RESUMEN
The effects of the halogenated aromatic amino acid 3,5-dibromo-D: -tyrosine (3,5-DBr-D: -Tyr) were studied in rat models of stroke and epileptic seizures caused by middle cerebral artery occlusion (MCAo) through respective intracerebral injection of endothelin-1 (ET-1) and intraperitoneal (i.p.) injection of pentylenetetrazole (PTZ). 3,5-DBr-D: -Tyr was administered as three bolus injections (30 or 90 mg/kg, i.p.) starting at 30, 90, and 180 min after ET-1 administration or as a single bolus (30 mg/kg, i.p.) 15 min prior to PTZ administration. Neurological deficits and infarct volume were estimated 3 days after ET-1 administration and seizure score was assessed during the first 20 min after PTZ administration. The safety of 3,5-DBr-D: -Tyr was evaluated in control animals using telemetry to measure cardiovascular parameters and immunostaining to assess the level of activated caspase-3. 3,5-DBr-D: -Tyr significantly improved neurological function and reduced infarct volume in the brain even when the treatment was initiated 3 h after the onset of MCAo. 3,5-DBr-D: -Tyr significantly depressed PTZ-induced seizures. 3,5-DBr-D: -Tyr did not cause significant changes in arterial blood pressure, heart rate and spontaneous locomotor activity, nor did it increase the number of activated caspase-3 positive cells in the brain. We conclude that 3,5-DBr-D: -Tyr, by alleviating the deleterious effects of MCAo and PTZ in rats with no obvious intrinsic effects on cardiovascular parameters and neurodegeneration, exhibits promising potential as a novel therapeutic direction for stroke and seizures.
Asunto(s)
Epilepsia/tratamiento farmacológico , Hidrocarburos Bromados/uso terapéutico , Accidente Cerebrovascular/tratamiento farmacológico , Tirosina/análogos & derivados , Animales , Presión Sanguínea/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatología , Caspasa 3/análisis , Modelos Animales de Enfermedad , Endotelina-1/efectos adversos , Epilepsia/inducido químicamente , Epilepsia/fisiopatología , Frecuencia Cardíaca/efectos de los fármacos , Hidrocarburos Bromados/administración & dosificación , Hidrocarburos Bromados/síntesis química , Infarto de la Arteria Cerebral Media/inducido químicamente , Masculino , Actividad Motora/efectos de los fármacos , Pentilenotetrazol/efectos adversos , Ratas , Ratas Sprague-Dawley , Índice de Severidad de la Enfermedad , Accidente Cerebrovascular/inducido químicamente , Accidente Cerebrovascular/fisiopatología , Tirosina/administración & dosificación , Tirosina/síntesis química , Tirosina/uso terapéuticoRESUMEN
Epidemiological studies indicate that parental smoking increases the risk for smoking in children. However, the underlying mechanisms by which parental smoking increases the risk for smoking are not known. The aim of these studies was to investigate if preadolescent tobacco smoke exposure, postnatal days 21-35, affects the rewarding effects of nicotine and nicotine withdrawal in adult rats. The rewarding effects of nicotine were investigated with the conditioned place preference procedure. Nicotine withdrawal was investigated with the conditioned place aversion procedure and intracranial self-stimulation (ICSS). Elevations in brain reward thresholds in the ICSS paradigm reflect a dysphoric state. Plasma nicotine and cotinine levels in the preadolescent rats immediately after smoke exposure were 188 ng/ml and 716 ng/ml, respectively. Preadolescent tobacco smoke exposure led to the development of nicotine dependence as indicated by an increased number of mecamylamine-precipitated somatic withdrawal signs in the preadolescent tobacco smoke exposed rats compared to the control rats. Nicotine induced a similar place preference in adult rats that had been exposed to tobacco smoke or air during preadolescence. Furthermore, mecamylamine induced place aversion in nicotine dependent rats but there was no effect of preadolescent tobacco smoke exposure. Finally, preadolescent tobacco smoke exposure did not affect the elevations in brain reward thresholds associated with precipitated or spontaneous nicotine withdrawal. These studies indicate that passive exposure to tobacco smoke during preadolescence leads to the development of nicotine dependence but preadolescent tobacco smoke exposure does not seem to affect the rewarding effects of nicotine or nicotine withdrawal in adulthood.
Asunto(s)
Exposición a Riesgos Ambientales/efectos adversos , Nicotina/farmacología , Recompensa , Síndrome de Abstinencia a Sustancias/fisiopatología , Contaminación por Humo de Tabaco/efectos adversos , Tabaquismo/etiología , Animales , Reacción de Prevención/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Cotinina/sangre , Estimulación Eléctrica , Masculino , Nicotina/antagonistas & inhibidores , Nicotina/sangre , Antagonistas Nicotínicos/farmacología , Antagonistas Nicotínicos/uso terapéutico , Ratas , Ratas Wistar , Tiempo de Reacción/efectos de los fármacos , Autoestimulación/efectos de los fármacos , Maduración Sexual , Síndrome de Abstinencia a Sustancias/sangre , Factores de Tiempo , Tabaquismo/sangre , Tabaquismo/tratamiento farmacológicoRESUMEN
BACKGROUND: We tested the hypothesis that in newborn rats, sevoflurane may cause seizures, neurotoxicity, and impairment in synaptic plasticity-effects that may be diminished by the Na-K-2Cl cotransporter 1 inhibitor, bumetanide. METHODS: Electroencephalography, activated caspase-3, and hippocampal long-term potentiation were measured in rats exposed to 2.1% sevoflurane for 0.5-6 h at postnatal days 4-17 (P4-P17). RESULTS: Arterial blood gas samples drawn at a sevoflurane concentration of 2.1% showed no evidence of either hypoxia or hypoventilation in spontaneously breathing rats. Higher doses of sevoflurane (e.g., 2.9%) caused respiratory depression. During anesthesia maintenance, the electroencephalography exhibited distinctive episodes of epileptic seizures in 40% of P4-P8 rats. Such seizure-like activity was not detected during anesthesia maintenance in P10-P17 rats. Emergence from 3 h of anesthesia with sevoflurane resulted in tonic/clonic seizures in some P10-P17 rats but not in P4-P8 rats. Bumetanide (5 micromol/kg, intraperitoneally) significantly decreased seizures in P4-P9 rats but did not affect the emergence seizures in P10-P17 rats. Anesthesia of P4 rats with sevoflurane for 6 h caused a significant increase in activated caspase-3 and impairment of long-term potentiation induction measured at 1 and 14-17 days after exposure to sevoflurane, respectively. Pretreatment of P4 rats with bumetanide nearly abolished the increase in activated caspase-3 but did not alleviate impairment of long-term potentiation. CONCLUSION: These results support the possibility that excitatory output of sevoflurane-potentiated gamma-aminobutyric acid type A/glycine systems may contribute to epileptogenic and neurotoxic effects in early postnatal rats.
Asunto(s)
Anestésicos por Inhalación/antagonistas & inhibidores , Anestésicos por Inhalación/toxicidad , Bumetanida/uso terapéutico , Diuréticos/uso terapéutico , Epilepsia/inducido químicamente , Epilepsia/prevención & control , Éteres Metílicos/antagonistas & inhibidores , Éteres Metílicos/toxicidad , Síndromes de Neurotoxicidad/prevención & control , Anestesia por Inhalación , Animales , Animales Recién Nacidos , Western Blotting , Caspasa 3/metabolismo , Electroencefalografía/efectos de los fármacos , Electrofisiología , Activación Enzimática/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Receptores de GABA-A/efectos de los fármacos , Receptores de GABA-A/fisiología , SevofluranoRESUMEN
RATIONALE: Tobacco smoke contains nicotine and many other compounds that act in concert on the brain reward system. Therefore, animal models are needed that allow the investigation of chronic exposure to the full spectrum of tobacco smoke constituents. OBJECTIVES: The aim of these studies was to investigate if exposure to tobacco smoke leads to nicotine dependence in rats. METHODS: The intracranial self-stimulation procedure was used to assess the negative affective aspects of nicotine withdrawal. Somatic signs were recorded from a checklist of nicotine abstinence signs. Nicotine self-administration sessions were conducted to investigate if tobacco smoke exposure affects the motivation to self-administer nicotine. Nicotinic receptor autoradiography was used to investigate if exposure to tobacco smoke affects central alpha7 nicotinic acetylcholine receptor (nAChR) and non-alpha7 nAChR levels (primarily alpha4beta2 nAChRs). RESULTS: The nAChR antagonist mecamylamine dose-dependently elevated the brain reward thresholds of the rats exposed to tobacco smoke and did not affect the brain reward thresholds of the untreated control rats. Furthermore, mecamylamine induced more somatic withdrawal signs in the smoke-exposed rats than in the control rats. Nicotine self-administration was decreased 1 day after the last tobacco smoke exposure sessions and was returned to control levels 5 days later. Tobacco smoke exposure increased the alpha7 nAChR density in the CA2/3 area and the stratum oriens and increased the non-alpha7 nAChR density in the dentate gyrus. CONCLUSION: Tobacco smoke exposure leads to nicotine dependence as indicated by precipitated affective and somatic withdrawal signs and induces an upregulation of nAChRs in the hippocampus.
Asunto(s)
Nicotina/administración & dosificación , Receptores Nicotínicos/efectos de los fármacos , Contaminación por Humo de Tabaco/efectos adversos , Tabaquismo/etiología , Animales , Autorradiografía , Giro Dentado/efectos de los fármacos , Giro Dentado/metabolismo , Relación Dosis-Respuesta a Droga , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Mecamilamina/administración & dosificación , Mecamilamina/farmacología , Motivación , Ratas , Ratas Wistar , Receptores Nicotínicos/genética , Receptores Nicotínicos/metabolismo , Autoadministración , Regulación hacia Arriba/efectos de los fármacos , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
RATIONALE: Discontinuation of chronic and excessive alcohol consumption leads to a dysphoric state in humans. It is not known if there are changes in brain reward function after the discontinuation of an alcohol liquid in rats. OBJECTIVES: The aim of these studies was to investigate the effect of withdrawal from an alcohol liquid diet on brain reward function and acute and protracted anxiety-like behavior. MATERIALS AND METHODS: The intracranial self-stimulation procedure was used to assess brain reward function, and the elevated plus maze test was used to assess anxiety-like behavior. RESULTS: Discontinuation of chronic, 12 weeks, exposure to a 6.2% v/v alcohol liquid diet lead to a minor deficit in brain reward function and did not increase anxiety-like behavior. Discontinuation of chronic, 12 weeks, exposure to a 10% v/v alcohol liquid diet lead to a pronounced deficit in brain reward function and increased anxiety-like behavior. Two weeks after discontinuation of the 10% v/v alcohol liquid diet, the rats with a history of alcohol dependence did not display increased anxiety-like behavior. Restraint stress increased anxiety-like behavior in the rats with a history of alcohol dependence, but not in the control rats. Brain reward thresholds were assessed during the chronic 10% v/v alcohol exposure period. During this period, there were no differences between the brain rewards thresholds of the alcohol and control rats. CONCLUSION: These findings indicate that withdrawal from a 10% v/v alcohol liquid diet leads to a pronounced deficit in brain reward function and acute and protracted anxiety-like behavior in rats.
Asunto(s)
Alcoholismo/psicología , Ansiedad/psicología , Conducta Animal/efectos de los fármacos , Encéfalo/fisiopatología , Recompensa , Síndrome de Abstinencia a Sustancias/psicología , Alcoholismo/complicaciones , Animales , Ansiedad/etiología , Encéfalo/efectos de los fármacos , Dieta , Etanol/administración & dosificación , Etanol/efectos adversos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratas , Ratas Wistar , Autoestimulación/efectos de los fármacos , Síndrome de Abstinencia a Sustancias/etiologíaRESUMEN
Tobacco addiction is a chronic disorder that is characterized by dysphoria upon smoking cessation and relapse after periods of abstinence. Previous research suggests that Neuropeptide Y (NPY) and Y1 receptor agonists attenuate negative affective states and somatic withdrawal signs. The aim of the present experiments was to investigate the effects of NPY and the specific Y1 receptor agonist [D-His(26)]-NPY on the deficit in brain reward function and somatic signs associated with nicotine withdrawal in rats. The intracranial self-stimulation procedure was used to assess the effects of nicotine withdrawal on brain reward function as this procedure can provide a quantitative measure of emotional states in rodents. Elevations in brain reward thresholds are indicative of a deficit in brain reward function. In the first experiment, NPY did not prevent the elevations in brain reward thresholds associated with precipitated nicotine withdrawal and elevated the brain reward thresholds of the saline-treated control rats. Similar to NPY, [D-His(26)]-NPY did not prevent the elevations in brain reward thresholds associated with precipitated nicotine withdrawal and elevated the brain reward thresholds of the saline-treated control rats. Neither NPY nor [D-His(26)]-NPY affected the response latencies. In a separate experiment, it was demonstrated that the specific Y1 receptor antagonist BIBP-3226 prevented the NPY-induced elevations in brain reward thresholds. NPY attenuated the overall somatic signs associated with precipitated nicotine withdrawal. [D-His(26)]-NPY did not affect the overall somatic signs associated with precipitated nicotine withdrawal, but decreased the number of abdominal constrictions. Both NPY and [D-His(26)]-NPY attenuated the overall somatic signs associated with spontaneous nicotine withdrawal. These findings indicate that NPY and [D-His(26)]-NPY attenuate somatic nicotine withdrawal signs, but do not prevent the deficit in brain reward function associated with precipitated nicotine withdrawal. In addition, NPY decreases the sensitivity to rewarding electrical stimuli via an Y1 dependent mechanism.
Asunto(s)
Encéfalo/efectos de los fármacos , Neuropéptido Y/análogos & derivados , Neuropéptido Y/uso terapéutico , Nicotina , Agonistas Nicotínicos , Receptores Acoplados a Proteínas G/agonistas , Receptores de Neuropéptido/agonistas , Recompensa , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Síndrome de Abstinencia a Sustancias/psicología , Animales , Arginina/análogos & derivados , Arginina/farmacología , Implantes de Medicamentos , Estimulación Eléctrica , Electrodos Implantados , Masculino , Ratas , Ratas Wistar , AutoestimulaciónRESUMEN
Tobacco dependence is a chronic disorder that is characterized by relapse after periods of abstinence. It has been hypothesized that the activation of brain stress systems mediates stress-induced relapse to smoking. The aim of these experiments was to investigate the role of corticotropin-releasing factor (CRF) and norepinephrine in stress-induced reinstatement of extinguished nicotine-seeking behavior. Rats were allowed to self-administer nicotine under a fixed-ratio 5 schedule for 14 days and then nicotine-seeking behavior was extinguished by substituting saline for nicotine. In experiment 1, footshocks reinstated extinguished nicotine-seeking behavior. In experiment 2, there was a trend for the CRF(1/2) receptor antagonist D-Phe CRF((12-41)) (5, 25microg, icv) to decrease stress-induced reinstatement of nicotine-seeking behavior. Footshock-induced reinstatement of nicotine-seeking behavior was observed only in a subset of stress-responsive rats (71%). D-Phe CRF((12-41)) significantly attenuated stress-induced reinstatement of nicotine-seeking behavior in this subset of rats. In experiment 3, the alpha2-adrenergic receptor agonist clonidine (20, 40microg/kg, sc) attenuated footshock-induced reinstatement of nicotine-seeking behavior. In experiment 4, the effects of D-Phe CRF((12-41)) and clonidine on responding for chocolate-flavored food pellets was investigated in order to determine if these compounds have sedative effects. D-Phe CRF((12-41)) did not affect responding for food pellets. Clonidine slightly, but significantly, decreased responding for food pellets. Clonidine decreased responding for food to a lesser degree than it decreased stress-induced reinstatement of nicotine-seeking behavior. These data provide support for the hypothesis that an increased activity of brain CRF and norepinephrine systems mediates stress-induced relapse to nicotine-seeking behavior.