RESUMO
In normal hormonal conditions, increased neuronal activity in the ventromedial hypothalamus (VMH) induces lordosis whereas activation of the preoptic area (POA) exerts an opposite effect. In the present work, we explored the effect of bilateral infusion of different doses of the apelin-13 (0.37, 0.75, 1.5, and 15 µg) in both brain areas on the expression of lordosis behavior. Lordosis quotient and lordosis reflex score were performed at 30, 120, and 240 min. Weak lordosis was observed following the 0.37 µg dose of apelin-13 at 30 min in the VMH of EB-primed rats; however, the rest of the doses induced significant lordosis relative to the control group. At 120 min, all doses induced lordosis behavior, while at 240 min, the highest dose of 15 µg did not induce significant differences. Interestingly, only the 0.75 µg infusion of apelin in the POA induced significant lordosis at 120 and 240 min. These results indicate that apelin-13 acts preferably in HVM and slightly in POA to initiate lordosis behavior in estrogen-primed rats.
Assuntos
Peptídeos e Proteínas de Sinalização Intercelular , Lordose , Área Pré-Óptica , Animais , Estradiol/farmacologia , Estrogênios/farmacologia , Hipotálamo/efeitos dos fármacos , Hipotálamo/patologia , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Lordose/induzido quimicamente , Área Pré-Óptica/efeitos dos fármacos , Área Pré-Óptica/patologia , Progesterona/farmacologia , Ratos , Comportamento Sexual Animal/efeitos dos fármacos , Núcleo Hipotalâmico Ventromedial/efeitos dos fármacos , Núcleo Hipotalâmico Ventromedial/patologiaRESUMO
RATIONALE: The behavioural effects elicited by chemical constituents of Cannabis sativa, such as cannabidiol (CBD), on the ventromedial hypothalamus (VMH) are not well understood. There is evidence that VMH neurons play a relevant role in the modulation of unconditioned fear-related defensive behavioural reactions displayed by laboratory animals. OBJECTIVES: This study was designed to explore the specific pattern of distribution of the CB1 receptors in the VMH and to investigate the role played by this cannabinoid receptor in the effect of CBD on the control of defensive behaviours and unconditioned fear-induced antinociception. METHODS: A panic attack-like state was triggered in Wistar rats by intra-VMH microinjections of N-methyl-D-aspartate (NMDA). One of three different doses of CBD was microinjected into the VMH prior to local administration of NMDA. In addition, the most effective dose of CBD was used after pre-treatment with the CB1 receptor selective antagonist AM251, followed by NMDA microinjections in the VMH. RESULTS: The morphological procedures demonstrated distribution of labelled CB1 receptors on neuronal perikarya situated in dorsomedial, central and ventrolateral divisions of the VMH. The neuropharmacological approaches showed that both panic attack-like behaviours and unconditioned fear-induced antinociception decreased after intra-hypothalamic microinjections of CBD at the highest dose (100 nmol). These effects, however, were blocked by the administration of the CB1 receptor antagonist AM251 (100 pmol) in the VMH. CONCLUSION: These findings suggest that CBD causes panicolytic-like effects and reduces unconditioned fear-induced antinociception when administered in the VMH, and these effects are mediated by the CB1 receptor-endocannabinoid signalling mechanism in VMH.
Assuntos
Canabidiol/toxicidade , Medo/fisiologia , Medição da Dor/métodos , Transtorno de Pânico/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Núcleo Hipotalâmico Ventromedial/metabolismo , Animais , Canabidiol/administração & dosagem , Medo/efeitos dos fármacos , Medo/psicologia , Injeções Intraventriculares , Masculino , N-Metilaspartato/administração & dosagem , Medição da Dor/efeitos dos fármacos , Medição da Dor/psicologia , Transtorno de Pânico/induzido quimicamente , Piperidinas/administração & dosagem , Pirazóis/administração & dosagem , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/antagonistas & inibidores , Núcleo Hipotalâmico Ventromedial/efeitos dos fármacosRESUMO
An injection of unesterified oestradiol (E2 ) facilitates receptive behaviour in E2 benzoate (EB)-primed, ovariectomised female rats when it is administered i.c.v. or systemically. The present study tested the hypothesis that inhibitors of protein kinase A (PKA), protein kinase G (PKG) or the Src/mitogen-activated protein kinase (MAPK) complex interfere with E2 facilitation of receptive behaviour. In Experiment 1, lordosis induced by i.c.v. infusion of E2 was significantly reduced by i.c.v. administration of Rp-cAMPS, a PKA inhibitor, KT5823, a PKG inhibitor, and PP2 and PD98059, Src and MAPK inhibitors, respectively, between 30 and 240 minutes after infusion. In Experiment 2, we determined whether the ventromedial hypothalamus (VMH) is one of the neural sites at which those intracellular pathways participate in lordosis behaviour induced by E2 . Administration of each of the four protein kinase inhibitors into the VMH blocked facilitation of lordosis induced by infusion of E2 also into the VMH. These data support the hypothesis that activation of several protein kinase pathways is involved in the facilitation of lordosis by E2 in EB-primed rats.
Assuntos
Antagonistas de Estrogênios/farmacologia , Lordose/fisiopatologia , Inibidores de Proteínas Quinases/farmacologia , Núcleo Hipotalâmico Ventromedial/fisiologia , Animais , Carbazóis/farmacologia , AMP Cíclico/análogos & derivados , AMP Cíclico/farmacologia , Estradiol/fisiologia , Feminino , Flavonoides/farmacologia , Infusões Intraventriculares , Lordose/induzido quimicamente , Masculino , Microinjeções , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/farmacologia , Ratos , Tionucleotídeos/farmacologia , Núcleo Hipotalâmico Ventromedial/efeitos dos fármacosRESUMO
According to the organizational-activational hypothesis, testosterone or its metabolite estradiol, can organize the brain in a male direction (permanently or for long periods) if exposure occurs during a critical (sensitive) time of brain development like the prenatal period. Male rodents with insufficient levels of testosterone during such critical period would irreversibly fail to display sexual partner preference for receptive females in adulthood. However, exposure to testosterone during puberty is believed to function as a second critical period for organization of brain and behavior. Thus, in the present study we explored the effects of neonatal gonadectomy at postnatal day 1 (GNX) on the partner preference of adult males and the size of some sexually dimorphic regions in the brain like the SDN-MPOA, SCN, MeApd and VMH; and challenged its irreversibility by providing exogenous testosterone during puberty. Our results indicated that neonatal GNX impaired partner preference for females and reduced the size of SDN-MPOA, MeApd and VMH, but not SCN. GNX males restored with testosterone in PD30-PD59 (GNXâ¯+â¯T) expressed partner preference for sexually receptive females and increased the size of SDN-MPOA and VMH, but not MeApd in adulthood. We conclude that neonatal castration and the lack of testosterone during the first month of life alters sexual behavior and brain dimorphism in adult male rats, but pubertal testosterone reverses the effects on behavior and brain dimorphism to some extent.
Assuntos
Castração/efeitos adversos , Casamento/psicologia , Testosterona/farmacologia , Fatores Etários , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Encéfalo/efeitos dos fármacos , Estradiol/farmacologia , Masculino , Área Pré-Óptica/efeitos dos fármacos , Ratos , Ratos Wistar , Comportamento Sexual Animal/efeitos dos fármacos , Maturidade Sexual , Núcleo Supraquiasmático/efeitos dos fármacos , Núcleo Hipotalâmico Ventromedial/efeitos dos fármacosRESUMO
The effects of cannabinoids in brain areas expressing cannabinoid receptors, such as hypothalamic nuclei, are not yet well known. Several studies have demonstrated the role of hypothalamic nuclei in the organisation of behavioural responses induced through innate fear and panic attacks. Panic-prone states are experimentally induced in laboratory animals through a reduction in the GABAergic activity. The aim of the present study was to examine panic-like elaborated defensive behaviour evoked by GABAA receptor blockade with bicuculline (BIC) in the dorsomedial division of the ventromedial hypothalamus (VMHdm). We also aimed to characterise the involvement of endocannabinoids and the CB1 cannabinoid receptor in the modulation of elaborated defence behavioural responses organised with the VMHdm. The guide-cannula was stereotaxicaly implanted in VMHdm and the animals were treated with anandamide (AEA) at different doses, and the effective dose was used after the pre-treatment with the CB1 receptor antagonist AM251, followed by GABAA receptor blockade in VMHdm. The results showed that the intra-hypothalamic administration of AEA at an intermediate dose (5 pmol) attenuated defence responses induced through the intra-VMHdm microinjection of bicuculline (40 ng). This effect, however, was inhibited when applied central microinjection of the CB1 receptor antagonist AM251 in the VMHdm. Moreover, AM251 potentiates de non-oriented escape induced by bicuculline, effect blocked by pre-treatment with the TRPV1 channel antagonist 6-I-CPS. These results indicate that AEA modulates the pro-aversive effects of intra-VMHdm-bicuculline treatment, recruiting CB1 cannabinoid receptors and the TRPV1 channel is involved in the AM251-related potentiation of bicuculline effects on non-oriented escape behaviour.
Assuntos
Reação de Fuga/fisiologia , Receptor CB1 de Canabinoide/fisiologia , Receptores de GABA-A/fisiologia , Canais de Cátion TRPV/fisiologia , Núcleo Hipotalâmico Ventromedial/fisiologia , Animais , Ácidos Araquidônicos/administração & dosagem , Bicuculina/administração & dosagem , Modelos Animais de Doenças , Endocanabinoides/administração & dosagem , Reação de Fuga/efeitos dos fármacos , Antagonistas de Receptores de GABA-A/administração & dosagem , Masculino , Transtorno de Pânico/induzido quimicamente , Transtorno de Pânico/fisiopatologia , Piperidinas/administração & dosagem , Alcamidas Poli-Insaturadas/administração & dosagem , Pirazóis/administração & dosagem , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/antagonistas & inibidores , Núcleo Hipotalâmico Ventromedial/efeitos dos fármacosRESUMO
Electrical stimulation of the periaqueductal gray matter and ventromedial hypothalamus in humans showed the involvement of both these structures in panic attacks. The aim of this work was to make clear the role of dorsal periaqueductal gray (dPAG) matter, dorsomedial hypothalamus (DMH) and the dorsomedial part of the ventromedial hypothalamus (dmVMH) in panic attack-like behaviors. DMH, dmVMH and dPAG of Wistar rats were treated with N-methyl- d-aspartic acid (NMDA) at different doses. The rodents were then kept in a polygonal arena with a burrow to record panic attack-like responses and oriented defensive behaviors. In dmVMH, 6nmol of NMDA elicited alertness, freezing and oriented escape. The same set of behaviors was elicited by DMH neurons when stimulated by 9nmol of NMDA. Treatment of dmVMH with 9nmol of NMDA elicited typical explosive behaviors followed by freezing and oriented behaviors. The stimulation of the dPAG with NMDA at different doses provoked alertness and freezing (1nmol) or alertness, freezing, tail twitching, explosive behavior and oriented escape (3nmol), and explosive behavior followed by long-lasting freezing (6nmol). These data suggest that mainly dPAG plays a role in panic attack-like behaviors that resemble panic syndrome in humans. However, hypothalamic nuclei like dmVMH that mainly elicits oriented escape, can also produce explosive reaction when stimulated with 9nmol NMDA, whereas, DMH plays a role in coordinating defensive behaviors.
Assuntos
Núcleo Hipotalâmico Dorsomedial/fisiologia , Emoções/fisiologia , Reação de Congelamento Cataléptica/fisiologia , Orientação/fisiologia , Substância Cinzenta Periaquedutal/fisiologia , Núcleo Hipotalâmico Ventromedial/fisiologia , Análise de Variância , Animais , Núcleo Hipotalâmico Dorsomedial/efeitos dos fármacos , Relação Dose-Resposta a Droga , Emoções/efeitos dos fármacos , Agonistas de Aminoácidos Excitatórios/farmacologia , Reação de Congelamento Cataléptica/efeitos dos fármacos , Masculino , Microinjeções , N-Metilaspartato/farmacologia , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Ratos , Ratos Wistar , Núcleo Hipotalâmico Ventromedial/efeitos dos fármacosRESUMO
OBJECTIVE: To investigate the hormones participating in early follicular development and hypothalamic neurotransmitters in rats during adulthood. DESIGN: Experimental basic study. SETTING: University animal laboratory. ANIMAL(S): Twenty-three neonatal rats injected with single subcutaneous injection of estradiol valerate (EV), testosterone propionate (TP), or dihydrotestosterone (DHT) and killed by decapitation at 60 days of age. INTERVENTION(S): Measurements of neurotransmitter in ventromedial hypothalamus-arcuate nucleus (VMH-AN) and ovarian morphometry in the adult rat. MAIN OUTCOME MEASURE(S): Noradrenaline (NA), dopamine (DA), serotonin (5-HT), glutamic acid (Glu), and gamma-aminobutyric acid (GABA) content by high performance liquid chromatography medial basal hypothalamus and ovarian morphology. RESULT(S): EV exposure increased 5-HT, DA, NA, and Glu and decreased GABA levels in the VMH-AN. Exposure to TP increased Glu and decreased 5-HT in the VMH-AN. Neonatal EV and TP decreased the number of primordial follicles but EV increased the atresia of antral follicles and TP decreased it. Neonatal exposure to DHT did not cause morphologic changes in the adult ovary. CONCLUSION(S): Neonatal exposure to EV activated the reproductive hypothalamus and permanently modified ovarian follicular development. TP exposure had some similar effects as EV at the hypothalamus, and it modified ovarian development mimicking the effects of EV. This last effect could be through TP conversion to estradiol because DHT, a nonaromatizable androgen, did not modify follicular development.
Assuntos
Estradiol/farmacologia , Hipotálamo/metabolismo , Neurotransmissores/metabolismo , Folículo Ovariano/efeitos dos fármacos , Síndrome do Ovário Policístico/induzido quimicamente , Testosterona/farmacologia , Fatores Etários , Envelhecimento/efeitos dos fármacos , Envelhecimento/metabolismo , Envelhecimento/fisiologia , Animais , Animais Recém-Nascidos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Estradiol/administração & dosagem , Feminino , Hormônios Hipotalâmicos/metabolismo , Hipotálamo/efeitos dos fármacos , Folículo Ovariano/fisiologia , Síndrome do Ovário Policístico/metabolismo , Ratos , Ratos Sprague-Dawley , Transmissão Sináptica/efeitos dos fármacos , Testosterona/administração & dosagem , Núcleo Hipotalâmico Ventromedial/efeitos dos fármacosRESUMO
Previous evidence has shown that facilitation of GABA/benzodiazepine-mediated neurotransmission in the ventromedial hypothalamus (VMH) inhibits both escape and inhibitory avoidance responses generated in the elevated T-maze test of anxiety (ETM). These defensive behaviors have been associated with panic and generalized anxiety, respectively. Aside from GABA/benzodiazepine receptors, the VMH also contains a significant number of serotonin (5-HT) receptors, including 1A, 2A and 2C subtypes. The purpose of the present study was to investigate the effect of the activation of 5-HT(1A) and 5-HT(2A/2C) receptors in the VMH on defensive behavioral responses in rats submitted to the ETM. For that, male Wistar rats were treated intra-VMH with the 5-HT(1A) agonist 8-OH-DPAT, with the 5-HT(2A/2C) agonist DOI, with the 5-HT(2C) selective agonist MK-212, or with the 5-HT(2A/2C) antagonist ketanserin and 10 min after were submitted to the ETM. Results showed that both DOI and MK-212 significantly decreased avoidance measurements, an anxiolytic-like effect, without altering escape. 8-OH-DPAT and ketanserin were without effect, although the last drug attenuated the effects of DOI. None of the drugs altered locomotor activity in an open field. These results suggest that 5-HT(2A/2C) receptors of the VMH are involved in the regulation of inhibitory avoidance and might be of relevance to the physiopathology of generalized anxiety.
Assuntos
Ansiedade/prevenção & controle , Receptor 5-HT2A de Serotonina/fisiologia , Receptor 5-HT2C de Serotonina/fisiologia , Serotoninérgicos/farmacologia , Núcleo Hipotalâmico Ventromedial/efeitos dos fármacos , Animais , Ansiedade/fisiopatologia , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologia , Reação de Fuga/efeitos dos fármacos , Reação de Fuga/fisiologia , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Ratos , Ratos Wistar , Receptor 5-HT2A de Serotonina/efeitos dos fármacos , Receptor 5-HT2C de Serotonina/efeitos dos fármacos , Núcleo Hipotalâmico Ventromedial/fisiologiaRESUMO
The involvement of muscarinic cholinoceptors within the ventromedial hypothalamic nuclei (VMH) on the exercise-induced increase in oxygen consumption (VO(2)) was investigated. Rats were fitted with bilateral cannulae into the VMH for local delivery of drugs. On the day of the experiments, the animals were submitted to running exercise (20 m/min; 5% grade) until the point of fatigue. VO(2) was continuously measured after bilateral injections of either 0.2 µL of 5 × 10(-9)mol methylatropine or 0.15M NaCl solution into the VMH. Control experiments were conducted in freely moving rats on the treadmill. Muscarinic blockade within the VMH reduced time to fatigue by 32% and enhanced the increase in VO(2) from the 8th until the 17th min of exercise when compared to the control trial. In fact, time to fatigue was negatively correlated to the rate of increase in VO(2) (r(2)=0.747; P<0.001). However, bilateral injections of methylatropine in freely moving rats did not change VO(2) in comparison to saline injections. In conclusion, muscarinic cholinoceptors within the VMH are activated during exercise to modulate the increase in metabolic rate. Furthermore, blocking muscarinic transmission leads to a faster increase in VO(2) that is associated with the early interruption of exercise.
Assuntos
Metabolismo Energético/fisiologia , Consumo de Oxigênio/fisiologia , Condicionamento Físico Animal/fisiologia , Receptores Muscarínicos/metabolismo , Núcleo Hipotalâmico Ventromedial/metabolismo , Animais , Derivados da Atropina/farmacologia , Fadiga/fisiopatologia , Masculino , Parassimpatolíticos/farmacologia , Ratos , Ratos Wistar , Núcleo Hipotalâmico Ventromedial/efeitos dos fármacosRESUMO
The effects of blocking ventromedial hypothalamic nucleus (VMH) muscarinic cholinoceptors on cardiovascular responses were investigated in running rats. Animals were anesthetized with pentobarbital sodium and fitted with bilateral cannulae into the VMH. After recovering from surgery, the rats were familiarized to running on a treadmill. The animals then had a polyethylene catheter implanted into the left carotid artery to measure blood pressure. Tail skin temperature (T(tail)), heart rate, and systolic, diastolic and mean arterial pressure were measured after bilateral injections of 0.2 microl of 5 x 10(-9) mol methylatropine or 0.15 M NaCl solution into the hypothalamus. Cholinergic blockade of the VMH reduced time to fatigue by 31 % and modified the temporal profile of cardiovascular and T(tail) adjustments without altering their maximal responses. Mean arterial pressure peak was achieved earlier in methylatropine-treated rats, which also showed a 2-min delay in induction of tail skin vasodilation, suggesting a higher sympathetic tonus to peripheral vessels. In conclusion, muscarinic cholinoceptors within the VMH are involved in a neuronal pathway that controls exercise-induced cardiovascular adjustments. Furthermore, blocking of cholinergic transmission increases sympathetic outflow during the initial minutes of exercise, and this higher sympathetic activity may be responsible for the decreased performance.