RESUMO
Opioid receptor antagonist naltrexone reduces alcohol consumption and relapse in both humans and rodents. This study investigated whether hypothalamic proopiomelanocortin (POMC) neurons (producing beta-endorphin and melanocortins) play a role in alcohol drinking behaviors. Both male and female mice with targeted deletion of two neuronal Pomc enhancers nPE1 and nPE2 (nPE-/-), resulting in hypothalamic-specific POMC deficiency, were studied in short-access (4-h/day) drinking-in-the-dark (DID, alcohol in one bottle, intermittent access (IA, 24-h cycles of alcohol access every other day, alcohol vs. water in a two-bottle choice) and alcohol deprivation effect (ADE) models. Wild-type nPE+/+ exposed to 1-week DID rapidly established stable alcohol drinking behavior with more intake in females, whereas nPE-/- mice of both sexes had less intake and less preference. Although nPE-/- showed less saccharin intake and preference than nPE+/+, there was no genotype difference in sucrose intake or preference in the DID paradigm. After 3-week IA, nPE+/+ gradually escalated to high alcohol intake and preference, with more intake in females, whereas nPE-/- showed less escalation. Pharmacological blockade of mu-opioid receptors with naltrexone reduced intake in nPE+/+ in a dose-dependent manner, but had blunted effects in nPE-/- of both sexes. When alcohol was presented again after 1-week abstinence from IA, nPE+/+ of both sexes displayed significant increases in alcohol intake (ADE or relapse-like drinking), with more pronounced ADE in females, whereas nPE-/- did not show ADE in either sex. Our results suggest that neuronal POMC is involved in modulation of alcohol 'binge' drinking, escalation and 'relapse', probably via hypothalamic-mediated mechanisms, with sex differences.
Assuntos
Insuficiência Adrenal/metabolismo , Consumo de Bebidas Alcoólicas/metabolismo , Obesidade/metabolismo , Pró-Opiomelanocortina/deficiência , Insuficiência Adrenal/genética , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Consumo de Bebidas Alcoólicas/genética , Animais , Etanol/farmacologia , Feminino , Genótipo , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Camundongos , Camundongos Knockout , Naltrexona/farmacologia , Obesidade/genética , Pró-Opiomelanocortina/genética , Pró-Opiomelanocortina/metabolismoRESUMO
Recent research suggests an involvement of pro-opiomelanocortin (POMC) gene products (e.g., beta-endorphin) in modulating cocaine-induced reward and addiction-like behaviors in rodents. In this study, we investigated whether chronic "binge" cocaine and its withdrawal altered POMC gene expression in the brain of rats. Male Fischer rats were treated with two different chronic (14-day) "binge" pattern cocaine administration regimens (three injections at 1-h intervals, i.p.): steady-dose (45mg/kg/day) and escalating-dose (90mg/kg on the last day). Although there was no POMC mRNA alteration after chronic steady-dose cocaine, a significant decrease in POMC mRNA levels in the hypothalamus was found after chronic escalating-dose cocaine. In contrast, after acute (1-day) withdrawal from chronic "binge" escalating-dose regimen, but not steady-dose regimen, there were increased hypothalamic POMC mRNA levels that persisted into 14days of protracted withdrawal. To study the role of the endogenous opioid systems in the cocaine withdrawal effects, we administered a single naloxone injection (1mg/kg) that caused elevated POMC mRNA levels observed 24h later in cocaine naïve rats, but it did not lead to further increases in cocaine-withdrawn rats. Our results suggest that during withdrawal from chronic "binge" escalating-dose cocaine: (1) there was a persistent increase in hypothalamic POMC gene expression; and (2) hyposensitivity of the POMC gene expression to naloxone indicates altered opioidergic tone at or above the hypothalamic level.
Assuntos
Transtornos Relacionados ao Uso de Cocaína/metabolismo , Cocaína/administração & dosagem , Inibidores da Captação de Dopamina/administração & dosagem , Hipotálamo/metabolismo , Pró-Opiomelanocortina/metabolismo , Síndrome de Abstinência a Substâncias/metabolismo , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Corticosterona/sangue , Hipotálamo/efeitos dos fármacos , Masculino , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , RNA Mensageiro/metabolismo , Ratos Endogâmicos F344 , Esquema de ReforçoRESUMO
Recent research suggests an involvement of pro-opiomelanocortin (POMC) gene products in modulating cocaine reward and addiction-like behaviors in rodents. In this study, we investigated whether cocaine-induced conditioned place preference (CPP) alters POMC gene expression in the brain or pituitary of rats. Sprague-Dawley rats were conditioned with 4 injections of 0, 10 or 30 mg/kg cocaine (i.p.) over 8 days and tested 4 days after the last conditioning session. Another group received the same pattern of cocaine injections without conditioning. POMC mRNA levels in the hypothalamus (including arcuate nucleus), amygdala and anterior pituitary, as well as plasma ACTH and corticosterone levels were measured. Cocaine place conditioning at 10 and 30 mg/kg doses increased POMC mRNA levels in a dose-dependent manner in the hypothalamus, with no effect in the amygdala. Cocaine CPP had no effect on POMC mRNA levels in the anterior pituitary or on plasma ACTH or corticosterone levels. In rats that received cocaine at 30 mg/kg without conditioning, there was no such effect on hypothalamic POMC mRNA levels. Alteration of POMC gene expression in the hypothalamus is region-specific after cocaine place conditioning, and dose-dependent. The increased POMC gene expression in the hypothalamus suggests that it is involved in the reward/learning process of cocaine-induced conditioning.
Assuntos
Transtornos Relacionados ao Uso de Cocaína/fisiopatologia , Cocaína/farmacologia , Condicionamento Psicológico/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Hipotálamo/fisiologia , Pró-Opiomelanocortina/genética , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/fisiologia , Animais , Condicionamento Psicológico/fisiologia , Inibidores da Captação de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/fisiologia , Masculino , Hipófise/efeitos dos fármacos , Hipófise/fisiologia , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , RecompensaRESUMO
In humans, stress is recognized as a major factor contributing to relapse to drug abuse in abstinent individuals; drugs of abuse themselves or withdrawal from such drugs act as stressors. In the animals, evidence suggests that centrally released arginine vasopressin in both amygdala and hypothalamus plays an important role in stress-related anxiogenic behaviors. The stress responsive hypothalamic-pituitary-adrenal axis is under tonic inhibition via endogenous opioids, and cocaine withdrawal stimulates hypothalamic-pituitary-adrenal activity. The present studies were undertaken to determine whether: (1) 14-day (chronic) "binge" pattern cocaine administration (45 mg/kg/day) or its withdrawal for 3 h (acute), 1 day (subacute) or 10 days (chronic) alters arginine vasopressin mRNA levels in amygdala or hypothalamus; (2) the opioid receptor antagonist naloxone (1mg/kg) alters arginine vasopressin mRNA or hypothalamic-pituitary-adrenal hormonal responses in acute cocaine withdrawal; and (3) there are associated changes of mu opioid receptor or proopiomelanocortin mRNA levels. In amygdala, arginine vasopressin mRNA levels were unchanged after chronic "binge" cocaine, but were increased during acute cocaine withdrawal. Naloxone completely blocked this increase. Neither chronic cocaine nor its acute withdrawal altered amygdalar mu opioid receptor mRNA levels. The increase in amygdalar arginine vasopressin mRNA levels was still observed after subacute withdrawal, but not after chronic withdrawal. Although hypothalamic-pituitary-adrenal tolerance developed with chronic "binge" cocaine, there were modestly elevated plasma adrenocorticotropin hormone levels during acute withdrawal. While naloxone produced modest adrenocorticotropin hormone elevations in cocaine-naïve rats, naloxone failed to elicit an adrenocorticotropin hormone response in cocaine-withdrawn rats. In hypothalamus, neither chronic cocaine nor acute withdrawal altered arginine vasopressin, proopiomelanocortin or mu opioid receptor mRNA levels. These results show that: (1) opioid receptors mediate increased amygdalar arginine vasopressin gene expression during acute cocaine withdrawal, and (2) cocaine withdrawal renders the hypothalamic-pituitary-adrenal axis insensitive to naloxone. Our findings suggest a potential role for amygdalar arginine vasopressin in the aversive consequences of early cocaine withdrawal.
Assuntos
Tonsila do Cerebelo/metabolismo , Arginina Vasopressina/efeitos dos fármacos , Arginina Vasopressina/metabolismo , Cocaína/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Síndrome de Abstinência a Substâncias/fisiopatologia , Animais , Arginina Vasopressina/genética , Expressão Gênica , Sistema Hipotálamo-Hipofisário/fisiologia , Hipotálamo/metabolismo , Masculino , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Sistema Hipófise-Suprarrenal/fisiologia , Pró-Opiomelanocortina/efeitos dos fármacos , Pró-Opiomelanocortina/metabolismo , RNA Mensageiro/análise , Ratos , Ratos Endogâmicos F344 , Receptores Opioides mu/efeitos dos fármacos , Receptores Opioides mu/metabolismoRESUMO
Repeated intake of opioids is associated with dose escalation and alterations in signal transduction at the G-protein-coupled receptor level. The current study utilized two experiments to identify factors in rats that influence consumption rates such as daily intake of self-administered morphine and receptor desensitization. In Experiment 1, rats self-administered either 0.30, 1.00, or 3.00 mg/kg/infusion morphine sulfate (morphine) during 7 daily 4-h sessions. For Experiment 2, rats were assigned to groups that self-administered either 1) self-regulated escalating doses of morphine, 2) a fixed dose of morphine, or 3) saline during 18-h sessions for 7 days to determine if dose control would increase consumption without significantly decreasing response rate. We then assessed morphine-stimulated [(35)S]GTPgammaS binding in the amygdala and thalamus from these three groups in Experiment 2. Results from Experiment 1 demonstrated that 0.30 mg/kg/morphine did not support stable self-administration. For Experiment 2, the self-escalation group self-administered more morphine than the fixed-dose group, yet maintained similar response rates. Additionally, self-escalation rats demonstrated decreased morphine-stimulated [(35)S]GTPgammaS binding in membranes prepared from amygdalar and thalamic nuclei compared to the fixed-dose and control groups. Our results suggest that session length inversely affects consumption rates for fixed doses of morphine. Self-regulated dosing of morphine is also associated with rapid escalation of daily consumption and no significant alterations in consumption rates. These results suggest subject-regulated dosing is a useful approach for modeling dose escalation associated with opioid dependence.
Assuntos
Tolerância a Medicamentos/fisiologia , Morfina/administração & dosagem , Morfina/farmacologia , Entorpecentes/administração & dosagem , Entorpecentes/farmacologia , Tonsila do Cerebelo/metabolismo , Animais , Relação Dose-Resposta a Droga , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Masculino , Dependência de Morfina , Ratos , Autoadministração , Tálamo/metabolismo , Fatores de TempoRESUMO
The hypothalamic-pituitary-adrenal (HPA) axis is regulated by stress-related excitatory inputs, and various inhibitory and negative-feedback controls by glucocorticoids and opioids, including pro-opiomelanocortin (POMC)-derived peptides. The role of POMC-derived peptides of pituitary origin in the modulation of brain POMC mRNA expression and opioid receptor binding was investigated using a line of transgenic mice that express a fusion gene composed of the pituitary expression-specific promoter region of the POMC gene driving the herpes simplex viral-1 thymidine kinase (TK). Male adult mice were treated with the antiherpes agent ganciclovir that selectively ablates cells expressing TK. Following treatment, POMC mRNA levels, measured by quantitative solution hybridization/RNase protection assays, were decreased by 48% in the pituitary of the TK+/+ mice, reflecting an expected loss of the pituitary corticotrope POMC cells. This treatment also significantly lowered pituitary beta-endorphin immunoreactivity content and plasma concentrations of corticosterone. In contrast, POMC mRNA levels were increased by 79% in the hypothalamus of the TK+/+ mice with pituitary POMC cell ablation. Binding of [(3)H]DAMGO to mu opioid receptors, as measured by quantitative autoradiography, was significantly reduced in several brain regions including the central grey, median raphe and superficial grey layer of the superior colliculus. These regions are innervated by hypothalamic POMC neurones. No significant differences in binding to either kappa or delta opioid receptors were found in the brain regions studied. These results suggest that POMC-derived peptides of pituitary origin may exert a tonic negative-feedback effect on hypothalamic POMC neurones. In turn, the downregulation of central mu opioid receptors in this model may be mediated through a mechanism related to hypothalamic POMC overexpression.
Assuntos
Hipotálamo/metabolismo , Mesencéfalo/metabolismo , Hipófise/metabolismo , Pró-Opiomelanocortina/fisiologia , RNA Mensageiro/metabolismo , Receptores Opioides mu/metabolismo , Tonsila do Cerebelo/metabolismo , Animais , Encéfalo/metabolismo , Corticosterona/sangue , Hormônio Liberador da Corticotropina/genética , Lobo Frontal/metabolismo , Masculino , Camundongos , Camundongos Transgênicos/genética , Hipófise/citologia , Pró-Opiomelanocortina/genética , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Receptores de Hormônio Liberador da Corticotropina/genética , Distribuição TecidualRESUMO
BACKGROUND: Endogenous corticotropin-releasing factor (CRF), its pituitary CRF1 receptor, and proopiomelanocortin (POMC) may be involved in the hypothalamic-pituitary-adrenal (HPA) responses to alcohol. METHODS: Alcohol (1.5 g/kg) or water was administered intragastrically to male Fischer rats after the "binge" pattern regimen, that is, three times daily at 1 hr intervals at the beginning of the light cycle. The levels of CRF, CRF1 receptor, and POMC mRNAs in the hypothalamic-pituitary axis were measured after acute (1 day) or chronic (14 days) binge pattern alcohol administration. Plasma levels of ACTH and corticosterone were measured to examine time-dependent alterations of HPA responses. RESULTS: Plasma ACTH and corticosterone levels were elevated dramatically after 1 day of acute binge pattern alcohol administration. After 14 days of chronic alcohol, however, no elevation in plasma ACTH levels and an attenuated elevation in plasma corticosterone levels were found. CRF mRNA levels in the hypothalamus were not altered after either acute or chronic alcohol administration. CRF1 receptor mRNA levels in the anterior pituitary were decreased significantly after acute administration, with no change after chronic alcohol administration. POMC mRNA levels in the anterior pituitary were not altered by either acute or chronic alcohol administration. In the hypothalamus, POMC mRNA levels were decreased significantly after acute but not chronic binge alcohol administration. CONCLUSIONS: These results suggest that (1) rats exposed to chronic binge alcohol develop tolerance in HPA activity, as shown by no elevation of ACTH and an attenuated corticosterone response to chronic alcohol after initial dramatic elevations by acute alcohol administration; (2) a concurrent acute decrease in CRF1 receptor mRNA levels in the anterior pituitary is associated with increased HPA activity, and (3) alterations of POMC gene expression in the hypothalamic region may have implications for a molecular understanding of the neuroendocrine response to alcohol.
Assuntos
Etanol/administração & dosagem , Hipotálamo/metabolismo , Adeno-Hipófise/metabolismo , Pró-Opiomelanocortina/genética , RNA Mensageiro/metabolismo , Receptores de Hormônio Liberador da Corticotropina/genética , Administração Oral , Hormônio Adrenocorticotrópico/sangue , Animais , Corticosterona/sangue , Masculino , Neuro-Hipófise/metabolismo , RatosRESUMO
There is increasing abuse of androgenic anabolic steroids (AAS) by non-athletes. AAS abuse has been associated with psychiatric symptoms such as mania, major depression and aggression and the development of dependence. Little is known about the effects of AAS on hypothalamic-pituitary-adrenal axis function or corticotropin releasing factor, which may be involved in mediating some of the psychiatric symptoms associated with AAS abuse. Male Sprague-Dawley rats received one daily intra-muscular injection of the AAS nandrolone decanoate (ND, 15 mg/kg) or vehicle for 3 days. Animals were sacrificed either 1 h or 24 h after the last injection, brain regions dissected and trunk blood collected. Corticotropin releasing factor (CRF), CRF receptor1 (CRF-R1) and proopiomelanocortin (POMC) mRNAs were measured with solution hybridization/RNase protection. Circulating levels of corticosterone and adrenocorticotropin hormone (ACTH) were determined using radioimmunoassays. One hour following the last injection, ND significantly increased circulating levels of both corticosterone and ACTH levels. In the amygdala, CRF mRNA levels were unchanged 1 h after the last injection of ND but were significantly reduced at 24 h. The same was found for hypothalamic POMC. No significant AAS effects were observed on: hypothalamic CRF mRNA; POMC mRNA in the amygdala or CRF R1 mRNA in the anterior pituitary.
Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Anabolizantes/farmacologia , Hipotálamo/efeitos dos fármacos , Nandrolona/análogos & derivados , Adeno-Hipófise/efeitos dos fármacos , Hormônio Adrenocorticotrópico/sangue , Hormônio Adrenocorticotrópico/genética , Tonsila do Cerebelo/metabolismo , Anabolizantes/administração & dosagem , Análise de Variância , Animais , Corticosterona/sangue , Corticosterona/genética , Hormônio Liberador da Corticotropina/genética , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Hipotálamo/metabolismo , Injeções Intramusculares , Masculino , Nandrolona/administração & dosagem , Nandrolona/farmacologia , Decanoato de Nandrolona , Adeno-Hipófise/metabolismo , Pró-Opiomelanocortina/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Radioimunoensaio , Ratos , Ratos Sprague-Dawley , Receptores de Hormônio Liberador da Corticotropina/genética , Fatores de TempoRESUMO
Acute administration of morphine stimulates the secretion of hypothalamic-pituitary-adrenal (HPA) hormones, ACTH, beta-endorphin and corticosterone in the rat. In this study we investigated the effects of repeated multiple-dose morphine on HPA activity under two different conditions: without or with water restriction stress. Rats received six intermittent injections of morphine (6.25 mg/kg per injection, s.c.) every 2 h and were killed 30 min after the last injection. The results were as follows. (1) Morphine significantly elevated plasma ACTH and corticosterone levels; water restriction also significantly increased ACTH secretion, but with no significant increase of plasma corticosterone levels. In contrast, rats treated with morphine under the water restriction condition failed to show any increases of either ACTH or corticosterone levels. (2) Morphine did not change pro-opiomelanocortin (POMC) mRNA levels in the anterior pituitary; whereas water restriction significantly increased the POMC mRNA levels. The water restriction-induced increases of POMC mRNA in the anterior pituitary were absent in the rats which received morphine. (3) Morphine significantly increased POMC mRNA levels in the hypothalamus; water restriction had no effect. The morphine-induced increases in POMC mRNA in the hypothalamus were absent in the rat under the water restriction condition. These findings, that the effects of morphine on HPA activation or POMC mRNA expression depend on the presence of stress, suggest a counter-regulatory role of opiates on a stress response and opioid gene expression.
Assuntos
Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Morfina/farmacologia , Entorpecentes/farmacologia , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Pró-Opiomelanocortina/metabolismo , Estresse Fisiológico/metabolismo , Hormônio Adrenocorticotrópico/sangue , Animais , Corticosterona/sangue , Esquema de Medicação , Sistema Hipotálamo-Hipofisário/metabolismo , Hipotálamo/metabolismo , Masculino , Adeno-Hipófise/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Pró-Opiomelanocortina/genética , RNA Mensageiro/genética , Ratos , Ratos WistarRESUMO
The effect of chronic cocaine exposure on the central serotonergic system in the rat was investigated using a selective 5-HT1A receptor agonist, [3H]8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT), and a 5-HT2A receptor antagonist, [3H]ketanserin, as tritiated ligands in a quantitative autoradiography study. Rats were administered cocaine in a "binge" pattern, 15 mg/kg/injection, three times a day, at 1-h intervals for 14 days to mimic the pattern often seen in human cocaine addicts. A significant decrease in the binding of [3H]8-OH-DPAT was found in the ventromedial hypothalamus (P < 0.001) and the dorsal dentate gyrus (P < 0.01) in rats administered cocaine as compared with rats injected with saline. No significant difference in the binding of [3H]ketanserin was found in frontal, parietal, agranular insular, and piriform cortices, caudate-putamen, olfactory tubercle, nucleus accumbens, thalamus, septohippocampal nucleus, and claustrum. Several studies have shown that 5-HT1A receptor agonists have antidepressant properties. Other studies, in animal models, have shown that 5-HT1A receptor agonists stimulate the hypothalamic-pituitary-adrenal axis, which is of interest, since chronic activation of this axis has been related to anxiety and depression. Our data show that the 5-HT1A component of the serotonergic system is altered following chronic "binge" pattern cocaine administration in an animal model and may be related to changes in the HPA axis and behavior.
Assuntos
Transtornos Relacionados ao Uso de Cocaína/metabolismo , Transtornos Relacionados ao Uso de Cocaína/psicologia , Giro Denteado/metabolismo , Regulação para Baixo/fisiologia , Hipotálamo/metabolismo , Receptores de Serotonina/biossíntese , Animais , Autorradiografia , Cocaína/administração & dosagem , Inibidores da Captação de Dopamina/administração & dosagem , Masculino , Ratos , Receptor 5-HT2A de Serotonina , Receptores 5-HT1 de SerotoninaRESUMO
The effects of memantine, a non-competitive NMDA-receptor antagonist used in the management of dementia, and its coadministration with acute 'binge' pattern cocaine on hypothalamic-pituitary-adrenal axis activity were investigated in the rat. Measurements 3 h after injections showed that memantine alone at 20 mg kg(-1) (i.p.), but not 10 mg kg(-1), increased corticotropin-releasing factor (CRF) mRNA levels in the hypothalamus and both adrenocorticotropic hormone and corticosterone levels in the blood, and decreased type I CRF receptor mRNA in the anterior pituitary. Our previous studies have shown that acute 'binge' cocaine increases CRF mRNA levels in the hypothalamus. In this study, pretreatment with memantine (10 and 20 mg kg(-1), i.p.) did not alter the up-regulation of hypothalamic CRF mRNA induced by acute 'binge' cocaine (3 x 15 mg kg(-1), i.p.). Of interest, pretreatment with memantine at 10 mg kg(-1), which alone had no effect on corticosterone levels, caused a greater elevation of corticosterone levels in combination with 'binge' cocaine than acute 'binge' cocaine alone, indicating that memantine does not attenuate 'binge' cocaine-stimulated hypothalamic-pituitary-adrenal activity. These results indicate that both memantine and acute 'binge' cocaine stimulate hypothalamic-pituitary-adrenal activity by activating CRF neurons in the hypothalamus.
Assuntos
Glândulas Suprarrenais/efeitos dos fármacos , Cocaína/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Hipotálamo/efeitos dos fármacos , Memantina/farmacologia , Hipófise/efeitos dos fármacos , Glândulas Suprarrenais/metabolismo , Glândulas Suprarrenais/fisiologia , Hormônio Adrenocorticotrópico/sangue , Animais , Cocaína/administração & dosagem , Hormônio Liberador da Corticotropina/genética , Hipotálamo/metabolismo , Hipotálamo/fisiologia , Masculino , Hipófise/metabolismo , Hipófise/fisiologia , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos F344RESUMO
Male Fischer rats received either methadone (a long-acting opioid agonist, 10 mg/kg/day) or saline (24 microliters/day) subcutaneously by osmotic minipumps for 7 days. Chronic steady-state methadone administration did not alter (a) corticotropin-releasing factor (CRF) mRNA in the hypothalamus, (b) proopiomelanocortin (POMC) and CRF type 1 receptor (CRF-R1) mRNAs in the anterior lobe and neurointermediate/posterior lobe of the pituitary, or (c) circulating levels of corticosterone. No change was found in levels of either POMC mRNA in the hypothalamus and amygdala, or CRF mRNA in the frontal cortex, olfactory bulb and amygdala. These results demonstrate that neither the activity of the hypothalamic-pituitary-adrenal axis, nor the beta-endorphin and CRF systems in the brain, are altered by steady-state occupancy of opioid receptors with the long-acting opioid agonist methadone.
Assuntos
Hormônio Liberador da Corticotropina/metabolismo , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Metadona/farmacologia , Entorpecentes/farmacologia , Adeno-Hipófise/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Pró-Opiomelanocortina/metabolismo , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Animais , Corticosterona/sangue , Hipotálamo/metabolismo , Bombas de Infusão Implantáveis , Masculino , Adeno-Hipófise/metabolismo , RNA Mensageiro/análise , Ratos , Ratos Endogâmicos F344RESUMO
Glucocorticoids have been shown to decrease CRF receptor binding in the anterior pituitary. To determine whether glucocorticoids or CRF peptide modulate CRF-R1 gene expression, CRF-R1 mRNA levels in rat pituitary and brain were measured after administration of a synthetic glucocorticoid, dexamethasone (DEX) or rat/human CRF (r/hCRF), using a sensitive solution hybridization RNase protection assay. DEX (400 micrograms/day) or r/hCRF (100 micrograms/kg/day) was administered twice daily for 5 days to male rats. DEX treatment caused a significant decrease in CRF-R1 mRNA levels in the anterior pituitary. Also, a significant positive correlation was found between CRF-R1 and POMC mRNA levels in the anterior pituitary of the individual animals: levels of both mRNAs were reduced by DEX. However, r/hCRF treatment had no significant effect on CRF-R1 mRNA levels in the anterior pituitary. In extrahypothalamic brain regions, mRNA levels of CRF-R1 did not change following either DEX or r/hCRF administration. Our data suggest that in addition to POMC and CRF genes, CRF-R1 gene may also be subject to negative feedback control by glucocorticoids.
Assuntos
Dexametasona/farmacologia , Glucocorticoides/farmacologia , Hipófise/efeitos dos fármacos , Pró-Opiomelanocortina/biossíntese , Receptores de Hormônio Liberador da Corticotropina/biossíntese , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Hormônio Liberador da Corticotropina/biossíntese , Hormônio Liberador da Corticotropina/genética , Hormônio Liberador da Corticotropina/farmacologia , Hipotálamo/efeitos dos fármacos , Masculino , Hibridização de Ácido Nucleico , Hipófise/metabolismo , Pró-Opiomelanocortina/genética , RNA Mensageiro/análise , Ratos , Ratos Endogâmicos F344 , Receptores de Hormônio Liberador da Corticotropina/genéticaRESUMO
The effect of chronically given morphine on the binding of ovine prolactin (oPRL) to specific areas in the male rat brain was studied. The drug was delivered through subcutaneously implanted miniosmotic pumps. The results indicated that the density of prolactin binding sites in the hypothalamus and the choroid plexus was significantly decreased in the acute phase of morphine administration but restored to control levels when tolerance to morphine was developed. The decrease in prolactin binding was contrasted by elevated plasma levels of the hormone. A negative correlation was found between the hormone concentration in plasma and the density of its binding sites in the hypothalamus and choroid plexus. The hormone-binding sites in these two regions were further characterized with regard to binding constants and molecular sizes. The relevance of the present results with respect to the hypothalamic control of prolactin secretion is discussed.
Assuntos
Encéfalo/metabolismo , Morfina/farmacologia , Receptores da Prolactina/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Plexo Corióideo/efeitos dos fármacos , Plexo Corióideo/metabolismo , Concentração de Íons de Hidrogênio , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Bombas de Infusão Implantáveis , Masculino , Peso Molecular , Morfina/administração & dosagem , Prolactina/sangue , Prolactina/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores da Prolactina/efeitos dos fármacosRESUMO
This study examined the effects of a computerized functional electrical stimulation exercise program on plasma beta-endorphin-like immunoreactivity (BEP-ir), cortisol levels and depression parameters in spinal cord-injured individuals. Nine subjects from 1.2 to 33.5 yr postinjury with both motor and sensory complete lesions between C5 and T12 participated. It was determined that patients who sustained spinal cord-injuries less than 5 yr before this study had lower than normal baseline levels of BEP-ir and flattened circadian rhythms. Patients who sustained their injury greater than 5 yr before this study had higher baseline levels of BEP-ir with some return to normal circadian rhythmicity. Baseline cortisol levels, regardless of time since injury, appeared to be dysregulated. Regular exercise with computerized functional electrical stimulation caused significantly (P less than 0.05) sustained increases in BEP-ir in all patients and improved the regulation of cortisol. Furthermore, the more strenuous the exercise training, greater increases in BEP-ir levels were seen. Last, depression scores improved, which suggests a possible association between subjective mood and BEP-ir levels.
Assuntos
Terapia por Estimulação Elétrica , Traumatismos da Medula Espinal/sangue , beta-Endorfina/sangue , Adulto , Ritmo Circadiano , Computadores , Depressão/sangue , Exercício Físico , Feminino , Humanos , Hidrocortisona/sangue , Masculino , Pessoa de Meia-Idade , Traumatismos da Medula Espinal/psicologia , Fatores de TempoAssuntos
Química Encefálica , Sistema Digestório/metabolismo , Endorfinas/metabolismo , Envelhecimento/metabolismo , Animais , Química Encefálica/efeitos dos fármacos , Encefalina Metionina/análogos & derivados , Encefalina Metionina/farmacologia , Cobaias , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Técnicas In Vitro , Masculino , Ratos , Especificidade da EspécieRESUMO
The effects of chronic treatment with methadone, a long-acting opiate agonist, and naltrexone, a long-acting opiate antagonist on brain immunoreactive beta-endorphin (IR-beta-EP) concentrations were studied in the rat. Male rats were treated for 30 days with either methadone, 2.5 mg/kg/day; naltrexone 2 mg/kg/day, or saline. In a repeat experiment, rats were treated for 36 days with either methadone 2.5 mg/kg/day; naltrexone 4 mg/kg/day, or saline. Brain regions were homogenized in 0.2 N HCl and assayed for IR-beta-EP by RIA. No change in the IR-beta-EP content of the hypothalamus, thalamus, midbrain, or amygdala was measured in either experiment after methadone treatment. Naltrexone, however, significantly lowered brain IR-beta-EP in both experiments. In the first study hypothalamic IR-beta-EP fell from 189 +/- 17 (SEM) to 132 +/- 7.0 ng/g wet weight of tissue after naltrexone treatment (p less than 0.01). In the second experiment naltrexone lowered IR-beta-EP in the hypothalamus from 23.4 +/- 3.6 to 15.5 +/- 1.2 ng/mg protein (p less than 0.005). Similar decreases in the IR-beta-EP content of the thalamus (from 6.74 +/- 0.59 to 4.59 +/- 0.38 ng/mg protein) and amygdala (from 1.31 +/- 0.08 to 0.90 +/- 0.10) were also measured (p less than 0.01). We conclude that occupancy of opiate receptors by an opiate antagonist reduces brain levels of IR-beta-EP and suggests that chronic opiate receptor blockade may result in a compensatory increase in brain beta-EP release.
Assuntos
Química Encefálica/efeitos dos fármacos , Endorfinas/análise , Metadona/farmacologia , Naloxona/análogos & derivados , Naltrexona/farmacologia , Animais , Hipotálamo/análise , Masculino , Radioimunoensaio , Ratos , Ratos Endogâmicos , beta-EndorfinaRESUMO
Narcotic withdrawal is often accompanied by an atypical depression with responds to resumption of narcotics. We hypothesized that methadone might exert its antidepressant effects through monoamine oxidase (MAO) inhibition. The current study examined 3H-methadone distribution in rat brain and effects on regional MAO activity with acute doses (2.5 mg/kg) which approximate those found during chronic methadone maintenance in man. Limbic areas (amygdala, basomedial hypothalamus, caudate-putamen, hippocampus, preoptic nucleus), as well as pituitary and liver were assayed for MAO activity and methadone concentration. MAO activities did not differ significantly in acute methadone or saline-treated cage-mates at 1 or 24 hr. The concentrations of methadone at 1 hr ranged between 17 and 223 ng/100 mg wet wt tissue in the preoptic nucleus and pituitary, respectively. No significant correlation was found between change in MAO activity (MAO methadone/MAO saline) and methadone concentration in any region at 1 or 24 hr. This study does not support the hypothesis that methadone acts as an antidepressant through MAO inhibition, at least not following acute administration of this exogenous opioid.