RESUMEN
Current epidemic obesity levels apply great medical and financial pressure to the strenuous economy of obesity-prone cultures, and neuropeptides involved in body weight regulation are regarded as attractive targets for a possible treatment of obesity in humans. The lateral hypothalamus and the nucleus accumbens shell (AcbSh) form a hypothalamic-limbic neuropeptide feeding circuit mediated by Melanin-Concentrating Hormone (MCH). MCH promotes feeding behavior via MCH receptor-1 (MCH1R) in the AcbSh, although this relationship has not been fully characterized. Given the AcbSh mediates reinforcing properties of food, we hypothesized that MCH modulates motivational aspects of feeding.Here we show that chronic loss of the rat MCH-precursor Pmch decreased food intake predominantly via a reduction in meal size during rat development and reduced high-fat food-reinforced operant responding in adult rats. Moreover, acute AcbSh administration of Neuropeptide-GE and Neuropeptide-EI (NEI), both additional neuropeptides derived from Pmch, or chronic intracerebroventricular infusion of NEI, did not affect feeding behavior in adult pmch(+/+) or pmch(-/-) rats. However, acute administration of MCH to the AcbSh of adult pmch(-/-) rats elevated feeding behavior towards wild type levels. Finally, adult pmch(-/-) rats showed increased ex vivo electrically evoked dopamine release and increased limbic dopamine transporter levels, indicating that chronic loss of Pmch in the rat affects the limbic dopamine system.Our findings support the MCH-MCH1R system as an amplifier of consummatory behavior, confirming this system as a possible target for the treatment of obesity. We propose that MCH-mediated signaling in the AcbSh positively mediates motivational aspects of feeding behavior. Thereby it provides a crucial signal by which hypothalamic neural circuits control energy balance and guide limbic brain areas to enhance motivational or incentive-related aspects of food consumption.
Asunto(s)
Conducta Alimentaria/fisiología , Hormonas Hipotalámicas/deficiencia , Hormonas Hipotalámicas/metabolismo , Motivación/fisiología , Precursores de Proteínas/deficiencia , Precursores de Proteínas/metabolismo , Animales , Peso Corporal/efectos de los fármacos , Condicionamiento Operante/efectos de los fármacos , Grasas de la Dieta/administración & dosificación , Grasas de la Dieta/farmacología , Dopamina/metabolismo , Conducta Alimentaria/efectos de los fármacos , Hiperfagia/fisiopatología , Hormonas Hipotalámicas/administración & dosificación , Hormonas Hipotalámicas/farmacología , Inyecciones Intraventriculares , Melaninas/administración & dosificación , Melaninas/farmacología , Motivación/efectos de los fármacos , Neostriado/efectos de los fármacos , Neostriado/metabolismo , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Oligopéptidos/administración & dosificación , Oligopéptidos/farmacología , Hormonas Hipofisarias/administración & dosificación , Hormonas Hipofisarias/farmacología , Ratas , Refuerzo en PsicologíaRESUMEN
RATIONALE: Fluoxetine (Prozac®) is the most frequently prescribed drug to battle depression in pregnant women, but its safety in the unborn child has not yet been established. Fluoxetine, a selective serotonin reuptake inhibitor, crosses the placenta, leading to increased extracellular serotonin levels and potentially neurodevelopmental changes in the fetus. OBJECTIVES: The purpose of this study was to elucidate the long-term consequences of prenatal fluoxetine in rats. METHODS: Pregnant rats were injected daily with 12 mg/kg fluoxetine or vehicle from gestational day 11 until birth, and the behavior of the offspring was monitored. RESULTS: Plasma fluoxetine transfer from mother to pup was 83%, and high levels of fluoxetine (13.0 µg/g) were detected in the pup brain 5 h after the last injection. Fluoxetine-treated dams gave birth to litters 15% smaller than usual and to pups of reduced weight (until postnatal day 7). Furthermore, prenatal fluoxetine exposure significantly increased anxiety in the novelty-suppressed feeding test, the footshock-induced conditioned place aversion test, and the elevated plus maze test (following footshock pre-exposure) during adulthood, and also significantly decreased components of social play behavior at 4 weeks of age, and a strong tendency for increased self-grooming and making less contact in adults. Behavioral despair, anhedonia, and sexual behavior were not different between treatment groups. Finally, the hypothermic response to the 5-HT(1A) agonist flesinoxan was observed at a lower dose in prenatally fluoxetine-exposed rats than in controls. CONCLUSIONS: Prenatal fluoxetine exposure in rats leads to detrimental behavioral outcomes in later life, which may partly be due to altered 5-HT(1A) receptor signaling.