RESUMO
This study examined the time course and possible mechanisms of agonist-induced desensitization of 5-hydroxytryptamine serotonin 2A receptors in the rat frontal cortex and hypothalamic paraventricular nucleus after 1, 4, and 7 days of treatment with (-)-1-(2,5-dimethoxy-4-iodophenyl)2-aminopropane HCl [(-)-DOI] (1 mg/kg i.p.), a selective 5-HT(2A/2C) receptor agonist. In the frontal cortex, 5-HT-mediated phospholipase C (PLC) enzyme activity decreased by 24 to 30% after 4 to 7 days of (-)-DOI treatment without any significant changes in the guanosine 5'-3-O-(thio)triphosphate-mediated PLC enzyme activity. Additionally, treatment with (-)-DOI did not significantly change the levels of G(alpha11), regulator of G protein signaling (RGS)4, or RGS7 proteins in the frontal cortex, whereas G(alphaq) protein levels in the frontal cortex decreased (47%) only after 7 daily (-)-DOI injections. The functional status of 5-HT(2A) receptors in the hypothalamic paraventricular nucleus was examined using 5-HT(2A) receptor-mediated increases in plasma hormone levels. Plasma adrenocorticotrophic hormone (ACTH) and oxytocin measurements showed that 5-HT(2A) receptor desensitization began after only 1 day of (-)-DOI treatment, and the desensitization continued to increase after 4 and 7 days of treatment (ACTH response decreased 64.2-67.7%; oxytocin response decreased 82.3-90.1%). There were no significant alterations in levels of G(alphaq) or G(alpha11) lamic paraventricular proteins in the hypothanucleus. In conclusion, these results suggest that chronically administered (-)-DOI induces desensitization of 5-HT(2A) receptors in vivo, via a reduction in the ability of 5-HT(2A) receptors to activate G proteins without consistently altering levels of G(alpha) proteins or RGS proteins.
Assuntos
Anfetaminas/farmacologia , Hipotálamo/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Receptor 5-HT2A de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/metabolismo , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Fosfolipases Tipo C/metabolismoRESUMO
Differential adaptive changes in serotonin2A [5-hydroxytryptamine (5-HT)2A] receptor signaling during treatment may be one mechanism involved in the latency of therapeutic improvement with antidepressants, such as fluoxetine. We examined the effects of fluoxetine (2, 3, 7, 21, or 42 days) on hypothalamic 5-HT2A receptor signaling. The hormone responses to an injection of the 5-HT2A receptor agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane HCl (DOI) were used as an index of hypothalamic 5-HT2A receptor function. Treatment with fluoxetine for 21 or 42 days produced diminished adrenocorticotropic hormone (ACTH) and oxytocin (but not corticosterone) responses to DOI injections (2.5 mg/kg i.p.; 15 min postinjection). Regulators of G protein signaling 4 and Galphaq protein levels in the hypothalamic paraventricular nucleus were not altered during fluoxetine treatment. Because previous studies indicate that treatment with fluoxetine for 21 days resulted in increased hormone responses to DOI when measured at 30 min after injection, we examined the effect of fluoxetine (21 days) on DOI-induced increase hormone levels at 15, 30, and 60 min after DOI injection. Fluoxetine decreased the oxytocin response at 15 but not at 30 min post-DOI injection, and potentiated the ACTH and corticosterone responses at 30 min post-DOI injection. For comparison, we examined the effect of fluoxetine on 5-HT2A receptor-mediated increase in phospholipase C (PLC) activity in the frontal cortex. 5-HT-stimulated, but not guanosine 5'-O-(3-thio)triphosphate-stimulated PLC activity was increased after 21 days of fluoxetine-treatment. Overall, these results indicate that chronic fluoxetine treatment can potentiate 5-HT2A receptor signaling in frontal cortex but differentially alters 5-HT2A receptor signaling in oxytocin-containing neurons and corticotropin-releasing factor-containing neurons in the paraventricular nucleus.
Assuntos
Fluoxetina/farmacologia , Indofenol/análogos & derivados , Neurônios/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/citologia , Córtex Pré-Frontal/efeitos dos fármacos , Receptores de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Hormônio Liberador da Corticotropina/metabolismo , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP , Proteínas Heterotriméricas de Ligação ao GTP/metabolismo , Indofenol/farmacologia , Masculino , Neurônios/metabolismo , Ocitocina/metabolismo , Córtex Pré-Frontal/metabolismo , Proteínas RGS/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor 5-HT2A de Serotonina , Receptores de Serotonina/efeitos dos fármacos , Transdução de Sinais/fisiologia , Fatores de Tempo , Fosfolipases Tipo C/metabolismoRESUMO
The 5-hydroxytryptamine(2A) and (2C) (5-HT(2A) and 5-HT(2C)) receptors are so closely related that selective agonists have not been developed until recently with the advent of (S)-2-(chloro-5-fluoro-indol-l-yl)-1-methylethylamine fumarate (Ro 60-0175), a putatively selective 5-HT(2C) receptor agonist. In the present study, Ro 60-0175 was used to analyze the importance of 5-HT(2C) receptors in hormone secretion. Injection of Ro 60-0175 (5 mg/kg s.c.) produced a maximum increase in plasma levels of adrenocorticotrophic hormone, oxytocin, and prolactin at 15 min postinjection and a maximum increase in plasma corticosterone levels at 60 min postinjection. Ro 60-0175-mediated increases in plasma hormone levels were dose-dependent (corticosterone ED(50) = 2.43 mg/kg; oxytocin ED(50) = 4.19 mg/kg; and prolactin ED(50) = 4.03 mg/kg). To assess the role of 5-HT(2C) and 5-HT(2A) receptors in mediating the hormone responses to Ro 60-0175, rats were pretreated with the 5-HT(2C) antagonist 6-chloro-5-methyl-1-[2-(2-methylpyridyl-3-oxy)-pyrid-5-yl carbonyl] indoline (SB 242084) or 5-HT(2A) antagonists (+/-)-2,3-dimethoxyphenyl-1-[2-4-(piperidine)-methanol] (MDL 100,907) before injection of Ro 60-0175 (5 mg/kg s.c.). Neither SB 242084 (0.1, 0.5, 1, and 5 mg/kg i.p.) nor MDL 100,907 (1, 5, and 10 microg/kg s.c.) significantly inhibited the Ro 60-0175-induced increases in plasma hormone levels. The data suggest that Ro 60-0175 increases hormone secretion by mechanisms independent of the activation of 5-HT(2C) and/or 5-HT(2A) receptors and suggest that Ro 60-0175 is not a highly selective 5-HT(2C) receptor agonist.
Assuntos
Etilaminas/farmacologia , Indóis/farmacologia , Receptores de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/farmacologia , Aminopiridinas/farmacologia , Animais , Interações Medicamentosas , Fluorbenzenos/farmacologia , Masculino , Piperidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor 5-HT2A de Serotonina , Receptor 5-HT2C de Serotonina , Antagonistas da Serotonina/farmacologia , Fatores de TempoRESUMO
Mivazerol is a new and selective alpha 2-adrenoceptor agonist which has demonstrated anti-ischemic effects, both in animals and in patients with myocardial ischemia. In the present study, mivazerol was evaluated for its ability to inhibit the release of catecholamines and serotonin (5-HT) in the hippocampus of freely moving rats, and also was compared to clonidine. In vivo microdialysis in combination with high-performance liquid chromatography (HPLC) was employed. Intravenous administration of mivazerol (8.0 micrograms/kg) had no effect on basal outflow of norepinephrine (NE), dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC). In contrast, clonidine (8.5 micrograms/kg, i.v.) attenuated the basal release of DOPAC, which has been proposed to reflect NE biosynthesis, suggesting that clonidine has an inhibitory effect on NE synthesis. In addition, both mivazerol and clonidine decreased the spontaneous release of 5-HT, which provided further evidence that alpha 2-adrenoceptors in the hippocampus modulate 5-HT. Sixty-min immobilization stress significantly increased the release of NE (177 +/- 28%), DA (209 +/- 46%) and DOPAC (337 +/- 72%). Mivazerol (2.5, 8.0 and 25 micrograms/kg, i.v.) completely prevented the immobilization stress-induced enhancement of NE, DA and DOPAC, which was equi-effective to clonidine at a dose of 8.5 micrograms/kg, i.v. These findings demonstrate that mivazerol has a profound modulatory effect on stress-induced neurotransmitter release in the hippocampus, at dose levels reported to protect against myocardial ischemia.
Assuntos
Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Agonistas alfa-Adrenérgicos/farmacologia , Monoaminas Biogênicas/metabolismo , Hipocampo/efeitos dos fármacos , Imidazóis/farmacologia , Estresse Psicológico/metabolismo , Animais , Clonidina/farmacologia , Dopamina/metabolismo , Hipocampo/metabolismo , Ácido Homovanílico/metabolismo , Imobilização , Masculino , Norepinefrina/metabolismo , Ratos , Ratos Sprague-Dawley , Serotonina/metabolismo , Fatores de TempoRESUMO
(-)-Huperzine-A has been shown to be a promising agent for the treatment of dementia of the Alzheimer type. This substance is rare in nature. We have been able to prepare a racemic mixture of (+/-)-huperzine-A in quantity. In the absence of a chiral synthetic procedure for (-)-huperzine-A, this study sought to determine whether the racemic mixture would yield an in vitro and in vivo pharmacological profile of activity similar to that of the natural compound. The synthetic racemic mixture (+/-)-huperzine-A was 3 times less potent than (-)-huperzine-A in vitro (IC50s of 3 x 10(-7) M and 10(-7) M, respectively) because the former consisted of a racemic mixture of the compound in which the (+)-huperzine component was considerably less potent (IC50 = 7 x 10(-6) M). A comparable magnitude of effect was also observed in studies conducted in vivo, in which, over a range of 0.1-2.0 mg/kg administered intraperitoneally (i.p.), both (-)-huperzine-A and (+/-)-huperzine-A exerted significant inhibition of acetylcholinesterase activity, in all brain regions tested (hippocampus, striatum, hypothalamus and frontal cortex). This inhibition of acetylcholinesterase activity was inversely related to levels of acetylcholine measured in the hippocampus and followed the same time course of effect. (-)-Huperzine-A and (+/-)-huperzine-A were shown to be more potent than physostigmine as inhibitors of acetylcholinesterase in vitro (IC50 = 6 x 10(-7) M).