RESUMEN
Stress is implicated in psychopathology characterized by cognitive dysfunction. Cognitive responses to stress are regulated by the locus coeruleus-norepinephrine (LC-NE) system. As social stress is a prevalent human stressor, this study determined the impact of repeated social stress on the relationship between LC neuronal activity and behavior during the performance of cognitive tasks. Social stress-exposed rats performed better at intradimensional set shifting (IDS) and made fewer perseverative errors during reversal learning (REV). LC neurons of control rats were task responsive, being activated after the choice and before reward. Social stress shifted LC neuronal activity from being task responsive to being reward responsive during IDS and REV. LC neurons of stressed rats were activated by reward and tonically inhibited by reward omission with incorrect choices. In contrast, LC neurons of stress-naive rats were only tonically inhibited by reward omission. Reward-related LC activation in stressed rats was unrelated to predictability because it did not habituate as learning progressed. The findings suggest that social stress history increases reward salience and impairs processes that compute predictability for LC neurons. These effects of social stress on LC neuronal activity could facilitate learning as indicated by improved performance in stressed rats. However, the ability of social stress history to enhance responses to behavioral outcomes may have a role in the association between stress and addictive behaviors. In addition, magnified fluctuations in LC activity in response to opposing behavioral consequences may underlie volatile changes in emotional arousal that characterize post-traumatic stress disorder.
Asunto(s)
Conducta de Elección/fisiología , Locus Coeruleus/fisiopatología , Neuronas/fisiología , Recompensa , Conducta Social , Estrés Psicológico/fisiopatología , Animales , Atención/fisiología , Electrodos Implantados , Función Ejecutiva/fisiología , Masculino , Pruebas Neuropsicológicas , Distribución Aleatoria , Ratas Long-Evans , Ratas Sprague-Dawley , Aprendizaje Inverso/fisiologíaRESUMEN
Classically, opioids produce their effects by activating Gi-proteins that inhibit adenylate cyclase activity. Previous studies proposed that mu-opioid receptors can also stimulate adenylate cyclase due to an initial transient coupling to Gs-proteins. Treatment with ultra-low doses of the nonselective opioid antagonist (-)-naloxone or its inactive enantiomer (+)-naloxone blocks this excitatory effect and enhances Gi-coupling. Previously we reported that infusion of the mu-opioid receptor agonist [D-Ala2, N-Me-Phe4, Glycinol5]-Enkephalin (DAMGO) into the mu-opioid receptor expressing lateral parabrachial nucleus increases feeding. Pretreatment with (-)-naloxone blocks this effect. We used this parabrachial circuit as a model to assess cellular actions of ultra-low doses of (-)-naloxone and (+)-naloxone in modifying the effects of DAMGO. Our results showed that an ultra-low concentration of (-)-naloxone (0.001 nM) and several concentrations of (+)-naloxone (0.01-10 nM) enhanced DAMGO-stimulated guanosine-5'-0-(γ-thio)-triphosphate incorporation in parabrachial sections in vitro. Further, we analyzed the relevance of these effects in vivo. In the present study, we show that (+)-naloxone can potentiate DAMGO-induced feeding at doses at which (-)-naloxone was an antagonist. These results implicated (+)-naloxone as a novel tool for studying mu-opioid receptor functions and suggest that (+)-naloxone may have therapeutic value to enhance clinical actions of opiate drugs.
Asunto(s)
Subunidades alfa de la Proteína de Unión al GTP Gi-Go/agonistas , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Neuronas/efectos de los fármacos , Puente/efectos de los fármacos , Receptores Opioides mu/agonistas , Transducción de Señal/efectos de los fármacos , Analgésicos Opioides/agonistas , Analgésicos Opioides/antagonistas & inhibidores , Analgésicos Opioides/farmacología , Animales , Conducta Animal/efectos de los fármacos , Sinergismo Farmacológico , Ingestión de Alimentos/efectos de los fármacos , Encefalina Ala(2)-MeFe(4)-Gli(5)/agonistas , Encefalina Ala(2)-MeFe(4)-Gli(5)/antagonistas & inhibidores , Encefalina Ala(2)-MeFe(4)-Gli(5)/farmacología , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/metabolismo , Técnicas In Vitro , Masculino , Proteínas del Tejido Nervioso/agonistas , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Concentración Osmolar , Puente/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores Opioides mu/metabolismo , EstereoisomerismoRESUMEN
Stress is implicated in diverse psychiatric disorders including substance abuse. The locus coeruleus-norepinephrine (LC-NE) system is a major stress response system that is also a point of intersection between stress neuromediators and endogenous opioids and so may be a site at which stress can influence drug-taking behaviors. As social stress is a common stressor for humans, this study characterized the enduring impact of repeated social stress on LC neuronal activity. Rats were exposed to five daily consecutive sessions of social stress using the resident-intruder model or control manipulation. LC discharge rate recorded 2 days after the last manipulation was decreased in stressed rats compared with controls. By 10 days after the last manipulation, LC rates were comparable between groups. Systemic administration of the opiate antagonist, naloxone, robustly increased LC discharge rate in a manner suggestive of opiate withdrawal, selectively in stressed rats when administered 2 or 10 days after the last manipulation. This was accompanied by behavioral signs of mild opiate withdrawal. Western blot and electron microscopic studies indicated that repeated social stress decreased corticotropin-releasing factor type 1 receptor and increased µ-opioid receptor levels in the LC. Together, the results suggest that repeated social stress engages endogenous opioid modulation of LC activity and induces signs of cellular and physical opiate dependence that endure after the stress. These cellular effects may predispose individuals with a history of repeated social stress to substance abuse behaviors.
Asunto(s)
Neuronas Adrenérgicas/metabolismo , Locus Coeruleus/metabolismo , Trastornos Relacionados con Opioides/fisiopatología , Receptores Opioides mu/metabolismo , Estrés Psicológico/fisiopatología , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Neuronas Adrenérgicas/efectos de los fármacos , Animales , Locus Coeruleus/efectos de los fármacos , Locus Coeruleus/fisiopatología , Masculino , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Trastornos Relacionados con Opioides/complicaciones , Trastornos Relacionados con Opioides/metabolismo , Trastornos Relacionados con Opioides/patología , Trastornos Relacionados con Opioides/psicología , Ratas , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Receptores Opioides mu/antagonistas & inhibidores , Estrés Psicológico/complicaciones , Estrés Psicológico/metabolismo , Estrés Psicológico/psicología , Síndrome de Abstinencia a Sustancias/psicologíaRESUMEN
The parabrachial nucleus (PBN) is an area of the brain stem that controls eating and contains endogenous opioids and their receptors. Previously, we demonstrated that acute activation of mu opioid receptors (MOPR) in the lateral PBN increased food consumption. MOPRs have been divided operationally into mu(1) and mu(2) receptor subtypes on the basis of the ability of naloxonazine (Nlxz) to block the former but not the latter. We used autoradiography to measure whether Nlxz blocks stimulation by the mu(1)/mu(2) agonist DAMGO (D-Ala2, N-Me-Phe4, Gly5-ol-enkephalin) of the incorporation of [(35)S]-guanosine 5'(gamma-thio)triphosphate ([(35)S]-GTPgammaS) into sections of the PBN. In vitro, Nlxz dose dependently inhibited receptor coupling in all areas of the PBN. The 1 muM concentration of Nlxz reduced stimulation by 93.1+/-5% in the lateral inferior PBN (LPBNi) and by 90.5+/-4% in the medial parabrachial subregion (MPBN). Administration of Nlxz directly into the LPBNi decreased both food intake and agonist stimulated coupling, ex vivo, for the 24-h period after infusion. Infusion of Nlxz into the intended area reduced food intake by 42.3% below baseline values. Nlxz infusion prevented DAMGO stimulation of G-protein coupling in LPBNi and markedly reduced this stimulation in the MPBN. The incomplete inhibition of DAMGO-stimulated coupling in the MPBN is most likely due to the limited diffusion of Nlxz from the site of infusion (LPBNi) into this brain region. In conclusion, this study demonstrates that the mu(1) opioid receptor subtype is present in the parabrachial nucleus of the pons and that these receptors serve to modulate feeding in rats.