RESUMEN
Human studies of substance use disorder show that psychological stress and drug availability interact following rehabilitation, contributing to the high relapse potential. Social stressors trigger particularly strong motivation for drug, but how this affects neuronal function to increase relapse is unknown. Animal models, which allow for the dissection of neural mechanisms, primarily utilize physical stressors to trigger relapse. To recapitulate psychosocial post-rehabilitation challenges in animals, we developed a model of social stress-potentiated methamphetamine (METH) seeking. Rats receive a single social defeat (SD) session after completion of self-administration and extinction of lever pressing. While a reminder of the SD was insufficient to reinstate METH seeking on its own, rats that received a reminder of SD followed by a METH-priming injection displayed potentiated reinstatement over METH-priming alone. Examination of neuronal activation patterns of the METH-primed reinstatement session identified c-Fos-immunoreactivity in the basolateral amygdala (BLA) as correlated with SD score, a measure of defeat latency. Rapidly defeated rats showed potentiated METH-primed reinstatement and elevated BLA c-Fos compared with controls. Conversely, rats that were undefeated during the social stress did not show potentiated METH-primed reinstatement or elevated BLA c-Fos. Interestingly, inactivation of the BLA with baclofen/muscimol prior to the stress reminder and METH-priming generated a potentiation of METH seeking in the undefeated rats, suggesting the BLA may mediate resilience to the stressor. This model provides a tool for the further dissection of neural mechanisms mediating social stress-potentiated relapse and for the development of relapse-reducing therapeutics.
Asunto(s)
Estimulantes del Sistema Nervioso Central/farmacología , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Metanfetamina/farmacología , Conducta Social , Estrés Psicológico/fisiopatología , Amígdala del Cerebelo/efectos de los fármacos , Análisis de Varianza , Animales , Baclofeno/farmacología , Corteza Cerebral/efectos de los fármacos , Condicionamiento Operante , Extinción Psicológica , Agonistas de Receptores de GABA-A/farmacología , Agonistas de Receptores GABA-B/farmacología , Relaciones Interpersonales , Masculino , Motivación , Muscimol/farmacología , Núcleo Accumbens/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas Long-Evans , Ratas Sprague-Dawley , Refuerzo en Psicología , AutoadministraciónRESUMEN
Depolymerizing actin in the amygdala through nonmuscle myosin II inhibition (NMIIi) produces a selective, lasting, and retrieval-independent disruption of the storage of methamphetamine-associated memories. Here we report a similar disruption of memories associated with amphetamine, but not cocaine or morphine, by NMIIi. Reconsolidation appeared to be disrupted with cocaine. Unlike in the amygdala, methamphetamine-associated memory storage was not disrupted by NMIIi in the hippocampus, nucleus accumbens, or orbitofrontal cortex. NMIIi in the hippocampus did appear to disrupt reconsolidation. Identification of the unique mechanisms responsible for NMII-mediated, amygdala-dependent disruption of memory storage associated with the amphetamine class may enable induction of retrieval-independent vulnerability to other pathological memories.
Asunto(s)
Encéfalo/efectos de los fármacos , Compuestos Heterocíclicos de 4 o más Anillos/toxicidad , Trastornos de la Memoria/inducido químicamente , Recuerdo Mental/efectos de los fármacos , Miosina Tipo II/metabolismo , Análisis de Varianza , Anestésicos Locales/administración & dosificación , Anestésicos Locales/farmacología , Animales , Encéfalo/metabolismo , Encéfalo/ultraestructura , Estimulantes del Sistema Nervioso Central/administración & dosificación , Estimulantes del Sistema Nervioso Central/farmacología , Cocaína/administración & dosificación , Cocaína/farmacología , Condicionamiento Operante/efectos de los fármacos , Condicionamiento Operante/fisiología , Espinas Dendríticas/efectos de los fármacos , Espinas Dendríticas/ultraestructura , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Trastornos de la Memoria/metabolismo , Trastornos de la Memoria/patología , Metanfetamina/administración & dosificación , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Microinyecciones , Derivados de la Morfina/administración & dosificación , Derivados de la Morfina/farmacologíaRESUMEN
Prolonged distress and dysregulated memory processes are the core features of post-traumatic stress disorder (PTSD) and represent the debilitating, persistent nature of the illness. However, the neurobiological mechanisms underlying the expression of these symptoms are challenging to study in human patients. Stress-enhanced fear learning (SEFL) paradigms, which encompass both stress and memory components in rodents, are emerging as valuable preclinical models of PTSD. Rodent models designed to study the long-term mechanisms of either stress or fear memory alone have identified a critical role for numerous epigenetic modifications to DNA and histone proteins. However, the epigenetic modifications underlying SEFL remain largely unknown. This review will provide a brief overview of the epigenetic modifications implicated in stress and fear memory independently, followed by a description of existing SEFL models and the few epigenetic mechanisms found to date to underlie SEFL. The results of the animal studies discussed here highlight neuroepigenetics as an essential area for future research in the context of PTSD through SEFL studies, because of its potential to identify novel candidates for neurotherapeutics targeting stress-induced pathogenic memories.
Asunto(s)
Epigénesis Genética , Trastornos por Estrés Postraumático/genética , Trastornos por Estrés Postraumático/metabolismo , Animales , Modelos Animales de Enfermedad , HumanosAsunto(s)
Hormonas Hipotalámicas/fisiología , Hipotálamo/citología , Péptidos y Proteínas de Señalización Intracelular/fisiología , Melaninas/fisiología , Neuronas/fisiología , Neuropéptidos/fisiología , Hormonas Hipofisarias/fisiología , Sueño/fisiología , Vigilia/fisiología , Animales , Humanos , OrexinasRESUMEN
Narp knockout (KO) mice demonstrate cognitive inflexibility and addictive behavior, which are associated with abnormal reactivity to a novel stimulus. To assess reactivity to novelty, we tested Narp KO and wild-type (WT) mice on a neophobia procedure. Both Narp KO and WT mice showed a similar decrease in consumption upon initial exposure to a novel flavor, but Narp KO mice did not increase consumption with subsequent exposures to the novel flavor like the WT mice. Therefore, Narp KO mice do not have abnormal reactivity to novelty but show deficits in adapting behavior to reflect the updated value of a stimulus.
Asunto(s)
Adaptación Psicológica/fisiología , Proteína C-Reactiva/deficiencia , Conducta Exploratoria/fisiología , Proteínas del Tejido Nervioso/deficiencia , Trastornos Fóbicos/fisiopatología , Recuperación de la Función/genética , Animales , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Actividad Motora/genética , Trastornos Fóbicos/genética , Factores de TiempoRESUMEN
The medial prefrontal cortex (mPFC) plays a key role in extinction learning. Previously, we found that expression of a neuronal activity-regulated pentraxin (Narp) dominant-negative construct in the mPFC of mice blocked extinction of morphine-conditioned place preference. To further investigate the role of mPFC Narp in the extinction of drug seeking, we tested whether mPFC Narp is necessary for the extinction of heroin self-administration in rats. Specifically, we injected an adeno-associated viral vector expressing a dominant-negative form of Narp (NarpN) into the infralimbic region of the mPFC of rats and compared lever presses during extinction to those of rats injected with a control virus. In contrast to our previous study, we found that injection of NarpN did not affect extinction of heroin self-administration. Our findings suggest that mPFC Narp is necessary for extinction of opiate seeking in the Pavlovian-conditioned place preference paradigm but not in the operant paradigm of drug self-administration.
Asunto(s)
Proteína C-Reactiva/metabolismo , Extinción Psicológica/efectos de los fármacos , Heroína/administración & dosificación , Narcóticos/administración & dosificación , Proteínas del Tejido Nervioso/metabolismo , Neuronas/efectos de los fármacos , Corteza Prefrontal/citología , Análisis de Varianza , Animales , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Proteína C-Reactiva/genética , Condicionamiento Clásico/efectos de los fármacos , Dependovirus/genética , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Masculino , Proteínas del Tejido Nervioso/genética , Neuronas/metabolismo , Ratas , Ratas Sprague-Dawley , Autoadministración , Factores de Tiempo , Transducción GenéticaRESUMEN
The neurochemical changes underlying human emotions and social behaviour are largely unknown. Here we report on the changes in the levels of two hypothalamic neuropeptides, hypocretin-1 and melanin-concentrating hormone, measured in the human amygdala. We show that hypocretin-1 levels are maximal during positive emotion, social interaction and anger, behaviours that induce cataplexy in human narcoleptics. In contrast, melanin-concentrating hormone levels are minimal during social interaction, but are increased after eating. Both peptides are at minimal levels during periods of postoperative pain despite high levels of arousal. Melanin-concentrating hormone levels increase at sleep onset, consistent with a role in sleep induction, whereas hypocretin-1 levels increase at wake onset, consistent with a role in wake induction. Levels of these two peptides in humans are not simply linked to arousal, but rather to specific emotions and state transitions. Other arousal systems may be similarly emotionally specialized.
Asunto(s)
Emociones/fisiología , Hormonas Hipotalámicas/metabolismo , Relaciones Interpersonales , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Melaninas/metabolismo , Neuropéptidos/metabolismo , Hormonas Hipofisarias/metabolismo , Adulto , Amígdala del Cerebelo/metabolismo , Animales , Conducta , Electrodos Implantados , Femenino , Humanos , Hipotálamo/metabolismo , Masculino , Microdiálisis , Persona de Mediana Edad , Orexinas , Ratas , Sueño/fisiología , Factores de Tiempo , Vigilia/fisiología , Adulto JovenRESUMEN
Narp knockout (KO) mice demonstrate an impaired extinction of morphine conditioned place preference (CPP). Because the medial prefrontal cortex (mPFC) has been implicated in extinction learning, we tested whether Narp cells in this region play a role in the extinction of morphine CPP. We found that intracranial injections of adenoassociated virus (AAV) expressing wild-type (WT) Narp into the mPFC of Narp KO mice rescued the extinction and the injection of AAV expressing a dominant negative form of Narp (NarpN) into the mPFC of WT mice impaired the extinction of morphine CPP. These findings suggest that Narp in the mPFC mediates the extinction of morphine CPP.
Asunto(s)
Proteína C-Reactiva/metabolismo , Condicionamiento Operante/fisiología , Extinción Psicológica/fisiología , Morfina/administración & dosificación , Narcóticos/administración & dosificación , Proteínas del Tejido Nervioso/metabolismo , Corteza Prefrontal/metabolismo , Análisis de Varianza , Animales , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Proteína C-Reactiva/deficiencia , Dependovirus/genética , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microinyecciones , Proteínas del Tejido Nervioso/deficienciaRESUMEN
There has been remarkable progress in deciphering the molecular mechanisms that mediate synaptic plasticity. Advances have stimulated interest in determining whether these plasticity mechanisms also mediate the long-lasting behavioral effects induced by drugs of abuse. The observation that drugs of abuse, such as cocaine or morphine, can elicit robust immediate early gene (IEG) responses similar to those induced by long-term potentiation stimulation has provided important support for this hypothesis. Evidence that repeated administration of cocaine produces alterations in expression and trafficking of AMPA receptors, processes that play a central role in synaptic plasticity, has also bolstered this view. Neuronal activity-regulated pentraxin (Narp), an IEG, has emerged as an attractive candidate to mediate long-term effects of drugs of abuse because it encodes a secreted protein that binds to the extracellular surface of AMPA receptors and regulates their trafficking. In this review we provide background information on Narp and closely related proteins, the neuronal pentraxins, and summarize studies of Narp knockout mice demonstrating that this IEG modulates long-term behavioral responses to drugs of abuse.
Asunto(s)
Plasticidad Neuronal , Receptores AMPA , Animales , Ratones Noqueados , Trastornos Relacionados con SustanciasRESUMEN
Neuronal activity regulated pentraxin (Narp) is a secreted protein that regulates α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors (AMPAR) aggregation and synaptogenesis. Mapping of Narp-positive neurons in brain has revealed it is prominently expressed in several limbic system projection pathways. Consistent with this localization pattern, Narp knockout mice show deficits in using the current value of a reinforcer to guide behavior, a critical function of the limbic system. To help assess whether this behavioral deficit is due to impairment of synaptogenesis during development or in modulating synaptic signaling in the mature brain, we have used a dominant negative Narp viral construct which blocks trafficking of endogenous Narp to axons. Focal injection of this viral construct into the medial prefrontal cortex (mPFC) of adult mice, a region containing Narp-positive projection neurons, blocked reinforcer devaluation. Thus, these results indicate that Narp released from mPFC neurons plays a key role in mediating synaptic changes underlying instrumental reinforcer devaluation.
Asunto(s)
Proteína C-Reactiva/metabolismo , Condicionamiento Operante/fisiología , Proteínas del Tejido Nervioso/metabolismo , Corteza Prefrontal/metabolismo , Refuerzo en Psicología , Análisis de Varianza , Animales , Conducta Animal , Proteína C-Reactiva/deficiencia , Toxina del Cólera/metabolismo , Vectores Genéticos/metabolismo , Proteínas Luminiscentes/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas del Tejido Nervioso/deficiencia , Vías Nerviosas/fisiología , Núcleo Accumbens/fisiologíaRESUMEN
Having recently shown that extinction of conditioned fear depends on L-type voltage-gated calcium channels (LVGCCs), we have been seeking other protocols that require this unusual induction mechanism. We tested latent inhibition (LI) of fear, because LI resembles extinction except that cue exposures precede, rather than follow, cue-shock pairing. Systemic injections of two LVGCC inhibitors, nifedipine and diltiazem, before pre-exposure blocked LI completely with no evidence of state-dependent learning. The results indicate that extinction and LI share a common molecular requirement and may support the notion that LI, like extinction, is a form of inhibitory learning.
Asunto(s)
Aprendizaje por Asociación/fisiología , Canales de Calcio Tipo L/fisiología , Condicionamiento Clásico/efectos de los fármacos , Miedo/efectos de los fármacos , Inhibición Neural/fisiología , Análisis de Varianza , Animales , Aprendizaje por Asociación/efectos de los fármacos , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo L/efectos de los fármacos , Condicionamiento Clásico/fisiología , Señales (Psicología) , Diltiazem/farmacología , Extinción Psicológica/fisiología , Miedo/fisiología , Inhibición Psicológica , Masculino , Ratones , Ratones Endogámicos C57BL , Inhibición Neural/efectos de los fármacos , Nifedipino/farmacologíaRESUMEN
Extinction of classically conditioned fear, like its acquisition, is active learning, but little is known about its molecular mechanisms. We recently reported that temporal massing of conditional stimulus (CS) presentations improves extinction memory acquisition, and suggested that temporal spacing was less effective because individual CS exposures trigger two opposing processes: (1) fear extinction, which is favored by CS massing, and (2) fear incubation (increase), which is favored by spacing. We here report the effects of manipulating the adrenergic system during massed or spaced CS presentations in fear-conditioned mice. We administered yohimbine (5 mg/kg), an alpha(2)-receptor antagonist, or propranolol (10 mg/kg), a beta-receptor antagonist, systemically prior to CS presentation sessions and recorded both short- and long-term changes in conditional freezing. Yohimbine treatment facilitated extinction of both cue and context fear with massed protocols. When given before spaced CS presentations, propranolol led to a persistent incubation of cue fear, whereas yohimbine led to persistent extinction, compared with vehicle-treated animals, which showed no change in fear. These results suggest that norepinephrine positively modulates the formation of fear extinction memories in mice. They also provide clear evidence that spaced CS presentations trigger both fear-reducing (extinction) and fear-increasing (incubation) mechanisms.
Asunto(s)
Agonistas Adrenérgicos/farmacología , Condicionamiento Clásico/efectos de los fármacos , Extinción Psicológica/efectos de los fármacos , Miedo/fisiología , Transmisión Sináptica/efectos de los fármacos , Animales , Aprendizaje por Asociación/efectos de los fármacos , Aprendizaje por Asociación/fisiología , Condicionamiento Clásico/fisiología , Pérdida de Tono Postural/efectos de los fármacos , Pérdida de Tono Postural/fisiología , Masculino , Memoria/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Norepinefrina/fisiología , Propranolol/farmacología , Yohimbina/farmacologíaRESUMEN
Rodent fear conditioning models both excitatory learning and the pathogenesis of human anxiety, whereas extinction of conditional fear is a paradigm of inhibitory learning and the explicit model for behavior therapy. Many studies support a general learning rule for acquisition: Temporally spaced training is more effective than massed training. The authors asked whether this rule applies to extinction of conditional fear in mice. The authors find that both short- and long-term fear extinction are greater with temporally massed presentations of the conditional stimulus (CS). The data also indicate that once CS presentations are sufficiently massed to initiate, or "induce," extinction learning, further CS presentations are more effective when spaced.
Asunto(s)
Condicionamiento Psicológico , Extinción Psicológica , Miedo , Animales , Inhibición Psicológica , Masculino , Ratones , Ratones Endogámicos C57BL , Factores de TiempoRESUMEN
It has been shown recently that extinction of conditional fear does not depend acutely on NMDA-type glutamate receptors, although other evidence has led to the hypothesis that L-type voltage-gated calcium channels (LVGCCs) play a role in conditional fear. We therefore tested the role of LVGCCs in the acquisition, expression, and extinction of conditional fear of cue and context in mice. Using systemic injections of two LVGCC inhibitors, nifedipine and nimodipine, which both effectively cross the blood-brain barrier, we show that LVGCCs are essential for the extinction, but not for the acquisition or expression, of conditional fear in mice.