RESUMEN
The orexin family of hypothalamic neuropeptides has been implicated in reinforcement mechanisms relevant to both food and drug reward. Previous behavioral studies with antagonists at the orexin A-selective receptor, OX(1), have demonstrated its involvement in behavioral sensitization, conditioned place-preference, and self-administration of drugs of abuse. Adult male Swiss-Webster mice were implanted with stimulating electrodes to the lateral hypothalamus and trained to perform intracranial self-stimulation (ICSS). The effects of the OX(1)-selective antagonist SB 334867 on brain stimulation-reward (BSR) and cocaine potentiation of BSR were measured. SB 334867 (10-30mg/kg, i.p.) alone had no effect on ICSS performance or BSR threshold. Cocaine (1.0-30mg/kgi.p.) dose-dependently potentiated BSR, measured as lowering of BSR threshold. This effect was not blocked by 30mg/kg SB 334867 at any cocaine dose tested. In agreement with previous reports, SB 334867 resulted in a reduction of body weight 24h after acute administration. Based on these data, it is concluded that orexins acting at OX(1) do not contribute to BSR; and are not involved in the reward-potentiating actions of cocaine on BSR. The data are discussed in the context of prior findings of SB 334867 effects on drug-seeking and drug-consuming behaviors.
Asunto(s)
Benzoxazoles/farmacología , Cocaína/administración & dosificación , Condicionamiento Operante/efectos de los fármacos , Inhibidores de Captación de Dopamina/administración & dosificación , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores de Neuropéptido/antagonistas & inhibidores , Recompensa , Urea/análogos & derivados , Animales , Encéfalo/efectos de los fármacos , Encéfalo/fisiología , Relación Dosis-Respuesta a Droga , Vías de Administración de Medicamentos , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Naftiridinas , Receptores de Orexina , Esquema de Refuerzo , Autoadministración , Urea/farmacologíaRESUMEN
OBJECTIVES: This study examined the association between prenatal cocaine exposure and children's self-regulation at 3 years of child age. In addition to direct effects of prenatal cocaine exposure on children's self-regulation, we hypothesized there would be indirect associations between cocaine exposure and self-regulation via higher maternal harshness and poor autonomic regulation in infancy. METHODS: The sample consisted of 216 mother-infant dyads recruited at delivery from local area hospitals (116 cocaine-exposed, 100 non-exposed). Infant autonomic regulation was measured at 7 months of age during an anger/frustration task, maternal harshness was coded from observations of mother-toddler interactions at 2 years of age, and children's self-regulation was measured at 3 years of age using several laboratory paradigms. RESULTS: Contrary to hypotheses, there were no direct associations between maternal cocaine use during pregnancy and children's self-regulation. However, results from testing our conceptual model including the indirect effects via maternal harshness or infant parasympathetic regulation indicated that this model fit the data well, χ(2) (23) = 34.36, p > 0.05, Comparative Fit Index = 0.95, RMSEA = 0.05. Cocaine using mothers displayed higher intensity of harshness toward their toddlers during lab interactions across a variety of tasks at 2 years of age (ß = 0.23, p < 0.05), and higher intensity of harshness at 2 years was predictive of lower self-regulation at 3 years (ß = -0.36, p < 0.01). Maternal cocaine use was also predictive of a non-adaptive increase in respiratory sinus arrhythmia (RSA) from baseline to the negative affect task, but RSA change in infancy was not predictive of self-regulation at 3 years. CONCLUSION: RESULTS are supportive of animal models indicating higher aggression among cocaine treated dams, and indicate that higher maternal harshness among cocaine using mothers is predictive of child self-regulatory outcomes in the preschool period.
RESUMEN
RATIONALE: Little is known about mechanisms underlying female rodent aggression during the late postpartum period with no pups present. Studies of aggression, dominance, and oxytocin (OT) response in cocaine-treated females are sparse. OBJECTIVES: This study was designed to examine dominance (drinking success) and aggression in a limited-access drinking model of water competition. Acute OT level measures were made on postpartum day (PPD) 36 in several brain regions of interest. Chronic and intermittent cocaine- and saline-treated and untreated rats 10 days post-weaning were tested (without pups) over PPDs 31-35 following cessation of cocaine treatment 10-30 days before testing. METHODS: Subjects were water-deprived overnight, and triads consisting of an untreated control (UN), a chronic continuous saline-treated (CS), and chronic continuous cocaine-treated (CC; 30 mg/kg/day throughout gestation) or a UN, an intermittent saline-treated (IS), and an intermittent cocaine-treated (IC; 30 mg/kg two consecutive days every 4 days throughout gestation until PPD 20) female were tested for aggression and drinking behavior during 5 min sessions on five consecutive days. The amygdala, medial preoptic area (MPOA), and ventral tegmental area were assayed for OT levels. RESULTS: CC and IC females were more aggressive than controls, but only IC females drank more often than controls. OT levels were lower in the MPOA of IC and CC females than in controls. CONCLUSIONS: Findings demonstrate that long after cessation of treatment, CC- and IC-treated non-lactating females (no pups present) had higher rates of aggression, altered drinking behavior, and acutely lower MPOA OT levels.
Asunto(s)
Agresión/efectos de los fármacos , Cocaína/toxicidad , Oxitocina/efectos de los fármacos , Predominio Social , Amígdala del Cerebelo/metabolismo , Animales , Cocaína/administración & dosificación , Conducta Competitiva/efectos de los fármacos , Ingestión de Líquidos , Esquema de Medicación , Femenino , Oxitocina/metabolismo , Periodo Posparto , Área Preóptica/metabolismo , Ratas , Ratas Sprague-Dawley , Factores de Tiempo , Área Tegmental Ventral/metabolismoRESUMEN
NR3A is the only NMDA receptor (NMDAR) subunit that downregulates sharply prior to the onset of sensitive periods for plasticity, yet the functional importance of this transient expression remains unknown. To investigate whether removal/replacement of juvenile NR3A-containing NMDARs is involved in experience-driven synapse maturation, we used a reversible transgenic system that prolonged NR3A expression in the forebrain. We found that removal of NR3A is required to develop strong NMDAR currents, full expression of long-term synaptic plasticity, a mature synaptic organization characterized by more synapses and larger postsynaptic densities, and the ability to form long-term memories. Deficits associated with prolonged NR3A were reversible, as late-onset suppression of transgene expression rescued both synaptic and memory impairments. Our results suggest that NR3A behaves as a molecular brake to prevent the premature strengthening and stabilization of excitatory synapses and that NR3A removal might thereby initiate critical stages of synapse maturation during early postnatal neural development.
Asunto(s)
Regulación hacia Abajo/fisiología , Memoria/fisiología , Neuronas/citología , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapsis/fisiología , Animales , Animales Recién Nacidos , Biofisica , Homólogo 4 de la Proteína Discs Large , Estimulación Eléctrica/métodos , Preferencias Alimentarias/fisiología , Proteínas Fluorescentes Verdes/genética , Guanilato-Quinasas , Hipocampo/citología , Inmunoprecipitación/métodos , Técnicas In Vitro , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Aprendizaje por Laberinto/fisiología , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Microscopía Electrónica de Transmisión/métodos , Plasticidad Neuronal/genética , Plasticidad Neuronal/fisiología , Neuronas/ultraestructura , Técnicas de Placa-Clamp/métodos , Receptores de N-Metil-D-Aspartato/genética , Reconocimiento en Psicología/fisiología , Tinción con Nitrato de Plata/métodos , Conducta Social , Potenciales Sinápticos/genética , Potenciales Sinápticos/fisiologíaRESUMEN
Ethanol consumption and smoking during pregnancy are common, despite the known adverse effects on the fetus. The teratogenicity of each drug independently is well established; however, the effects of concurrent exposure to ethanol and nicotine in preclinical models remain unclear. This study examined the impact of simultaneous prenatal exposure to both ethanol and nicotine on offspring ethanol preference behaviors and oxytocin system dynamics. Rat dams were given liquid diet (17% ethanol derived calories (EDC)) on gestational day (GD) 5 and 35% EDC from GD 6-20 and concurrently an osmotic minipump delivered nicotine (3-6mg/kg/day) from GD 4-postpartum day 10. Offspring were tested for ethanol preference during adolescence (postnatal day (PND) 30-43) and again at adulthood (PND 60-73), followed by assays for oxytocin mRNA expression and receptor binding in relevant brain regions. Prenatal exposure decreased ethanol preference in males during adolescence, and decreased consumption and preference in females during adulthood compared to controls. Oxytocin receptor binding in the nucleus accumbens and hippocampus was increased in adult prenatally exposed males only. Prenatal exposure to these drugs sex-specifically decreased ethanol preference behavior in offspring unlike reports for either drug separately. The possible role of oxytocin in reduction of ethanol consumption behavior is highlighted.
Asunto(s)
Consumo de Bebidas Alcohólicas , Conducta de Elección/efectos de los fármacos , Etanol/toxicidad , Nicotina/toxicidad , Efectos Tardíos de la Exposición Prenatal , Receptores de Oxitocina/metabolismo , Animales , Interacciones Farmacológicas , Femenino , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Oxitocina/metabolismo , Embarazo , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Caracteres SexualesRESUMEN
Impaired onset of maternal behavior in first generation rat dams was previously correlated with rearing by cocaine-treated dams and prenatal cocaine exposure. Pup-induced maternal behavior in non-lactating rats has not been examined with regard to cocaine exposure and rearing conditions. First generation male and female juveniles and young adult males reared by cocaine-treated or control dams and prenatally exposed to either cocaine or control conditions were tested for pup-induced maternal behavior at postnatal days 28 and 60. We now report disruptions in pup-induced maternal behavior in both 28 and 60 day old first generation offspring attributable to rearing condition and prenatal cocaine exposure.
Asunto(s)
Envejecimiento , Anestésicos Locales/toxicidad , Conducta Animal/efectos de los fármacos , Cocaína/toxicidad , Conducta Materna/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal , Análisis de Varianza , Animales , Femenino , Masculino , Conducta Materna/fisiología , Embarazo , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
The link between impaired maternal behavior (MB) and cocaine treatment could result from drug-induced decreases in maternal reactivity to offspring, prenatal drug exposure (PDE) in offspring that could alter their ability to elicit MB, or the interaction of both, which could subsequently impair MB of the 1st-generation dams. Following chronic or intermittent cocaine or saline treatment during gestation, rat dams rearing natural or cross-fostered litters were compared along with untreated dams for MB. Untreated 1st-generation females with differentially treated rearing dams and PDE were tested for MB with their natural litters. The authors report disruptions in MB in dams and their 1st-generation offspring, attributable to main and interaction effects of maternal treatment, litter PDE, and rearing experience.