RESUMEN
OBJECTIVE: The present study evaluated the effect of systemic injection of the CRF1 receptor antagonist R121919, the corticosterone synthesis inhibitor metyrapone and central amygdala (CeA) injections of the nonselective CRF antagonist D-Phe-CRF(12-41) in rats in which binge eating was evoked by stress and cycles of food restriction. METHOD: Female rats were subjected or not to repeated cycles of regular chow food restriction/ad libitum feeding during which they were also given limited access (2 h) to palatable food. On the test day, rats were either exposed or not to the sight of the palatable food for 15 min without allowing access, before assessing food consumption. RESULTS: Systemic injections of R121919, but not of the metyrapone, blocked binge-like eating behavior. Restricted and stressed rats showed up-regulation of crh1 receptor mRNA signal in the bed nucleus of the stria terminalis and CeA but not in basolateral amygdala (BLA) or in the paraventricular nucleus. Injection D-Phe-CRF(12-41) in CeA but not in the BLA-blocked binge-like eating behavior. DISCUSSION: These findings demonstrate that extra-hypothalamic CRF1 receptors, rather than those involved in endocrine functions, are involved in binge eating and the crucial role of CRF receptors in CeA. CRF1 receptor antagonism may represent a novel pharmacological treatment for binge-related eating disorders.
Asunto(s)
Trastorno por Atracón/genética , Conducta Alimentaria/efectos de los fármacos , Receptores de Hormona Liberadora de Corticotropina/inmunología , Animales , Femenino , Humanos , Ratas , Ratas Sprague-DawleyRESUMEN
We developed recently a binge-eating model in which female rats with a history of intermittent food restriction show binge-like palatable food consumption after 15 min exposure to the sight of the palatable food. This "frustration stress" manipulation also activates the hypothalamic-pituitary-adrenal stress axis. Here, we determined the role of the stress neurohormone corticotropin-releasing factor (CRF) in stress-induced binge eating in our model. We also assessed the role of CRF receptors in the bed nucleus of the stria terminalis (BNST), a brain region implicated in stress responses and stress-induced drug seeking, in stress-induced binge eating. We used four groups that were first exposed or not exposed to repeated intermittent cycles of regular chow food restriction during which they were also given intermittent access to high-caloric palatable food. On the test day, we either exposed or did not expose the rats to the sight of the palatable food for 15 min (frustration stress) before assessing food consumption for 2 h. We found that systemic injections of the CRF1 receptor antagonist R121919 (2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7 dipropylamino pyrazolo[1,5-a]pyrimidine) (10-20 mg/kg) and BNST (25-50 ng/side) or ventricular (1000 ng) injections of the nonselective CRF receptor antagonist D-Phe-CRF(12-41) decreased frustration stress-induced binge eating in rats with a history of food restriction. Frustration stress also increased Fos (a neuronal activity marker) expression in ventral and dorsal BNST. Results demonstrate a critical role of CRF receptors in BNST in stress-induced binge eating in our rat model. CRF1 receptor antagonists may represent a novel pharmacological treatment for bingeing-related eating disorders.
Asunto(s)
Bulimia/etiología , Privación de Alimentos , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Núcleos Septales/metabolismo , Estrés Psicológico/complicaciones , Animales , Conducta Consumatoria/efectos de los fármacos , Conducta Consumatoria/fisiología , Hormona Liberadora de Corticotropina/análogos & derivados , Hormona Liberadora de Corticotropina/farmacología , Femenino , Inyecciones Intraventriculares , Proteínas Oncogénicas v-fos/metabolismo , Pirimidinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Hormona Liberadora de Corticotropina/agonistas , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Núcleos Septales/efectos de los fármacos , Factores de TiempoRESUMEN
Alcohol abuse is associated with long-term reductions in fronto-cortical volume and limbic metabolism. However, an unanswered question in alcohol research is whether these alterations are the sole consequence of chronic alcohol use, or contain heritable contributions reflecting biological propensity toward ethanol addiction. Animal models of genetic predisposition to alcohol dependence can be used to investigate the role of inborn brain abnormalities in the aetiology of alcoholism. Here we used magnetic resonance imaging (MRI) in the Marchigian-Sardinian (msP) alcohol-preferring rats to assess the presence of inherited structural or functional brain alterations. Alcohol-naïve msP (N=22) and control rats (N=26) were subjected to basal cerebral blood volume (bCBV) mapping followed by voxel-based morphometry (VBM) of grey matter and tract-based spatial statistics mapping of white matter fractional anisotropy. msP rats exhibited significantly reduced bCBV, an established marker of resting brain function, in focal cortico-limbic and thalamic areas, together with reduced grey matter volume in the thalamus, ventral tegmental area, insular and cingulate cortex. No statistically significant differences in fractional anisotropy were observed between groups. These findings highlight the presence of inborn grey matter and metabolic abnormalities in alcohol-naïve msP rats, the localization and sign of which are remarkably similar to those mapped in abstinent alcoholics and subjects at high risk for alcohol dependence. Collectively, these results point for a significant role of heritable neurofunctional brain alterations in biological propensity toward ethanol addiction, and support the translational use of advanced imaging methods to describe the circuital determinants of vulnerability to drug addiction.
Asunto(s)
Alcoholismo/metabolismo , Alcoholismo/patología , Lóbulo Frontal/anomalías , Sistema Límbico/metabolismo , Animales , Anisotropía , Corteza Cerebral/anomalías , Modelos Animales de Enfermedad , Imagen por Resonancia Magnética , Ratas , Ratas WistarRESUMEN
Drug addiction is a chronic relapsing disorder characterized by compulsive drug seeking and use. Environmental conditioning factors are among the major determinants of relapse in abstinent cocaine users. Here we describe a role of the neuropeptide S (NPS) system in regulating relapse. In rats with a history of cocaine self-administration, presentation of stimuli predictive of drug availability reinstates drug seeking, triggering relapse. Intracerebroventricular (ICV) injection of NPS increased conditioned reinstatement of cocaine seeking, whereas peripheral administration of the NPS receptor antagonist SHA 68 reduced it. Manipulation of the NPS receptor system did not modify cocaine self-administration. We also found that ICV NPS administration activates c-Fos expression in hypocretin-1/orexin-A (Hcrt-1/Ox-A) immunoreactive neurons in the lateral hypothalamus (LH) and in the perifornical area (PeF). Of note, intra-LH and intra-PeF administration of NPS increased conditioned reinstatement of cocaine responding, an effect that was selectively blocked with the Hcrt-1/Ox-A receptor selective antagonist SB334867. Finally, results showed that intra-LH injection of the NPS antagonist [D-Cys(tBu) (5)]NPS blocked cue-induced cocaine seeking, indicating a role for this system in the pathophysiology of drug relapse.
Asunto(s)
Trastornos Relacionados con Cocaína/etiología , Hipotálamo/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Neuropéptidos/metabolismo , Neuropéptidos/fisiología , Animales , Cocaína/administración & dosificación , Señales (Psicología) , Vías de Administración de Medicamentos , Hipotálamo/citología , Neuronas , Neuropéptidos/administración & dosificación , Neuropéptidos/antagonistas & inhibidores , Neurotransmisores , Orexinas , Ratas , Ratas Long-Evans , RecurrenciaRESUMEN
The present study examined the effect of two A(2A) adenosine receptor (AR) agonists, CGS 21680 and VT 7, on high-palatability food (HPF) intake in a model of binge eating in sated rats and on low-palatability food (LPF) intake in food-deprived rats. Binge eating was induced in female rats by three 8-day cycles of food restriction/refeeding, followed by acute stress. Two groups of rats were used: NR+NS rats normally fed and not stressed and R+S rats exposed to cycles of food restriction/refeeding and then stressed. R+S rats had higher intake of HPF than the NR+NS controls. The two A(2A)AR agonists were tested at doses of 0.1 and 0.05 mg/kg intraperitoneally; VT 7 did not modify locomotor activity at either dose, whereas CGS 21680 only slightly reduced it at the higher dose tested. The injection of 0.1 mg/kg of both agonists markedly reduced HPF intake both in R+S and in NR+NS rats. The dose of 0.05 mg/kg was inactive. CGS 21680 and VT 7, 0.1 mg/kg, also reduced the standard LPF intake in 24 h food-deprived rats; however, they did not reduce water intake, indicating that their effect on food intake is selective. The dose of 0.05 mg/kg was inactive. Thus, A(2A)AR agonists exert a rather general effect on food intake, inhibiting both HPF intake in sated rats and LPF intake in food-deprived rats. They may potentially be useful pharmacological agents to control binge-related eating disorders and to reduce food overconsumption associated with obesity.
Asunto(s)
Agonistas del Receptor de Adenosina A2/uso terapéutico , Adenosina/análogos & derivados , Depresores del Apetito/uso terapéutico , Trastorno por Atracón/tratamiento farmacológico , Conducta Alimentaria/efectos de los fármacos , Fenetilaminas/uso terapéutico , Receptor de Adenosina A2A/metabolismo , Tionucleósidos/uso terapéutico , Adenosina/administración & dosificación , Adenosina/uso terapéutico , Agonistas del Receptor de Adenosina A2/administración & dosificación , Animales , Depresores del Apetito/administración & dosificación , Regulación del Apetito/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Ingestión de Energía/efectos de los fármacos , Femenino , Preferencias Alimentarias , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/metabolismo , Fenetilaminas/administración & dosificación , Ratas , Ratas Sprague-Dawley , Receptor de Adenosina A2A/química , Respuesta de Saciedad/efectos de los fármacos , Tionucleósidos/administración & dosificaciónRESUMEN
Amphotericin B is a polyene macrolide derived from Streptomyces nodosus. Introduced into therapy in 1957, for decades amphotericin B has been the "gold standard" for fighting systemic fungal infections. In order to facilitate its systemic use, much attention has been paid to the development of pharmaceutical forms that could reduce its toxicity, especially for the kidney. Because of its low solubility in water and excellent solubility in lipids, amphotericin B is an ideal candidate for lipid-based formulations. Three different lipid formulations for intravenous infusion are currently commercially available: liposomal amphotericin (AmBisome), Amphotericin lipid complex (Abelcet) and Amphotericin colloidal dispersion (Amphocil). The three lipid formulations of amphotericin B show significantly different structural, physical, chemical, pharmacokinetic, pharmacodynamic and toxicological characteristics. Several lines of evidence indicate that the three formulations of amphotericin B are not therapeutically equivalent. First, they are not bioequivalent. Second, even though a complete picture of controlled clinical research designed to compare effectiveness and safety of the three lipid formulations is not available, all the clinical studies analyzed report clear differences in toxicity between the three formulations. AmBisome appears to be clearly less toxic than the other two formulations, in terms of nephrotoxicity and of incidence of infusion-related adverse events. Third, the therapeutic non-equivalence of the three lipid formulations of amphotericin B is further supported by statements of Conferences and Scientific Societies that in their recommendations have awarded different grading to the three lipid formulations. (www.actabiomedica.it).
Asunto(s)
Anfotericina B/farmacocinética , Infecciones Bacterianas/tratamiento farmacológico , Química Farmacéutica , Lípidos/farmacocinética , Anfotericina B/administración & dosificación , Antibacterianos/administración & dosificación , Antibacterianos/farmacocinética , Infecciones Bacterianas/metabolismo , Portadores de Fármacos , Composición de Medicamentos , Humanos , Infusiones Intravenosas , Lípidos/administración & dosificación , Equivalencia TerapéuticaRESUMEN
BACKGROUND: Alcohol withdrawal refers to a cluster of symptoms that may occur from suddenly ceasing the use of alcohol after chronic or prolonged ingestion. These symptoms make alcohol abstinence difficult and increase the risk of relapse in recovering alcoholics. In previous studies, we demonstrated that treatment with Nociceptin/orphanin FQ (N/OFQ) significantly reduces alcohol consumption and attenuates alcohol-seeking behavior induced by environmental conditioning factors or by stress in rats. In this study, we evaluated whether activation of brain NOP receptors may also attenuate alcohol withdrawal signs in rats. METHODS: For this purpose, animals were subjected to a 6-day chronic alcohol intoxication (by intragastric administration), and at 8, 10, and 12 hours following cessation of alcohol exposure, they were treated intracerebroventricularly (ICV) with N/OFQ (0.0, 1.0, and 3.0 µg/rat). Somatic withdrawal signs were scored after ICV treatment. In a subsequent experiment, to evaluate N/OFQ effects on alcohol withdrawal-induced anxiety, another group of rats was subjected to ethanol intoxication and after 1 week was tested for anxiety behavior in the elevated plus maze (EPM). In the last experiment, an additional group of rats was tested for anxiety elicited by acute ethanol intoxication (hangover anxiety). For this purpose, animals received an acute dose (3.0 g/kg) of 20% alcohol and 12 hour later were tested in the EPM following ICV N/OFQ (0.0, 1.0, and 2.0 µg/rat). RESULTS: Results showed that N/OFQ significantly reduced the expression of somatic withdrawal signs and reversed anxiety-like behaviors associated with both chronic and acute alcohol intoxication. N/OFQ did not affect anxiety scores in nondependent animals. CONCLUSIONS: These findings suggest that the N/OFQ-NOP receptor system may represent a promising target for the development of new treatments to ameliorate alcohol withdrawal symptoms.
Asunto(s)
Ansiedad/tratamiento farmacológico , Depresores del Sistema Nervioso Central/toxicidad , Etanol/toxicidad , Neurotransmisores/farmacología , Péptidos Opioides/farmacología , Fragmentos de Péptidos/farmacología , Receptores Opioides/agonistas , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Alcoholismo/metabolismo , Animales , Ansiedad/inducido químicamente , Encéfalo , Depresores del Sistema Nervioso Central/sangre , Modelos Animales de Enfermedad , Etanol/sangre , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratas , Ratas Wistar , Síndrome de Abstinencia a Sustancias/metabolismo , Factores de Tiempo , Receptor de NociceptinaRESUMEN
Nociceptin/orphanin FQ (N/OFQ), the nociceptin opioid peptide (NOP) receptor ligand, increases feeding when injected centrally. Initial data suggest that N/OFQ blocks the development of a conditioned taste aversion (CTA). The current project further characterized the involvement of N/OFQ in the regulation of hunger vs. aversive responses in rats by employing behavioral, immunohistochemical, and real-time PCR methodology. We determined that the same low dose of the NOP antagonist [Nphe(1)]N/OFQ(1-13)NH(2) delivered via the lateral ventricle diminishes both N/OFQ- and deprivation-induced feeding. This anorexigenic effect did not stem from aversive consequences, as the antagonist did not cause the development of a CTA. When [Nphe(1)]N/OFQ(1-13)NH(2) was administered with LiCl, it moderately delayed extinction of the LiCl-induced CTA. Injection of LiCl + antagonist compared with LiCl alone generated an increase in c-Fos immunoreactivity in the central nucleus of the amygdala. The antagonist alone elevated Fos immunoreactivity in the paraventricular nucleus of the hypothalamus, nucleus of the solitary tract, and central nucleus of the amygdala. Hypothalamic NOP mRNA levels were decreased during energy intake restriction induced by aversion, as well as in non-CTA rats food-restricted to match CTA-reduced consumption. Brain stem NOP was upregulated only in aversion. Prepro-N/OFQ mRNA showed a trend toward upregulation in restricted rats (P = 0.068). We conclude that the N/OFQ system promotes feeding by affecting the need to replenish lacking calories and by reducing aversive responsiveness. It may belong to mechanisms that shift a balance between the drive to ingest energy and avoidance of potentially tainted food.
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Conducta Animal , Encéfalo/metabolismo , Condicionamiento Psicológico , Ingestión de Alimentos , Ingestión de Energía , Hambre , Péptidos Opioides/metabolismo , Transducción de Señal , Amígdala del Cerebelo/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Tronco Encefálico/metabolismo , Condicionamiento Psicológico/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Energía/efectos de los fármacos , Extinción Psicológica , Regulación de la Expresión Génica , Hambre/efectos de los fármacos , Hipotálamo/metabolismo , Inmunohistoquímica , Inyecciones Intraventriculares , Cloruro de Litio/administración & dosificación , Masculino , Antagonistas de Narcóticos , Péptidos Opioides/genética , Fragmentos de Péptidos/administración & dosificación , Proteínas Proto-Oncogénicas c-fos/metabolismo , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores Opioides/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/efectos de los fármacos , Factores de Tiempo , Receptor de Nociceptina , NociceptinaRESUMEN
Neuropeptide S (NPS) is a recently discovered neurotransmitter that binds to its cognate G-protein coupled receptor, NPSR. Previous studies have shown that central administration of this peptide induces anxiolytic-like effects, promotes arousal and inhibits feeding in the same dose range. In the present study, we sought to investigate further the unique physiopharmacological profile of the NPS system by characterizing its effects on palatable food consumption in rats and comparing it with the effect of the classical anxiolytic benzodiazepine midazolam. The results demonstrated that midazolam (5.0 or 10.0 mg/kg) increases palatable food consumption, while intracerebroventricular (ICV) administration of NPS markedly reduces it. The anorectic effect of NPS (0.1-1.0 nmol per rat, ICV) was prevented by ICV pretreatment with the NPSR antagonist [D-Cys(tBU)(5)]NPS (20.0-60.0 nmol per rat). Pretreatment with the nonselective corticotrophin-releasing factor receptor (CRF) antagonist alpha-helical CRF 9-41 (6.25 and 12.5 nmol per rat) completely reversed the hypophagic action of CRF (0.4 nmol per rat, ICV) but did not prevent the anorectic effect of ICV NPS (1.0 nmol per rat). Brain site-specific microinjection experiments revealed that NPS markedly inhibits palatable food intake if administered into the paraventricular nucleus of the hypothalamus (PVN). A similar but smaller and shorter lasting reduction of feeding was observed following intra-lateral hypothalamus administration, whereas no effect was observed following injection into the central amygdala. The present study demonstrates that NPS evokes a potent inhibition of palatable food consumption and that the PVN is an important site of action for its effect.
Asunto(s)
Ingestión de Alimentos/efectos de los fármacos , Preferencias Alimentarias/efectos de los fármacos , Inhibición Neural/efectos de los fármacos , Neuropéptidos/farmacología , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Análisis de Varianza , Animales , Hormona Liberadora de Corticotropina/farmacología , Relación Dosis-Respuesta a Droga , Moduladores del GABA/farmacología , Antagonistas de Hormonas/farmacología , Masculino , Midazolam/farmacología , Neuropéptidos/antagonistas & inhibidores , Núcleo Hipotalámico Paraventricular/fisiología , Fragmentos de Péptidos/farmacología , Ratas , Ratas WistarRESUMEN
The present study was undertaken to develop an animal model exploiting food cue-induced increased motivation to obtain food under operant self-administration conditions. To demonstrate the predictive validity of the model, rimonabant, fluoxetine, sibutramine and topiramate, administered 1 hour before the experiment, were tested. For 5 days, female Wistar rats were trained to self-administer standard 45 mg food pellets in one daily session (30 minutes) under FR1 (fixed ratio 1) schedule of reinforcement. Rats were then trained to an FR3 schedule and finally divided into two groups. The first group (control) was subjected to a standard 30 minutes FR3 food self-administration session. The second group was exposed to five presentations of levers and light for 10 seconds each (every 3 minutes in 15 minutes total). At the completion of this pre-session phase, a normal 30-minute session (as in the control group) started. Results showed that pre-exposure to environmental stimuli associated to food deliveries increased response for food when the session started. Corticosterone and adrenocorticotropic hormone plasma levels, measured after the 15-minute pre-exposure, were also significantly increased. No changes were observed for the other measured hormones (growth hormone, prolactin, thyroid-stimulating hormone, luteinizing hormone, insulin, amylin, gastric inhibitor polypeptide, ghrelin, leptin, peptide YY and pancreatic polypeptide). Rimonabant, sibutramine and fluoxetine significantly reduced food intake in both animals pre-exposed and in those not pre-exposed to food-associated cues. Topiramate selectively reduced feeding only in pre-exposed rats. The present study describes the development of a new animal model to investigate cue-induced increased motivation to obtain food. This model shows face and predictive validity, thus, supporting its usefulness in the investigation of new potential treatments of binge-related eating disorders. In addition, the present findings confirm that topiramate may represent an important pharmacotherapeutic approach to binge-related eating.
Asunto(s)
Condicionamiento Operante , Ambiente , Conducta Alimentaria , Sistema Hipotálamo-Hipofisario/fisiología , Sistema Hipófiso-Suprarrenal/fisiología , Hormona Adrenocorticotrópica/sangre , Animales , Fármacos Antiobesidad/administración & dosificación , Fármacos Antiobesidad/farmacología , Depresores del Apetito/administración & dosificación , Depresores del Apetito/farmacología , Cannabinoides/antagonistas & inhibidores , Corticosterona/sangre , Señales (Psicología) , Ciclobutanos/administración & dosificación , Ciclobutanos/farmacología , Femenino , Fluoxetina/administración & dosificación , Fluoxetina/farmacología , Fructosa/administración & dosificación , Fructosa/análogos & derivados , Fructosa/farmacología , Humanos , Motivación/efectos de los fármacos , Piperidinas/administración & dosificación , Piperidinas/farmacología , Pirazoles/administración & dosificación , Pirazoles/farmacología , Ratas , Reproducibilidad de los Resultados , Rimonabant , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , TopiramatoRESUMEN
RATIONALE: Nociceptin/orphanin FQ (N/OFQ) has been proposed to be a functional antagonist of corticotropin-releasing factor (CRF) in relation to its anti-stress action and its ability to antagonize the anorectic effect of CRF in rats without exhibiting affinity for CRF receptors. The bed nucleus of the stria terminalis (BST) is highly sensitive to the inhibitory effect of N/OFQ on CRF-induced anorexia. OBJECTIVE: The present study was aimed at further evaluating the role of the BST in the functional antagonism between N/OFQ and CRF by examining it at molecular level and in the context of CRF-induced anxiety in the rat. MATERIALS AND METHODS: First, in situ hybridization experiments investigated the expression of the pro-N/OFQ precursor and of NOP receptors in several brain areas 6 h after injection of CRF (0.2 and 1 microg/rat) into the lateral cerebroventricle (LV). Second, the elevated plus maze test was used to evaluate whether N/OFQ, injected into the BST (0.05 and 0.5 microg/rat) or into the LV (0.5, 1.8, and 2.4 microg/rat), inhibits the anxiogenic-like effect evoked by LV injection of CRF (1 microg/rat) in rats. RESULTS: The in situ hybridization study showed that LV injection of CRF 1 microg/rat increases NOP receptor expression in the BST, while no change of the N/OFQ precursor was observed. On the other hand, N/OFQ injection into the BST blocks the anxiogenic effect of CRF at doses lower than those required by LV injection (0.5 vs 1.8 microg/rat, respectively). CONCLUSION: These data provide further support for the hypothesis that N/OFQ may behave as functional antagonist of CRF and suggest that this antagonism may occur within the BST.
Asunto(s)
Hormona Liberadora de Corticotropina/fisiología , Péptidos Opioides/fisiología , Núcleos Septales/fisiología , Animales , Ansiedad/inducido químicamente , Ansiedad/tratamiento farmacológico , Hormona Liberadora de Corticotropina/farmacología , Hibridación in Situ , Inyecciones Intraventriculares , Masculino , Aprendizaje por Laberinto , Péptidos Opioides/biosíntesis , ARN Mensajero/biosíntesis , Ratas , Ratas Wistar , Receptores Opioides/biosíntesis , Núcleos Septales/metabolismo , Receptor de Nociceptina , NociceptinaRESUMEN
BACKGROUND: Activation of the NOP receptor by its endogenous ligand nociceptin/orphanin FQ reduces ethanol intake in genetically selected alcohol preferring Marchigian Sardinian alcohol preferring (msP) rats. Here we evaluated whether buprenorphine, a partial agonist at micro-opioid and NOP receptors, would reduce ethanol consumption in msP rats via activation of NOP receptors. METHODS: Marchigian Sardinian alcohol preferring rats trained to drink 10% alcohol 2 hours/day were injected with buprenorphine (.03, .3, 3.0, or 6.0 mg/kg intraperitoneally [IP]) 90 min before access to ethanol. RESULTS: Similar to prototypical micro-agonists, the two lowest doses of buprenorphine significantly increased ethanol consumption (p < .01); in contrast, the two highest doses reduced it (p < .05). Pretreatment with naltrexone (.25 mg/kg IP) prevented the increase of ethanol intake induced by .03 mg/kg of buprenorphine (p < .001) but did not affect the inhibition of ethanol drinking induced by 3.0 mg/kg of buprenorphine. Conversely, pretreatment with the selective NOP receptor antagonist UFP-101 (10.0 or 20.0 microg/rat) abolished the suppression of ethanol drinking by 3.0 mg/kg of buprenorphine. CONCLUSIONS: Buprenorphine has dualistic effects on ethanol drinking; low doses increase alcohol intake via stimulation of classic opioid receptors, whereas higher doses reduce it via activation of NOP receptors. We suggest that NOP agonistic properties of buprenorphine might be useful in the treatment of alcoholism.
Asunto(s)
Consumo de Bebidas Alcohólicas/tratamiento farmacológico , Buprenorfina/uso terapéutico , Antagonistas de Narcóticos/uso terapéutico , Péptidos Opioides/metabolismo , Receptores Opioides/metabolismo , Consumo de Bebidas Alcohólicas/genética , Análisis de Varianza , Animales , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Ingestión de Líquidos/efectos de los fármacos , Conducta de Ingestión de Líquido/efectos de los fármacos , Vías de Administración de Medicamentos , Interacciones Farmacológicas , Ingestión de Alimentos/efectos de los fármacos , Etanol/metabolismo , Conducta Exploratoria/efectos de los fármacos , Masculino , Naltrexona/uso terapéutico , Péptidos Opioides/farmacología , Ratas , Receptores Opioides mu/fisiología , Factores de Tiempo , Receptor de Nociceptina , NociceptinaRESUMEN
Wistar Ottawa Karlsburg W (WOKW) rats and their controls, dark agouti (DA), present different features: in particular, DA rats are lean, while the WOKW are obese and present symptoms of hypertension, dyslipidemia, hyperinsulinemia, and impaired glucose tolerance. The present study tested the hypothesis that these two strains would demonstrate different sensitivity to nociceptin/orphanin FQ (N/OFQ). N/OFQ was injected into the lateral brain ventricle (LBV) of sated DA and WOKW rats, and corticosterone levels in both strains were measured after LBV injection of N/OFQ. LBV N/OFQ injections dose-dependently produced a significant increase in food intake (4 h) in DA rats, but not in WOKW. However, corticosterone levels were increased by N/OFQ to a greater degree in WOKW than in DA rats. Gene sequencing and gene expression of ORL1 receptor and cocaine-amphetamine regulated transcript (Cart) peptide were evaluated to study the difference in N/OFQ-induced feeding behavior in the two strains. WOKW rats had a different amino acid sequence of Cart peptide and a significantly higher expression of Cart in the hypothalamus. The present data show that DA and WOKW rats demonstrate different sensitivity to N/OFQ, and suggest that Cart peptide might be the underlying mechanism of this difference.
Asunto(s)
Anfetaminas/farmacología , Cocaína/farmacología , Conducta Alimentaria/efectos de los fármacos , Proteínas del Tejido Nervioso/fisiología , Péptidos Opioides/farmacología , ARN Mensajero/genética , Animales , Inyecciones Intraventriculares , Ratas , Ratas Endogámicas F344 , Ratas Wistar , Especificidad de la Especie , NociceptinaRESUMEN
The influence of peripheral nociceptin/orphanin FQ (N/OFQ) on cold restraint-induced gastric mucosal damage in the rat was investigated. Exposure to cold-restraint for 3 and 4h caused the formation of hemorrhagic lesions in the glandular portion of the stomach. N/OFQ dose-dependently decreased lesion formation, in the range 0.03-1 microg/kg/h i.p. Its effect was reversed by the selective NOP receptor antagonist [Nphe(1)Arg(14)Lys(15)]N/OFQ-NH(2) (UFP-101), 30 microg/kg/h ip. The selective NOP receptor agonist [(pF)Phe(4)Aib(7)Arg(14)Lys(15)]N/OFQ-NH(2) (UFP-112), 0.01-0.3 microg/kg/h i.p., similarly reduced lesion formation. Light and scanning electron microscopy confirmed the protective activity of N/OFQ. Cold-restraint stress causes a reduction in mucus content and in adhering mucus layer, partly counteracted by N/OFQ. These results suggest that N/OFQ counteracts acute stress-induced gastric mucosal damage by interacting with NOP receptor and by influencing mucous cell activity.
Asunto(s)
Mucosa Gástrica/efectos de los fármacos , Péptidos Opioides/farmacología , Fragmentos de Péptidos/farmacología , Animales , Frío/efectos adversos , Mucosa Gástrica/lesiones , Mucosa Gástrica/metabolismo , Masculino , Microscopía Electrónica de Rastreo , Antagonistas de Narcóticos , Péptidos Opioides/administración & dosificación , Péptidos Opioides/metabolismo , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/metabolismo , Ratas , Ratas Wistar , Receptores Opioides/metabolismo , Restricción Física/efectos adversos , Estrés Fisiológico/complicaciones , Estrés Fisiológico/metabolismo , Receptor de NociceptinaRESUMEN
Alcoholic patients and experimental animals exposed to ethanol display biochemical signs of oxidative damage, suggesting a possible role of free radicals in causing some of the toxic effects of alcohol. The ester derivative, ethyl pyruvate (EP) is stable in solution and should function as an antioxidant and energy precursor. In the present study, the effect of ethanol intake on plasma membrane fluidity, lipid oxidation and antioxidant enzyme activities (GPx, CAT and SOD) were first evaluated. Secondly, the consequences of ethyl pyruvate treatment on the physico-chemical properties of erythrocyte plasma membranes were investigated. The results obtained demonstrate that ethanol induces an increase in lipid peroxidation, a reduction of GPx activity and fluidity in the hydrophilic-hydrophobic region of the bilayer, moreover an increase of fluidity in hydrophobic part of the plasma membrane was measured. When rats were treated with ethyl pyruvate a partially protective effect can be observed for the hydrophilic-hydrophobic region tested by Laurdan, while EP cannot restore the DPH anisotropy values to the control values. In summary, our data indicate that treatment with EP can only partially reduce ethanol plasma membrane perturbation. Since this study shows an ethyl pyruvate dose-dependent effect, it is important to consider the amount of EP required to maintain the right level of membrane fluidity and polarity. These results could be interesting in order to investigate if EP, due to its radical scavenging effect, can prevent oxidative damage induced by ethanol intake and can protect against injure related with ethanol intake.
Asunto(s)
Membrana Eritrocítica/efectos de los fármacos , Etanol/farmacología , Estrés Oxidativo , Piruvatos/farmacología , Animales , Catalasa/metabolismo , Membrana Eritrocítica/enzimología , Membrana Eritrocítica/metabolismo , Glutatión Peroxidasa/metabolismo , Masculino , Ratas , Superóxido Dismutasa/metabolismoRESUMEN
RATIONALE: It has been suggested that endocannabinoid mechanisms are involved in the control of ethanol consumption. OBJECTIVES: The aims of the present study were (1) to evaluate the role of the endocannabinoid system in the control of operant ethanol self-administration and in the reinstatement of ethanol seeking, when induced by stress or conditioned stimuli and (2) to offer new insights on the specificity of such a role. METHODS: Rats were administered intraperitoneally with the selective cannabinoid CB1 receptor antagonist, SR-141716A, 30 min before operant self-administration or reinstatement sessions. Two schedules of reinforcement, the fixed-ratio 1 (FR1) and the progressive ratio (PR), were used to study 10% (w/v) alcohol and 5.0% sucrose self-administration. NaCl (2% w/v) intake in sodium-depleted rats was studied only under the FR1 program. RESULTS: Treatment with SR-141716A (0.3-3.0 mg/kg) significantly attenuated FR1 alcohol self-administration and lowered the break point for ethanol under PR. SR-141716A also markedly inhibited the reinstatement of alcohol seeking elicited by presentation of cues predictive of drug availability. Conversely, the cannabinoid antagonist did not prevent the reinstatement of alcohol seeking induced by foot-shock stress. Lever pressing for sucrose under FR1 and PR schedules was also significantly decreased by SR-141716A treatment, whereas the drug modestly and only at the highest dose decreased 2% NaCl self-administration. CONCLUSIONS: Results emphasize that endocannabinoid mechanisms play a major role in the control of ethanol self-administration and in the reinstatement of conditioned ethanol seeking. However, these effects extend to the control of operant behaviours motivated by natural rewards (i.e. sucrose). On the other hand, SR-141716A only weakly reduces NaCl self-administration in sodium-depleted rats, in which salt intake is largely controlled by homeostatic mechanisms. Overall, these observations demonstrate that the inhibition of operant behaviour following blockade of CB1 receptors by SR-141716A is linked to a reduction of reward-related responding and is not related to drug-induced motor deficits.
Asunto(s)
Consumo de Bebidas Alcohólicas/tratamiento farmacológico , Piperidinas/farmacología , Pirazoles/farmacología , Receptor Cannabinoide CB1/antagonistas & inhibidores , Consumo de Bebidas Alcohólicas/psicología , Animales , Depresores del Sistema Nervioso Central/sangre , Condicionamiento Operante/efectos de los fármacos , Señales (Psicología) , Electrochoque , Etanol/sangre , Extinción Psicológica/efectos de los fármacos , Masculino , Ratas , Ratas Wistar , Esquema de Refuerzo , Rimonabant , Autoadministración , Cloruro de Sodio/farmacología , Sacarosa/farmacologíaRESUMEN
It has been recently reported that acute intracerebroventricular injection of 1 nmol/rat of the non-selective melanocortin 3 and 4 receptor (MC3/4) agonist MTII reduces ethanol intake in female AA alcohol-preferring rats and alters opioid peptide levels in the ventral tegmental area of rats. To better understand the role of the MC system in the control of ethanol intake, we tested the acute and chronic effects of lateral ventricular (LV) injections of 0.01-1 nmol MTII, of 0.1-1 nmol of the MC3/4R receptor antagonist agouti related peptide (AgRP), and 0.1-0.5 nmol of the MC3/4R receptor antagonist SHU9119 on food, water, and 10% ethanol intake in Marchigian-Sardinian alcohol-preferring (msP) rats, which spontaneously ingest pharmacologically relevant quantities of ethanol both under short and long term access conditions. The data showed that with 2h/day ethanol access, LV MTII injections reduced intake of food and ethanol intakes. When food, water, and ethanol were available ad libitum and 0.01 nmol MTII was given by daily LV injection, however, ethanol intake was reduced for only the first 2 days, whereas food intake was reduced for all 5 days of treatment. Finally, acute LV injection of neither AgRP nor SHU9119 affected ethanol intake under ad libitum conditions, although both antagonists significantly increased food and water intake. In conclusion, these data fail to support a role for endogenous MC3/4R in the control of spontaneous ethanol intake in the msP rat. MC3/4R agonism, however, reduced ethanol intake in association with reduced food intake, suggesting that MTII might reduce nutrient-related controls of ethanol intake rather than, or in addition to, reward-related controls of ethanol intake.
Asunto(s)
Consumo de Bebidas Alcohólicas/metabolismo , Conducta Animal/efectos de los fármacos , Receptor de Melanocortina Tipo 3/antagonistas & inhibidores , Receptor de Melanocortina Tipo 3/metabolismo , Receptor de Melanocortina Tipo 4/antagonistas & inhibidores , Receptor de Melanocortina Tipo 4/metabolismo , alfa-MSH/análogos & derivados , Proteína Relacionada con Agouti/farmacología , Consumo de Bebidas Alcohólicas/psicología , Animales , Conducta Animal/fisiología , Esquema de Medicación , Etanol/administración & dosificación , Etanol/antagonistas & inhibidores , Conducta Alimentaria/efectos de los fármacos , Conducta Alimentaria/fisiología , Inyecciones Intraventriculares , Masculino , Hormonas Estimuladoras de los Melanocitos/farmacología , Fragmentos de Péptidos/farmacología , Ratas , Receptor de Melanocortina Tipo 3/fisiología , Receptor de Melanocortina Tipo 4/fisiología , alfa-MSH/administración & dosificación , alfa-MSH/farmacologíaRESUMEN
Central administration of low doses of nociceptin/orphanin FQ (N/OFQ), the endogenous ligand of the opioid-like orphan receptor NOP, have been shown to reduce ethanol consumption, ethanol-induced conditioned place preference and stress-induced reinstatement of alcohol-seeking behavior in alcohol preferring rats. The present study evaluated the effect of continuous (7 days) lateral brain ventricle infusions of N/OFQ (0, 0.25, 1, 4, and 8 microg/h), by means of osmotic mini-pumps, on 10% ethanol intake in Marchigian-Sardinian alcohol-preferring (msP) rats provided 2h or 24h access to it. N/OFQ dose-dependently increased food intake in msP rats. On the other hand, in contrast to previous studies with acute injections, continuous lateral brain ventricle infusion of high doses of N/OFQ increased ethanol consumption when the ethanol solution was available for 24h/day or 2h/day. The present study demonstrates that continuous activation of the opioidergic N/OFQ receptor does not blunt the reinforcing effects of ethanol. Moreover, the data suggest that continuous activation of the opioidergic N/OFQ receptor is not a suitable way to reduce alcohol abuse.
Asunto(s)
Consumo de Bebidas Alcohólicas , Alcoholismo/fisiopatología , Relación Dosis-Respuesta a Droga , Ingestión de Alimentos/efectos de los fármacos , Inyecciones Intraventriculares , Péptidos Opioides/farmacología , Animales , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Etanol/administración & dosificación , Masculino , Ratas , Ratas Endogámicas , Factores de Tiempo , Vasodilatadores/farmacología , NociceptinaRESUMEN
Central injection of Nociceptin/Orphanin FQ (N/OFQ), inhibits the anorectic effect of corticotropin-relasing factor (CRF) and stress in rats. Recently, Urocortin II (Ucn II) and Urocortin III (Ucn III), two selective CRF(2) receptor agonists, have been identified. Here, we investigated the effect of intracerebroventricular (ICV) injection of 0.25, 0.75, 1.50 or 3 nmol/rat of Ucn II or Ucn III on food and water intake in food deprived rats. The effect of N/OFQ on Ucn II and UCNIII-induced anorexia was also studied. Results showed a greater inhibition of food consumption by Ucn II than Ucn III. Pretreatment with N/OFQ (0.25-2.0 nmol/rat) did not block the effects of Ucn II and UCNIII. Conversely, injection of N/OFQ (0.25-2.0 nmol/rat) blocked the anorectic effect of CRF (0.1 nmol/rat). These findings suggest that N/OFQ selectively prevent the anorectic effect mediated by activation of the CRF(1) receptor system.
Asunto(s)
Anorexia/metabolismo , Péptidos Opioides/fisiología , Receptores de Hormona Liberadora de Corticotropina/fisiología , Animales , Ingestión de Líquidos/fisiología , Inyecciones Intraventriculares , Masculino , Ratas , Ratas Wistar , Urocortinas/administración & dosificación , Urocortinas/fisiología , NociceptinaRESUMEN
Different reports suggest that nociceptin/orphanin FQ (N/OFQ) may have either anxiolytic- or anxiogenic-like effect in rodents. Since N/OFQ elicits hypolocomotion, which undergoes rapid tolerance, and hypolocomotion may be associated to emotional consequences, the present study was designed to investigate the effect of N/OFQ on anxiety after development of tolerance to its hypolocomotor effect. The effect of single or double intracerebroventricular (i.c.v.) injection of N/OFQ was evaluated on anxiety-related behaviors in rats, in the elevated plus maze (EPM) and conditioned defensive burying (CDB) tests. After single administration, N/OFQ displayed an anxiogenic-like pattern of response on the elevated plus maze but hypolocomotion was also observed. Conversely, in the CDB test, N/OFQ induced a clear-cut anxiolytic pattern. To produce tolerance to N/OFQ-induced hypolocomotion the peptide was administered by two i.c.v. injections separated by 120 min; in these conditions it decreased the expression of anxiety-related behaviors in both tests without affecting locomotor activity. The nociceptin/orphanin FQ peptide (NOP) receptor antagonist UFP-101 significantly reduced the effects of N/OFQ to control values in either tests. Corticosterone levels were significantly increased after a single N/OFQ administration (not in a dose-dependent manner) but this increase did not reach significance after double administration (1 nmol/rat). Our results support the idea that N/OFQ may act as an anxiolytic-like agent in the rat; the apparent anxiogenic-like effect observed following its single administration in the EPM may be consequent to its effect on locomotion.