RESUMEN
Both the 5-HT(2A) receptor (R) antagonist M100907 and the 5-HT(2C) R agonist MK212 attenuate cocaine-induced dopamine release and hyperlocomotion. This study examined whether these drugs interact to reduce cocaine hyperlocomotion and Fos expression in the striatum and prefrontal cortex. We first determined from dose-effect functions a low dose of both M100907 and MK212 that failed to alter cocaine (15 mg/kg, i.p.) hyperlocomotion. Subsequently, we examined whether these subthreshold doses given together would attenuate cocaine hyperlocomotion, consistent with a 5-HT(2A)/5-HT(2C) R interaction. Separate groups of rats received two sequential drug injections 5 min apart immediately before a 1-h locomotion test as follows: (1) saline + saline, (2) saline + cocaine, (3) 0.025 mg/kg M100907 + cocaine, (4) 0.125 mg/kg MK212 + cocaine, or (5) cocktail combination of 0.025 mg/kg M100907 and 0.125 mg/kg MK212 + cocaine. Brains were extracted for Fos immunohistochemistry 90 min after the second injection. We next examined the effects of 0.025 mg/kg M100907 and 0.125 mg/kg MK212, alone and in combination, on spontaneous locomotor activity. While neither drug given alone produced any effects, the M100907/MK212 cocktail attenuated cocaine hyperlocomotion as well as cocaine-induced Fos expression in the dorsolateral caudate-putamen (CPu), but had no effect on spontaneous locomotion. The findings suggest that 5-HT(2A) Rs and 5-HT(2C) Rs interact to attenuate cocaine hyperlocomotion and Fos expression in the CPu, and that the CPu is a potential locus of the interactive effects between these 5-HT(2) R subtypes on behavior. Further research investigating combined 5-HT(2A) R antagonism and 5-HT(2C) R agonism as a treatment for cocaine dependence is warranted.
Asunto(s)
Núcleo Caudado/efectos de los fármacos , Cocaína/farmacología , Locomoción/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Putamen/efectos de los fármacos , Receptor de Serotonina 5-HT2A/metabolismo , Receptor de Serotonina 5-HT2C/metabolismo , Animales , Núcleo Caudado/metabolismo , Núcleo Caudado/fisiología , Fluorobencenos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Masculino , Piperidinas/farmacología , Proteínas Proto-Oncogénicas c-fos/genética , Putamen/metabolismo , Putamen/fisiología , Pirazinas/farmacología , Ratas , Ratas Sprague-Dawley , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Antagonistas del Receptor de Serotonina 5-HT2/farmacologíaRESUMEN
RATIONALE: The action of serotonin (5-HT) at the 5-HT(2A) receptor subtype is thought to be involved in cocaine-seeking behavior that is motivated by exposure to drug-associated cues and drug priming. 5-HT(2A) receptors are densely clustered in the ventromedial prefrontal cortex (vmPFC), an area that plays a role in mediating cocaine-seeking behavior. OBJECTIVES: This study examined the hypothesis that M100907, a 5-HT(2A) receptor antagonist, infused directly in the vmPFC attenuates cue- and cocaine-primed reinstatement of cocaine-seeking behavior. METHODS: Rats trained to self-administer cocaine (0.75 mg/kg, i.v.) paired with light and tone cues underwent extinction training during which operant responses produced no consequences. Once behavior extinguished, rats were tested for reinstatement of responding elicited by either response-contingent presentations of the cocaine-paired light/tone cues or by cocaine-priming injections (10 mg/kg, i.p.) within 1 min after pretreatment with microinfusions of M100907 (0.1, 0.3, 1.0, or 1.5 µg/0.2 µl/side) into the vmPFC. RESULTS: Intra-vmPFC M100907 decreased cue-elicited reinstatement at the two highest doses (1.0 and 1.5 µg) but produced only a slight decrease in cocaine-primed reinstatement that was not dose dependent. The decrease in cue reinstatement was not likely due to impaired ability to respond since intra-vmPFC M100907 infusions had minimal effect on cocaine self-administration and no effect on cue-elicited sucrose-seeking behavior, or spontaneous or cocaine-induced locomotion. M100907 infusions into the adjacent anterior cingulate cortex had no effect on cue reinstatement. CONCLUSIONS: The results suggest that the blockade of 5-HT(2A) receptors in the vmPFC selectively attenuates the incentive motivational effects of cocaine-paired cues.
Asunto(s)
Cocaína/administración & dosificación , Fluorobencenos/farmacología , Piperidinas/farmacología , Receptor de Serotonina 5-HT2A/metabolismo , Antagonistas del Receptor de Serotonina 5-HT2/farmacología , Animales , Conducta Animal/efectos de los fármacos , Condicionamiento Operante/efectos de los fármacos , Señales (Psicología) , Relación Dosis-Respuesta a Droga , Fluorobencenos/administración & dosificación , Masculino , Piperidinas/administración & dosificación , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT2A/efectos de los fármacos , Autoadministración , Antagonistas del Receptor de Serotonina 5-HT2/administración & dosificación , Sacarosa/administración & dosificaciónRESUMEN
Serotonin 2C receptor (5-HT(2C)R) agonists administered systemically attenuate both cocaine-primed and cue-elicited reinstatement of extinguished cocaine-seeking behavior. To further elucidate the function of these receptors in addiction-like processes, this study examined the effects of microinfusing the 5-HT(2C)R agonist MK212 (0, 10, 30, 100 ng/side/0.2 microl) into the medial prefrontal cortex (mPFC) on cocaine self-administration and reinstatement of extinguished cocaine-seeking behavior. Male Sprague-Dawley rats were trained to self-administer cocaine (0.75 mg/kg, i.v.) paired with light and tone cues. Once responding stabilized, rats received MK212 microinfusions before tests for maintenance of cocaine self-administration. Next, extinction training to reduce cocaine-seeking behavior, defined as responses performed without cocaine reinforcement available, occurred until low extinction baselines were achieved. Rats then received MK212 microinfusions before tests for reinstatement of extinguished cocaine-seeking behavior elicited by cocaine-priming injections (10 mg/kg, i.p.) or response-contingent presentations of the cocaine-associated cues; operant responses during cocaine-primed reinstatement tests produced no consequences. MK212 microinfusions into the prelimbic and infralimbic, but not anterior cingulate, regions of the mPFC dose-dependently attenuated both cocaine-primed and cue-elicited reinstatement of extinguished cocaine-seeking behavior, but did not reliably affect cocaine self-administration. A subsequent experiment showed that the effects of MK212 (100 ng/side/0.2 microl) on reinstatement of extinguished cocaine-seeking behavior were blocked by co-administration of the 5-HT(2C)R antagonist SB242084 (200 ng/side/0.2 microl). MK212 administered alone into the mPFC as a drug prime produced no discernable effects on cocaine-seeking behavior. These findings suggest that stimulation of 5-HT(2C)Rs in the mPFC attenuates the incentive motivational effects produced by sampling cocaine or exposure to drug-paired cues.
Asunto(s)
Trastornos Relacionados con Cocaína/tratamiento farmacológico , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/fisiología , Pirazinas/uso terapéutico , Agonistas de Receptores de Serotonina/uso terapéutico , Aminopiridinas/farmacología , Animales , Trastornos Relacionados con Cocaína/psicología , Condicionamiento Operante/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Interacciones Farmacológicas , Extinción Psicológica/efectos de los fármacos , Indoles/farmacología , Masculino , Pirazinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT2C/metabolismo , Refuerzo en Psicología , Autoadministración , Antagonistas de la Serotonina/farmacologíaRESUMEN
Dieting to control body weight involves cycles of deprivation from palatable food that can promote compulsive eating. The present study shows that rats withdrawn from intermittent access to palatable food exhibit overeating of palatable food upon renewed access and an affective withdrawal-like state characterized by corticotropin-releasing factor-1 (CRF(1)) receptor antagonist-reversible behaviors, including hypophagia, motivational deficits to obtain less palatable food, and anxiogenic-like behavior. Withdrawal was accompanied by increased CRF expression and CRF(1) electrophysiological responsiveness in the central nucleus of the amygdala. We propose that recruitment of anti-reward extrahypothalamic CRF-CRF(1) systems during withdrawal from palatable food, analogous to abstinence from abused drugs, may promote compulsive selection of palatable food, undereating of healthier alternatives, and a negative emotional state when intake of palatable food is prevented.
Asunto(s)
Conducta Compulsiva , Hormona Liberadora de Corticotropina/metabolismo , Dieta , Ingestión de Alimentos/fisiología , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Amígdala del Cerebelo/citología , Amígdala del Cerebelo/metabolismo , Animales , Conducta Adictiva/metabolismo , Conducta Adictiva/psicología , Conducta Animal/fisiología , Ingestión de Alimentos/psicología , Electrofisiología , Masculino , Aprendizaje por Laberinto , Pirimidinas/metabolismo , Ratas , Ratas Wistar , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Recompensa , Estrés Psicológico/metabolismo , Estrés Psicológico/psicología , Síndrome de Abstinencia a Sustancias/metabolismo , Síndrome de Abstinencia a Sustancias/psicologíaRESUMEN
Narcotic analgesics are commonly prescribed drugs in patients with chronic hepatitis C (CHC) infection. In vitro data have shown that morphine enhances hepatitis C virus replication in human hepatic cells, however the effect of narcotics on hepatitis C virus disease progression remains uncertain. The aim of this study was to evaluate the potential effects of narcotic analgesic use on the progression of hepatic fibrosis in patients with CHC infection. We identified CHC patients who had been seen at our institution and had undergone a liver biopsy between 1990 and 2005. Their charts were reviewed for the presence of narcotic analgesic and known risk factors for progression of hepatic fibrosis including male sex, age > or =40, obesity, diabetes, and alcohol abuse. All biopsy were reviewed and fibrosis scores were standardized using the Batts and Ludwig scoring system (stage 0 to 4). A total of 1147 evaluable patients were identified and 171 of these had narcotic analgesic use. In univariate analysis, narcotic analgesic use was associated with the presence of alcohol abuse (P<0.001), obesity (P=0.02), and advanced fibrosis defined as stage 3 to 4 fibrosis (P=0.02), but not with male sex or diabetes. In multivariate logistic regression analysis, obesity [odds ratio (OR) 1.68 (confidence interval (CI), 1.21-2.33)], alcohol abuse [OR 1.45 (CI, 1.04-2.02)], age > or =40 [OR 1.85 (CI, 1.22-2.89)], and diabetes [OR 2.43 (CI, 1.41-4.14)] all independently predicted advanced liver fibrosis but narcotic analgesic use did not [OR 1.71 (CI, 0.99-2.89)]. As the amount of narcotic analgesic use increased from no use, to <3 months use, to > or =3 months use, the frequency of obesity, alcohol abuse, and advanced fibrosis increased accordingly (P=0.005), suggesting that it is difficult to separate these known risk factors from narcotic use as the cause for advanced fibrosis in this population.