RESUMO
Ghrelin (Ghr) is a peptide produced peripherally and centrally. It participates in the modulation of different biological processes. In our laboratory we have shown that (a) Ghr administration, either intracerebroventricular or directly into the hippocampus enhanced memory consolidation in a step down test in rats (b) the effect of Ghr upon memory decreases in animals pretreated with a serotonin (5-HT) reuptake inhibitor, Fluoxetine, suggesting that Ghr effects in the hippocampus could be related to the availability of 5-HT. It has been demonstrated that Ghr inhibits 5-HT release from rat hypothalamic synaptosomes. Taking in mint these evidences, we studied the release of radioactive 5-HT to the superfusion medium from hippocampal slices treated with two doses of Ghr (0.3 and 3 nm/µl). Ghr inhibited significantly the 5-HT release in relation to those superfused with artificial cerebrospinal fluid (ACSF) (H = 9.48, df = 2, p ≤ 0.05). In another set of experiments, Ghr was infused into the CA1 area of hippocampus of the rats immediately after training in the step down test and the 5-HT release from slices was studied 24h after Ghr injection showing that in this condition also the 5-HT release was inhibited (H = 11.72, df = 1, p ≤ 0.05). In conclusion, results provide additional evidence about the neurobiological bases of Ghr action in hippocampus.
Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Fluoxetina/farmacologia , Grelina , Hipocampo/metabolismo , Memória/efeitos dos fármacos , Receptores de Serotonina/metabolismo , Serotonina/metabolismo , Animais , Aprendizagem da Esquiva/fisiologia , Fluoxetina/efeitos adversos , Grelina/administração & dosagem , Grelina/uso terapêutico , Hipocampo/efeitos dos fármacos , Injeções Intraventriculares , Masculino , Memória/fisiologia , Microtomia , Ratos , Ratos Wistar , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Trítio/análiseRESUMO
It has been shown that a single exposure to amphetamine is sufficient to induce long-term behavioral, neurochemical, and neuroendocrine sensitization in rats. Dopaminergic neurotransmission in the nucleus accumbens and the caudate-putamen plays a critical role in the addictive properties of drugs of abuse. Angiotensin (Ang) II receptors are found on the soma and terminals of mesolimbic dopaminergic neurons and it has been shown that Ang II acting through its AT1 receptors facilitates dopamine release. The hypothesis was tested that Ang II AT1 receptors are involved in the neuroadaptative changes induced by a single exposure to amphetamine and that such changes are related to the development of behavioral and neurochemical sensitization. For this purpose, the study examined the expression of amphetamine-enhanced (0.5 mg kg⻹ i.p.) locomotor activity in animals pretreated with candesartan, an AT1 blocker, (3 mg kg⻹ p.o. x 5 days), 3 weeks after an amphetamine injection (5 mg kg⻹ i.p.). Dopaminergic hyperreactivity was tested by measuring the 3H-DA release in vitro from caudate-putamen and nucleus accumbens slices, induced by K+ stimulus. It was confirmed the behavioral sensitization in the two-injection protocol and candesartan pretreatment attenuate this response. It was also found that AT1 blockade pretreatment did not affect the locomotor response to dopamine agonists. In respect to the neurochemical sensitization tested using ex vivo 3H-DA release experiments it was found that AT1 receptor pretreatment blunted the enhanced response induced by K+ stimulus. The results support the idea that the development of neuroadaptive changes induced by amphetamine involves brain AT1 Ang II receptor activation.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Transtornos Relacionados ao Uso de Anfetaminas/psicologia , Anfetamina/toxicidade , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Comportamento Animal/efeitos dos fármacos , Receptor Tipo 1 de Angiotensina/metabolismo , Anfetamina/antagonistas & inibidores , Transtornos Relacionados ao Uso de Anfetaminas/fisiopatologia , Animais , Comportamento Animal/fisiologia , Modelos Animais de Doenças , Injeções Intraperitoneais , Masculino , Técnicas de Cultura de Órgãos , Ratos , Ratos Wistar , Receptor Tipo 1 de Angiotensina/fisiologiaRESUMO
1. The aim of the present work is to demonstrate the interaction between the glutamatergic/NMDA and dopaminergic systems in the medial zona incerta on the control of luteinizing hormone and prolactin secretion and the influence of reproductive hormones. 2. Proestrus and ovariectomized rats were primed with estrogen and progesterone to induce high or low levels of luteinizing hormone and prolactin. 2-Amino-7-phosphonoheptanoic acid, an NMDA receptor antagonist, and dopamine were injected in the medial zona incerta. Blood samples were withdrawn every hour between 1,600 and 2,000 hours or 2,200 hours via intracardiac catheter from conscious rats. Additional groups of animals injected with the NMDA receptor antagonist were killed 1 or 4 h after injection. Dopamine and its metabolite 3,4-dihydroxyphenylacetic acid were measured in different hypothalamic regions. 3. 2-Amino-7-phosphonoheptanoic acid blocked the ovulatory luteinizing hormone surge in proestrus rats. 2-Amino-7-phosphonoheptanoic acid also blocked the increase in luteinizing hormone induced by ovarian hormones in ovariectomized rats, an effect that was partially reversed by dopamine injection. Conversely, the increased release of luteinizing hormone and prolactin induced by dopamine was prevented by 2-amino-7-phosphonoheptanoic acid. We found that the NMDA antagonist injection decreased the dopaminergic activity--as evaluated by the 3,4-dihydroxyphenylacetic acid/dopamine ratio--in the medio basal hypothalamus and increased in the preoptic area. 4. Our results show an stimulatory role of NMDA receptors on the ovulatory luteinizing hormone release and on luteinizing hormone release induced by sexual hormones and demonstrate that the stimulatory effect of dopamine on luteinizing hormone and prolactin is mediated by the NMDA receptors. These results suggest a close interaction between the glutamatergic and dopaminergic incertohypothalamic systems on the control of luteinizing hormone and prolactin release.
Assuntos
Hipotálamo/metabolismo , Hormônio Luteinizante/metabolismo , Vias Neurais/metabolismo , Prolactina/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Subtálamo/metabolismo , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Dopamina/metabolismo , Dopamina/farmacologia , Estrogênios/metabolismo , Estrogênios/farmacologia , Ciclo Estral/efeitos dos fármacos , Ciclo Estral/fisiologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Ácido Glutâmico/metabolismo , Hipotálamo/citologia , Vias Neurais/citologia , Vias Neurais/efeitos dos fármacos , Ovulação/efeitos dos fármacos , Ovulação/fisiologia , Área Pré-Óptica/citologia , Área Pré-Óptica/metabolismo , Progesterona/metabolismo , Progesterona/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Subtálamo/citologia , Subtálamo/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologiaRESUMO
The effect of intracerebroventricular (icv) injection of allopregnanolone (5alpha-pregnan-3alpha-ol-20-one) on the dopaminergic and reproductive function in ovariectomized rats primed with estrogen and progesterone was investigated. Thirty minutes after icv allopregnanolone injection, the sexual receptivity, luteinizing hormone (LH) release, dopamine content, and release in the medial basal hypothalamus (MBH) and preoptic area (POA) were determined. After allopregnanolone injection, LH serum levels were reduced (p < 0.001) and lordosis behavior was inhibited (p < 0.005). Intracerebroventricular injection of bicuculline (a gamma-aminobutyric acidA [GABAA] antagonist) alone was ineffective. The injection of allopregnanolone plus bicuculline blocked the effects of allopregnanolone on sexual receptivity and on LH serum levels. At the same time, endogenous dopamine concentration in both the MBH and POA was augmented (p < 0.005 and p < 0.006, respectively) and the turnover rate decreased in both structures. Moreover, in vitro 3H-dopamine release from MBH and POA was lower in rats injected with allopregnanolone in comparison with vehicle-treated rats. These results suggest that allopregnanolone influences the dopaminergic mechanisms in female rats, which may, in turn, be responsible for the reduced reproductive activity. Allopregnanolone may exert its effects on sexual behavior through GABAA receptor modulation and a decrease in dopaminergic activity in the MBH and POA. These actions could explain the inhibition of LH release.
Assuntos
Dopamina/metabolismo , Hipotálamo/efeitos dos fármacos , Hormônio Luteinizante/sangue , Pregnanolona/farmacologia , Comportamento Sexual Animal/efeitos dos fármacos , Animais , Bicuculina/farmacologia , Feminino , Antagonistas GABAérgicos/farmacologia , Hipotálamo/metabolismo , Hormônio Luteinizante/metabolismo , Ovariectomia , Postura/fisiologia , Pregnanolona/administração & dosagem , Ratos , Ratos Sprague-Dawley , Comportamento Sexual Animal/fisiologiaRESUMO
1. The neurosteroids are compounds derived from steroid hormones and synthesized in the nervous system. They can modulate different neurotransmitter pathways. In previous work we demonstrated that progesterone modulates dopamine release induced by the glutamatergic agonist N-methyl-D-aspartic acid (NMDA). 2. The aim of this work was to evaluate a possible modulatory role of the progesterone metabolite allopregnanolone on NMDA-evoked [3H]dopamine release from corpus striatum slices obtained from cycling and ovariectomized female rats. 3. We used a dynamic superfusion method to evaluate the release of [3H]dopamine. Allopregnanolone at 50-600 nM was added to the superfusion buffer (Krebs-Ringer-bicarbonate-glucose. pH 7.4. with constant O2/CO2 gassing). The results are expressed as a percentage over basal [3H]dopamine loaded by the tissue. 4. Allopregnanolone (50 and 100 nM) increased the NMDA-evoked [3H]dopamine release from estrus rats. The remaining doses did not show significant changes in the pattern of release. This effect was not observed in diestrus rats. The ovariectomy abolished the facilitatory effect of allopregnanolone on NMDA-evoked 2 [3H]dopamine release. 5. Subcutaneous administration of exogenous estrogen (25 mg/rat) and progesterone (1 mg/rat) restored the facilitatory effect on dopaminergic input. 6. These results suggest that allopregnanolone is a neurosteroid able to modulate dopamine release in an ovarian-hormone-fluctuation-dependent manner and provide further support for a role of allopregnanolone as a modulator of glutamatergic-dopaminergic interaction in the corpus striatum.