRESUMO
Relatively little is known about serotonergic involvement in pair-bonding despite its putative role in regulating social behavior. Here we sought to determine if pharmacological elevation of serotonin 1A (5-HT1A) receptor activity would lead to changes in social behavior in pair-bonded male titi monkeys (Callicebus cupreus). Adult males in established heterosexual pairs were injected daily with the selective 5-HT1A agonist 8-OH-DPAT or saline for 15days using a within-subjects design. Social behavior with the female pair-mate was quantified, and plasma concentrations of oxytocin, vasopressin, and cortisol were measured. When treated with saline, subjects showed reduced plasma oxytocin concentrations, while 8-OH-DPAT treatment buffered this decrease. Treatment with 8-OH-DPAT also led to decreased plasma cortisol 15minutes post-injection and decreased social behavior directed toward the pair-mate including approaching, initiating contact, lipsmacking, and grooming. The reduction in affiliative behavior seen with increased activity at 5-HT1A receptors indicates a substantial role of serotonin activity in the expression of social behavior. In addition, results indicate that the effects of 5-HT1A agonism on social behavior in adulthood differ between rodents and primates.
Assuntos
8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Comportamento Animal/efeitos dos fármacos , Ligação do Par , Pitheciidae , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Animais , Feminino , Hidrocortisona/sangue , Masculino , Ocitocina/sangue , Pitheciidae/fisiologia , Pitheciidae/psicologia , Receptor 5-HT1A de Serotonina/metabolismo , Serotonina/farmacologia , Comportamento Social , Vasopressinas/sangueRESUMO
d-lysergic diethylamide (LSD) is a hallucinogenic drug that interacts with the serotonin (5-HT) system binding to 5-HT1 and 5-HT2 receptors. Little is known about its potential interactions with the dopamine (DA) neurons of the ventral tegmental area (VTA). Using in-vivo electrophysiology in male adult rats, we evaluated the effects of cumulative doses of LSD on VTA DA neuronal activity, compared these effects to those produced on 5-HT neurons in the dorsal raphe nucleus (DRN), and attempted to identify the mechanism of action mediating the effects of LSD on VTA DA neurons. LSD, at low doses (5-20µg/kg, i.v.) induced a significant decrease of DRN 5-HT firing activity through 5-HT2A and D2 receptors. At these low doses, LSD did not alter VTA DA neuronal activity. On the contrary, at higher doses (30-120µg/kg, i.v.), LSD dose-dependently decreased VTA DA firing activity. The depletion of 5-HT with p-chlorophenylalanine did not modulate the effects of LSD on DA firing activity. The inhibitory effects of LSD on VTA DA firing activity were prevented by the D2 receptor antagonist haloperidol (50µg/kg, i.v.) and by the 5-HT1A receptor antagonist WAY-100,635 (500µg/kg, i.v.). Notably, pretreatment with the trace amine-associate receptor 1 (TAAR1) antagonist EPPTB (5mg/kg, i.v.) blocked the inhibitory effect of LSD on VTA DA neurons. These results suggest that LSD at high doses strongly affects DA mesolimbic neuronal activity in a 5-HT independent manner and with a pleiotropic mechanism of action involving 5-HT1A, D2 and TAAR1 receptors.
Assuntos
Dopamina/metabolismo , Alucinógenos/farmacologia , Dietilamida do Ácido Lisérgico/farmacologia , Receptor 5-HT1A de Serotonina/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animais , Benzamidas/farmacologia , Masculino , Neurônios/efeitos dos fármacos , Piperazinas/farmacologia , Piridinas/farmacologia , Pirrolidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Serotonina/metabolismo , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/metabolismoRESUMO
Inhibitory 5-HT(1a) receptors are located on serotonin (5-HT) neurons (autoreceptors) as well as neurons of the respiratory network (heteroreceptors). Thus, effects on breathing of 5-HT(1a) agonists, such as (R)-(+)-8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT), could either be due to decreased firing of 5-HT neurons or direct effects on the respiratory network. Mice in which the transcription factor LMX1B is genetically deleted selectively in Pet1-1-expressing cells (Lmx1b(f/f/p)) essentially have complete absence of central 5-HT neurons, providing a unique opportunity to separate the effect of activation of downstream 5-HT(1a) heteroreceptors from that of autoreceptors. We used rhythmically active medullary slices from wild-type (WT) and Lmx1b(f/f/p) neonatal mice to differentiate autoreceptor versus heteroreceptor effects of 8-OH-DPAT on hypoglossal nerve respiratory output. 8-OH-DPAT transiently increased respiratory burst frequency in Lmx1b(f/f/p) preparations, but not in WT slices. This excitation was abolished when synaptic inhibition was blocked by GABAergic/glycinergic receptor antagonists. Conversely, after 10 min of application, frequency in Lmx1b(f/f/p) slices was not different from baseline, whereas it was significantly depressed in WT slices. In WT mice in vivo, subcutaneous injection of 8-OH-DPAT produced similar biphasic respiratory effects as in Lmx1b(f/f/p) mice. We conclude that 5-HT1a receptor agonists have two competing effects: rapid stimulation of breathing due to excitation of the respiratory network, and delayed inhibition of breathing due to autoreceptor inhibition of 5-HT neurons. The former effect is presumably due to inhibition of inhibitory interneurons embedded in the respiratory network.
Assuntos
Receptor 5-HT1A de Serotonina/metabolismo , Mecânica Respiratória/fisiologia , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Animais , Animais Recém-Nascidos , Feminino , Masculino , Camundongos , Camundongos Knockout , Técnicas de Cultura de Órgãos , Ligação Proteica/fisiologia , Respiração/efeitos dos fármacos , Centro Respiratório/efeitos dos fármacos , Centro Respiratório/fisiologia , Mecânica Respiratória/efeitos dos fármacos , Neurônios Serotoninérgicos/efeitos dos fármacos , Neurônios Serotoninérgicos/fisiologiaRESUMO
The serotonin1A receptor is an important member of the G protein-coupled receptor (GPCR) family. It is involved in the generation and modulation of a variety of cognitive and behavioral functions and serves as a drug target. Previous work from our laboratory has established the sensitivity of the function of the serotonin1A receptor to membrane cholesterol. Solubilization of the hippocampal serotonin1A receptor utilizing the zwitterionic detergent CHAPS is accompanied by loss of cholesterol and results in reduction in specific ligand binding. Replenishment of cholesterol to solubilized membranes restores specific ligand binding to the receptor. We utilized this strategy of sterol replenishment of solubilized membranes to explore the stereospecific stringency of cholesterol for receptor function. We used two stereoisomers of cholesterol, ent-cholesterol (enantiomer of cholesterol) and epi-cholesterol (a diastereomer of cholesterol), for this purpose. Importantly, we show here that while ent-cholesterol could replace cholesterol in supporting receptor function, epi-cholesterol could not. These results imply that the requirement of membrane cholesterol for the serotonin1A receptor function is diastereospecific, yet not enantiospecific. Our results extend and help define specificity of the interaction of membrane cholesterol with the serotonin1A receptor, and represent the first report utilizing ent-cholesterol to examine stereospecificity of GPCR-cholesterol interaction.
Assuntos
Membrana Celular/química , Colesterol/análogos & derivados , Colesterol/química , Hipocampo/química , Receptor 5-HT1A de Serotonina/química , Animais , Bovinos , Detergentes/química , Difenilexatrieno/química , Polarização de Fluorescência , Corantes Fluorescentes/química , Ensaio Radioligante , Receptor 5-HT1A de Serotonina/isolamento & purificação , Solubilidade , Espectrometria de Fluorescência , EstereoisomerismoRESUMO
INTRODUCTION: The neurobiological control of ejaculation is not completely understood. Both serotonin (5-HT) and oxytocin (OXT) play a role in the control of male sexual parameters, putatively via overlapping neuronal networks. AIM: The aim of this study was to determine whether activation of 5-HT1A receptors (5-HT1A Rs) reduces the ejaculatory threshold via the direct activation of (OXT) neurons in the paraventricular hypothalamic nucleus (PVN). METHODS: In experiment 1, male rats received acute bilateral infusions of the selective 5-HT1A R antagonist WAY-100635 (1 and 10 µg) or vehicle into the PVN, followed by acute subcutaneous (s.c.) injection of the potent 5-HT1 A R agonist 8-OH-DPAT (0.4 mg/kg) or saline. In experiment 2, male rats received acute bilateral infusions of 8-OH-DPAT (1 and 10 µg) or vehicle into the PVN. In experiment 3, male rats received acute intracerebroventricular (i.c.v.) infusion of a selective OXT receptor antagonist (OXTR-A, 75 and 750 ng) followed by acute s.c. injection of 8-OH-DPAT (0.4 mg/kg) or saline. The effects of these drug treatments on sexual behavior were measured. MAIN OUTCOME MEASURES: Copulation latency, ejaculation latency, mount and intromission frequency, and ejaculation frequency of sexually experienced adult male Wistar rats during 30-minute sexual behavior tests with a receptive female were the main outcome measures. RESULTS: Male sexual behavior was not affected by intra-PVN infusion of WAY-100635 or 8-OH-DPAT, or by i.c.v. infusion of OXTR-A alone. However, the facilitation of ejaculation (reduced mount and intromission frequency and ejaculation latency) induced by systemic 8-OH-DPAT could be attenuated by either intra-PVN infusion of WAY-100635 or by i.c.v. infusion of OXTR-A. CONCLUSIONS: Activation of OXT neurons plays a moderate role in the pro-ejaculatory effects of systemic 8-OH-DPAT, but extracellular 5-HT levels may influence the strength of the effects.
Assuntos
8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Ejaculação/efeitos dos fármacos , Ocitocina/efeitos dos fármacos , Piperazinas/farmacologia , Piridinas/farmacologia , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Comportamento Sexual Animal/efeitos dos fármacos , Animais , Masculino , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Ratos , Ratos Wistar , Serotonina/farmacologia , Transmissão SinápticaRESUMO
Astrocytes are abundant neuron-supporting glial cells that harbor a powerful arsenal of neuroprotective antioxidative molecules and neurotrophic factors. Here we examined whether enrichment with healthy striatal astrocytes can provide neuroprotection against progressive dopaminergic neurodegeneration. Serotonin 1A (5-HT1A) agonist 8-OH-DPAT induced astrocyte proliferation and increased metallothionein-1/-2 (MT-1/-2), antioxidative molecules, in cultured astrocytes and the striatum of mice. Primary cultured mesencephalic dopamine neurons were protected against oxidative stress by preincubation with conditioned media from 8-OH-DPAT-treated astrocytes. These protective effects were canceled by 5-HT1A antagonist or MT-1/-2-specific antibody. Furthermore, reduction of nigrostriatal dopaminergic neurons in 6-hydroxydopamine-lesioned parkinsonian model mice was significantly abrogated by repeated injections of 8-OH-DPAT. Treatment with 8-OH-DPAT markedly increased the expression of MT in striatal astrocytes in the hemi-parkinsonian mice. Our study provides a promising therapeutic strategy of neuroprotection against oxidative stress and progressive dopaminergic neurodegeneration by demonstrating the efficacy of targeting 5-HT1A receptors in astrocytes.
Assuntos
Astrócitos/metabolismo , Neurônios Dopaminérgicos/fisiologia , Doença de Parkinson/patologia , Receptor 5-HT1A de Serotonina/metabolismo , 8-Hidroxi-2-(di-n-propilamino)tetralina/administração & dosagem , Adrenérgicos/toxicidade , Animais , Astrócitos/efeitos dos fármacos , Encéfalo/citologia , Buspirona/farmacologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Técnicas de Cocultura , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Relação Dose-Resposta a Droga , Embrião de Mamíferos , Feminino , Lateralidade Funcional/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Oxidopamina/toxicidade , Doença de Parkinson/etiologia , Doença de Parkinson/prevenção & controle , Gravidez , Ratos , Ratos Sprague-Dawley , Agonistas do Receptor de Serotonina/administração & dosagem , Água/farmacologiaRESUMO
While serotonin (5-HT) can stimulate the hypothalamic-pituitary-interrenal stress axis in fish, the specific site(s) of 5-HT action are poorly understood. In this study, goldfish (Carassius auratus) were injected intraperitoneally with either saline or the 5-HT1A/7 receptor agonist 8-OH-DPAT at a dose of 100 or 400 µg/kg body weight and sampled 1.5 and 8 h post-injection. Relative to unhandled controls, the saline and 100 µg/kg 8-OH-DPAT treatments elicited similar transient 5- to 7-fold increases in plasma cortisol and the 400 µg/kg 8-OH-DPAT dosage resulted in a sustained 16-fold increase in cortisol levels. Although the 5-HT1A receptor is expressed in the brain preoptic area (POA), the pituitary and the head kidney, neither the saline nor the 8-OH-DPAT treatments affected the mRNA abundance of POA corticotropin-releasing factor and pituitary pro-opiomelanocortin or plasma adrenocorticotropic hormone (ACTH) levels. To assess the direct actions of 5-HT on cortisol secretion relative to those of ACTH, head kidney tissue were superfused with 10(-7)M 5-HT, ACTH or a combined 5-HT/ACTH treatment. Overall, the ACTH and 5-HT/ACTH treatments resulted in higher peak cortisol and total cortisol release than in the 5-HT treatment but the response time to peak cortisol release was shorter in the combined treatment than in either the 5-HT or ACTH alone treatments. Both 8-OH-DPAT and cisapride, a 5-HT4 receptor agonist, also stimulated cortisol release in vitro and their actions were reversed by selective 5-HT1A and 5-HT4 receptor antagonists, respectively. Finally, double-labeling with anti-tyrosine hydroxylase and anti-5-HT revealed that the chromaffin cells of the head kidney contain 5-HT. Thus, in goldfish, 5-HT can directly stimulate cortisol secretion from the interrenals via multiple 5-HT receptor subtypes and the chromaffin cells may be involved in the paracrine regulation of cortisol secretion via 5-HT.