RESUMEN
Harmful alcohol consumption is a major socioeconomic burden to the health system, as it can be the cause of mortality of heavy alcohol drinkers. The dopaminergic (DAergic) system is thought to play an important role in the pathogenesis of alcohol drinking behaviour; however, its exact role remains elusive. Fibroblast growth factor 2 (FGF-2), a neurotrophic factor, associated with both the DAergic system and alcohol consumption, may play an important role in DAergic neuroadaptations during alcohol abuse. Within this study, we aimed to clarify the role of endogenous FGF-2 on the DAergic system and whether there is a possible link to alcohol consumption. We found that lack of FGF-2 reduces the alcohol intake of mice. Transcriptome analysis of DAergic neurons revealed that FGF-2 knockout (FGF-2 KO) shifts the molecular fingerprint of midbrain dopaminergic (mDA) neurons to DA subtypes of the ventral tegmental area (VTA). In line with this, proteomic changes predominantly appear also in the VTA. Interestingly, these changes led to an altered regulation of the FGF-2 signalling cascades and DAergic pathways in a region-specific manner, which was only marginally affected by voluntary alcohol consumption. Thus, lack of FGF-2 not only affects the gene expression but also the proteome of specific brain regions of mDA neurons. Our study provides new insights into the neuroadaptations of the DAergic system during alcohol abuse and, therefore, comprises novel targets for future pharmacological interventions.
Asunto(s)
Alcoholismo , Área Tegmental Ventral , Ratones , Animales , Área Tegmental Ventral/metabolismo , Neuronas Dopaminérgicas/metabolismo , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Alcoholismo/genética , Alcoholismo/metabolismo , Proteómica , Consumo de Bebidas AlcohólicasRESUMEN
Relapse to alcohol abuse, often caused by cue-induced alcohol craving, is a major challenge in alcohol addiction treatment. Therefore, disrupting the cue-alcohol memories can suppress relapse. Upon retrieval, memories transiently destabilize before they reconsolidate in a process that requires protein synthesis. Evidence suggests that the mammalian target of rapamycin complex 1 (mTORC1), governing the translation of a subset of dendritic proteins, is crucial for memory reconsolidation. Here, we explored the involvement of two regulatory pathways of mTORC1, phosphoinositide 3-kinase (PI3K)-AKT and extracellular regulated kinase 1/2 (ERK1/2), in the reconsolidation process in a rat (Wistar) model of alcohol self-administration. We found that retrieval of alcohol memories using an odor-taste cue increased ERK1/2 activation in the amygdala, while the PI3K-AKT pathway remained unaffected. Importantly, ERK1/2 inhibition after alcohol memory retrieval impaired alcohol-memory reconsolidation and led to long-lasting relapse suppression. Attenuation of relapse was also induced by post-retrieval administration of lacosamide, an inhibitor of collapsin response mediator protein-2 (CRMP2)-a translational product of mTORC1. Together, our findings indicate the crucial role of ERK1/2 and CRMP2 in the reconsolidation of alcohol memories, with their inhibition as potential treatment targets for relapse prevention.
Asunto(s)
Alcoholismo , Péptidos y Proteínas de Señalización Intercelular , Consolidación de la Memoria , Proteína Quinasa 1 Activada por Mitógenos , Proteína Quinasa 3 Activada por Mitógenos , Proteínas del Tejido Nervioso , Animales , Masculino , Ratas , Alcoholismo/metabolismo , Alcoholismo/tratamiento farmacológico , Amígdala del Cerebelo/metabolismo , Amígdala del Cerebelo/efectos de los fármacos , Etanol , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Memoria/efectos de los fármacos , Consolidación de la Memoria/efectos de los fármacos , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas Wistar , Recurrencia , AutoadministraciónRESUMEN
Alcohol abuse accounts for 3.3 million deaths annually, rendering it a global health issue. Recently, fibroblast growth factor 2 (FGF-2) and its target, fibroblast growth factor receptor 1 (FGFR1), were discovered to positively regulate alcohol-drinking behaviors in mice. We tested whether alcohol intake and withdrawal alter DNA methylation of Fgf-2 and Fgfr1 and if there is a correlation regarding mRNA expression of these genes. Blood and brain tissues of mice receiving alcohol intermittently over a six-week period were analyzed using direct bisulfite sequencing and qRT-PCR analysis. Assessment of Fgf-2 and Fgfr1 promoter methylation revealed changes in the methylation of cytosines in the alcohol group compared with the control group. Moreover, we showed that the altered cytosines coincided with binding motives of several transcription factors. We also found that Fgf-2 and Fgfr1 gene expression was significantly decreased in alcohol-receiving mice compared with control littermates, and that this effect was specifically detected in the dorsomedial striatum, a brain region involved in the circuitry of the reward system. Overall, our data showed alcohol-induced alterations in both mRNA expression and methylation pattern of Fgf-2 and Fgfr1. Furthermore, these alterations showed a reward system regional specificity, therefore, resembling potential targets for future pharmacological interventions.
Asunto(s)
Factor 2 de Crecimiento de Fibroblastos , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos , Animales , Ratones , Consumo de Bebidas Alcohólicas , Metilación de ADN , Etanol , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismo , Receptores de Factores de Crecimiento de Fibroblastos/metabolismo , ARN Mensajero/metabolismoRESUMEN
Habits are a prominent feature of both adaptive and maladaptive behavior. Yet, despite substantial research efforts, there are currently no well-established experimental procedures for habit induction in humans. It is likely that laboratory experimental settings, as well as the session-based structure typically used in controlled experiments (also outside the lab), impose serious constraints on studying habits and other effects that are sensitive to context, motivation, and training duration and frequency. To overcome these challenges, we devised a unique real-world free-operant task structure, implemented through a novel smartphone application, whereby participants could freely enter the app (24 hours a day, 7 days a week) to win rewards. This procedure is free of typical laboratory constraints, yet well controlled. Using the canonical sensitivity to outcome devaluation criterion, we successfully demonstrated habit formation as a function of training duration, a long-standing challenge in the field. Additionally, we show a positive relationship between multiple facets of engagement/motivation and goal-directedness. We suggest that our novel paradigm can be used to study the neurobehavioral and psychological mechanism underlying habits in humans. Moreover, the real-world free-operant framework can potentially be used to examine other instrumental behavior-related questions, with greater face validity in naturalistic conditions.
RESUMEN
Alcohol use disorder (AUD) is a chronic, relapsing disorder, characterized by escalating alcohol drinking and loss of control, with very limited available treatments. We recently reported that the expression of fibroblast growth factor 2 (Fgf2) is increased in the striatum of rodents following long-term excessive alcohol drinking and that the systemic or intra-striatal administration of recombinant FGF2 increases alcohol consumption. Here, we set out to determine whether the endogenous FGF2 plays a role in alcohol drinking and reward, by testing the behavioural phenotype of Fgf2 knockout mice. We found that Fgf2 deficiency resulted in decreased alcohol consumption when tested in two-bottle choice procedures with various alcohol concentrations. Importantly, these effects were specific for alcohol, as a natural reward (sucrose) or water consumption was not affected by Fgf2 deficiency. In addition, Fgf2 knockout mice failed to show alcohol-conditioned place preference (CPP) but showed normal fear conditioning, suggesting that deletion of the growth factor reduces alcohol's rewarding properties. Finally, Fgf2 knockout mice took longer to recover from the loss of righting reflex and showed higher blood alcohol concentrations when challenged with an intoxicating alcohol dose, suggesting that their ethanol metabolism might be affected. Together, our results show that the endogenous FGF2 plays a critical role in alcohol drinking and reward and indicate that FGF2 is a positive regulator of alcohol-drinking behaviours. Our findings suggest that FGF2 is a potential biomarker for problem alcohol drinking and is a potential target for pharmacotherapy development for AUD.
Asunto(s)
Etanol , Factor 2 de Crecimiento de Fibroblastos , Consumo de Bebidas Alcohólicas/genética , Consumo de Bebidas Alcohólicas/metabolismo , Animales , Cuerpo Estriado , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Factor 2 de Crecimiento de Fibroblastos/farmacología , Ratones , RecompensaRESUMEN
The main characteristic of alcohol use disorder is the consumption of large quantities of alcohol despite the negative consequences. The transition from the moderate use of alcohol to excessive, uncontrolled alcohol consumption results from neuroadaptations that cause aberrant motivational learning and memory processes. Here, we examine studies that have combined molecular and behavioural approaches in rodents to elucidate the molecular mechanisms that keep the social intake of alcohol in check, which we term 'stop pathways', and the neuroadaptations that underlie the transition from moderate to uncontrolled, excessive alcohol intake, which we term 'go pathways'. We also discuss post-transcriptional, genetic and epigenetic alterations that underlie both types of pathways.
Asunto(s)
Consumo de Bebidas Alcohólicas/efectos adversos , Encéfalo/metabolismo , Conducta de Ingestión de Líquido/fisiología , Etanol/efectos adversos , Red Nerviosa/metabolismo , Transducción de Señal/fisiología , Animales , Encéfalo/fisiopatología , HumanosRESUMEN
Relapse to alcohol abuse is often caused by exposure to potent alcohol-associated cues. Therefore, disruption of the cue-alcohol memory can prevent relapse. It is believed that memories destabilize and become prone for updating upon their reactivation through retrieval and then restabilize within 6 h during a "reconsolidation" process. We recently showed that relapse to cocaine seeking in a place-conditioning paradigm could be prevented by counterconditioning the cocaine cues with aversive outcomes following cocaine-memory retrieval. However, to better model addiction-related behaviors, self-administration models are necessary. Here, we demonstrate that relapse to alcohol seeking can be prevented by aversive counterconditioning conducted during alcohol-memory reconsolidation, in the place conditioning and operant self-administration paradigms, in mice and rats, respectively. We found that the reinstatement of alcohol-conditioned place preference was abolished only when aversive counterconditioning with water flooding was given shortly after alcohol-memory retrieval. Furthermore, rats trained to lever press for alcohol showed decreased context-induced renewal of alcohol-seeking responding when the lever pressing was punished with foot-shocks, shortly, but not 6 h, after memory retrieval. These results suggest that aversive counterconditioning can prevent relapse to alcohol seeking only when performed during alcohol-memory reconsolidation, presumably by updating, or replacing, the alcohol memory with aversive information. Finally, we found that aversive counterconditioning preceded by alcohol-memory retrieval was characterized by the upregulation of brain-derived neurotrophic factor (Bdnf) mRNA expression in the medial prefrontal cortex, suggesting that BDNF may play a role in the memory updating process.
Asunto(s)
Trastornos Relacionados con Alcohol/terapia , Condicionamiento Operante/fisiología , Etanol/farmacología , Consolidación de la Memoria/fisiología , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , RecurrenciaRESUMEN
Alcohol and nicotine are widely abused legal substances worldwide. Relapse to alcohol or tobacco seeking and consumption after abstinence is a major clinical challenge, and is often evoked by cue-induced craving. Therefore, disruption of the memory for the cue-drug association is expected to suppress relapse. Memories have been postulated to become labile shortly after their retrieval, during a "memory reconsolidation" process. Interference with the reconsolidation of drug-associated memories has been suggested as a possible strategy to reduce or even prevent cue-induced craving and relapse. Here, we surveyed the growing body of studies in animal models and in humans assessing the effectiveness of pharmacological or behavioral manipulations in reducing relapse by interfering with the reconsolidation of alcohol and nicotine/tobacco memories. Our review points to the potential of targeting the reconsolidation of these memories as a strategy to suppress relapse to alcohol drinking and tobacco smoking. However, we discuss several critical limitations and boundary conditions, which should be considered to improve the consistency and replicability in the field, and for development of an efficient reconsolidation-based relapse-prevention therapy.
Asunto(s)
Etanol/efectos adversos , Consolidación de la Memoria/efectos de los fármacos , Nicotina/efectos adversos , Conducta/efectos de los fármacos , Humanos , Biosíntesis de Proteínas/efectos de los fármacos , Receptores de Superficie Celular/metabolismoRESUMEN
Excessive alcohol intake leads to mesostriatal neuroadaptations, and to addiction phenotypes. We recently found in rodents that alcohol increases fibroblast growth factor 2 (FGF2) expression in the dorsomedial striatum (DMS), which promotes alcohol consumption. Here, we show that systemic or intra-DMS blockade of the FGF2 receptor, FGF receptor-1 (FGFR1), suppresses alcohol consumption, and that the effects of FGF2-FGFR1 on alcohol drinking are mediated via the phosphoinositide 3 kinase (PI3K) signaling pathway. Specifically, we found that sub-chronic alcohol treatment (7 d × 2.5 g/kg, i.p.) increased Fgfr1 mRNA expression in the dorsal hippocampus and dorsal striatum. However, prolonged and excessive voluntary alcohol consumption in a two-bottle choice procedure increased Fgfr1 expression selectively in DMS. Importantly, systemic administration of the FGFR1 inhibitor PD173074 to mice, as well as its infusion into the DMS of rats, decreased alcohol consumption and preference, with no effects on natural reward consumption. Finally, inhibition of the PI3K, but not of the mitogen-activated protein kinase (MAPK) signaling pathway, blocked the effects of FGF2 on alcohol intake and preference. Our results suggest that activation of FGFR1 by FGF2 in the DMS leads to activation of the PI3K signaling pathway, which promotes excessive alcohol consumption, and that inhibition of FGFR1 may provide a novel therapeutic target for alcohol use disorder.SIGNIFICANCE STATEMENT Long-term alcohol consumption causes neuroadaptations in the mesostriatal reward system, leading to addiction-related behaviors. We recently showed that alcohol upregulates the expression of fibroblast growth factor 2 (FGF2) in dorsomedial striatum (DMS) or rats and mice, and in turn, FGF2 increases alcohol consumption. Here, we show that long-term alcohol intake also increases the expression of the FGF2 receptor, FGFR1 in the DMS. Importantly, inhibition of FGFR1 activity by a selective receptor antagonist reduces alcohol drinking, when given systemically or directly into the DMS. We further show that the effects of FGF2-FGFR1 on alcohol drinking are mediated via activation of the PI3K intracellular signaling pathway, providing an insight on the mechanism for this effect.
Asunto(s)
Consumo de Bebidas Alcohólicas/genética , Cuerpo Estriado/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/efectos de los fármacos , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Animales , Depresores del Sistema Nervioso Central/farmacología , Conducta de Elección/efectos de los fármacos , Etanol/farmacología , Femenino , Factor 2 de Crecimiento de Fibroblastos/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Pirimidinas/farmacología , Ratas , Ratas Wistar , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/biosíntesis , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genéticaRESUMEN
Fibroblast growth factor 2 (FGF2) is a member of the FGF-family, which consists of 22 members, with four known FGF receptors (five in humans). Over the last 30 years, FGF2 has been extensively studied for its role in cell proliferation, differentiation, growth, survival and angiogenesis during development, as well as for its role in adult neurogenesis and regenerative plasticity. Over the past decade, FGF2 has been implicated in learning and memory, as well as in several neuropsychiatric disorders, including anxiety, stress, depression and drug addiction. In this review, we present accumulating evidence indicating the involvement of FGF2 in neuroadaptations caused by drugs of abuse, namely, amphetamine, cocaine, nicotine and alcohol. Moreover, evidence suggests that FGF2 is a positive regulator of alcohol and drug-related behaviors. Thus, although additional studies are yet required, we suggest that reducing FGF2 activity may provide a novel therapeutic approach for substance use disorders.
Asunto(s)
Factor 2 de Crecimiento de Fibroblastos/metabolismo , Drogas Ilícitas/metabolismo , Trastornos Relacionados con Sustancias/metabolismo , Animales , Dopaminérgicos/administración & dosificación , Dopaminérgicos/metabolismo , Factor 2 de Crecimiento de Fibroblastos/antagonistas & inhibidores , Humanos , Drogas Ilícitas/efectos adversos , Aprendizaje/efectos de los fármacos , Aprendizaje/fisiología , Memoria/efectos de los fármacos , Memoria/fisiología , Trastornos Relacionados con Sustancias/tratamiento farmacológicoRESUMEN
Glial cell line-derived neurotrophic factor (GDNF) has been extensively studied for its role in the development and maintenance of the midbrain dopaminergic system, although evidence suggests that GDNF also plays a role in drug and alcohol addiction. This review focuses on the unique actions of GDNF in the mechanisms that prevent the transition from recreational alcohol use to abuse. Specifically, we describe studies in rodents suggesting that alcohol acutely increases GDNF expression in the ventral tegmental area, which enables the activation of the mitogen-activated protein kinase signaling pathway and the gating of alcohol intake. We further provide evidence to suggest that GDNF acts in the ventral tegmental area via both nongenomic and genomic mechanisms to suppress alcohol consumption. In addition, we describe findings indicating that when this endogenous protective pathway becomes dysregulated, alcohol intake levels escalate. Finally, we describe the potential use of GDNF inducers as a novel therapeutic approach to treat alcohol use disorder.
Asunto(s)
Alcoholismo/etiología , Factor Neurotrófico Derivado de la Línea Celular Glial/fisiología , Alcoholismo/fisiopatología , Depresores del Sistema Nervioso Central/farmacología , Neuronas Dopaminérgicas/fisiología , Etanol/farmacología , Humanos , Sistema Límbico/patología , Trastornos Mentales/etiología , Trastornos Mentales/fisiopatología , Núcleo Accumbens/fisiología , Transducción de Señal/fisiología , Tegmento Mesencefálico/fisiologíaRESUMEN
Repeated alcohol intake leads to mesostriatal neuroadaptations, resulting in drinking escalation and addiction phenotypes. Fibroblast growth factor 2 (FGF2) has been shown to interact with the mesostriatal dopaminergic system, and has been implicated in the actions of psychostimulants in the brain, and in several psychiatric disorders. Here, we report on a positive regulatory feedback loop of alcohol and FGF2 in rodent models. Specifically, we found that acute alcohol exposure (2.5 g/kg, i.p.) increased the mRNA expression of Fgf2 in the dorsal hippocampus, nucleus accumbens, and dorsal striatum. Longer alcohol exposure (7 d × 2.5 g/kg, i.p.) restricted these increases to the dorsal striatum, and the latter effect was blocked by the dopamine D2-like receptor antagonist haloperidol. Voluntary prolonged and excessive alcohol consumption in a 2-bottle choice procedure increased Fgf2 expression selectively in dorsomedial striatum (DMS) of both mice and rats. Importantly, we found that systemic administration of recombinant FGF2 (rFGF2) in mice, or rFGF2 infusion into the dorsal striatum or DMS of rats, increased alcohol consumption and preference, with no similar effects on saccharin or sucrose consumption. Finally, we found that inhibition of the endogenous FGF2 function in the DMS, by an anti-FGF2 neutralizing antibody, suppressed alcohol consumption and preference. Together, our results suggest that alcohol consumption increases the expression of Fgf2 in the DMS, and that striatal FGF2 promotes alcohol consumption, suggesting that FGF2 in the DMS is a positive regulator of alcohol drinking.SIGNIFICANCE STATEMENT Long-term alcohol intake may lead to neuroadaptations in the mesostriatal reward system, resulting in addiction phenotypes. Fibroblast growth factor 2 (FGF2) is crucial for the development and maintenance of the mesostriatal dopaminergic system. Here, we provide evidence for the involvement of FGF2 in alcohol-drinking behaviors. We show that alcohol increases Fgf2 expression in the dorsal striatum, an effect mediated via dopamine D2-like receptors. Importantly, we show that infusion of recombinant FGF2 into the dorsomedial striatum increases alcohol consumption, whereas inhibiting the endogenous FGF2 function suppresses consumption. Thus, FGF2 is an alcohol-responsive gene constituting a positive regulatory feedback loop with alcohol. This loop leads to facilitation of alcohol consumption, marking FGF2 as a potential new therapeutic target for alcohol addiction.
Asunto(s)
Consumo de Bebidas Alcohólicas/fisiopatología , Cuerpo Estriado/fisiopatología , Retroalimentación Fisiológica , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Plasticidad Neuronal , Consumo de Bebidas Alcohólicas/patología , Animales , Femenino , Masculino , Ratones Endogámicos C57BL , RatasRESUMEN
Moderate social consumption of alcohol is common; however, only a small percentage of individuals transit from social to excessive, uncontrolled alcohol drinking. This suggests the existence of protective mechanisms that prevent the development of alcohol addiction. Here, we tested the hypothesis that the glial cell line-derived neurotrophic factor (GDNF) in the mesolimbic system [e.g. the nucleus accumbens (Acb) and ventral tegmental area (VTA)] is part of such a mechanism. We found that GDNF knockdown, by infecting rat Acb neurons with a small hairpin RNA (shRNA) targeting the GDNF gene, produced a rapid escalation to excessive alcohol consumption and enhanced relapse to alcohol drinking. Conversely, viral-mediated overexpression of the growth factor in the mesolimbic system blocked the escalation from moderate to excessive alcohol drinking. To access the mechanism underlying GDNF's actions, we measured the firing rate of dopaminergic (DAergic) neurons in the VTA after a history of excessive alcohol intake with or without elevating GDNF levels. We found that the spontaneous firing rate of DAergic neurons in the VTA was reduced during alcohol withdrawal and that GDNF reversed this alcohol-induced DA deficiency. Together, our results suggest that endogenous GDNF in the mesolimbic system controls the transition from moderate to excessive alcohol drinking and relapse via reversal of alcohol-dependent neuro-adaptations in DAergic VTA neurons.
Asunto(s)
Consumo de Bebidas Alcohólicas/fisiopatología , Factor Neurotrófico Derivado de la Línea Celular Glial/fisiología , Sistema Límbico/fisiología , Núcleo Accumbens/fisiología , Área Tegmental Ventral/fisiología , Adaptación Fisiológica/fisiología , Animales , Condicionamiento Operante , Neuronas Dopaminérgicas/fisiología , Regulación hacia Abajo/fisiología , Técnicas de Silenciamiento del Gen , Factor Neurotrófico Derivado de la Línea Celular Glial/deficiencia , Masculino , Ratas Long-Evans , Recurrencia , Autoadministración , Regulación hacia Arriba/fisiologíaRESUMEN
The mammalian (or mechanistic) target of rapamycin (mTOR) complex 1 (mTORC1) is a serine and threonine kinase that regulates cell growth, survival, and proliferation. mTORC1 is a master controller of the translation of a subset of mRNAs. In the central nervous system mTORC1 plays a crucial role in mechanisms underlying learning and memory by controlling synaptic protein synthesis. Here, we review recent evidence suggesting that the mTORC1 signaling pathway promotes neuroadaptations following exposure to a diverse group of drugs of abuse including stimulants, cannabinoids, opiates, and alcohol. We further describe potential molecular mechanisms by which drug-induced mTORC1 activation may alter brain functions. Finally, we propose that mTORC1 is a focal point shared by drugs of abuse to mediate drug-related behaviors such as reward seeking and excessive drug intake, and offer future directions to decipher the contribution of the kinase to mechanisms underlying addiction. Recent studies suggesting that exposure to diverse classes of drugs of abuse as well as exposure to drug-associated memories lead to mTORC1 kinase activation in the limbic system. In turn, mTORC1 controls the onset and the maintenance of pathological neuroadaptions that underlie several features of drug addiction such as drug seeking and relapse. Therefore, we propose that targeting mTORC1 and its effectors is a promising strategy to treat drug disorders.
Asunto(s)
Adaptación Fisiológica/efectos de los fármacos , Drogas Ilícitas/farmacología , Complejos Multiproteicos/efectos de los fármacos , Complejos Multiproteicos/fisiología , Serina-Treonina Quinasas TOR/efectos de los fármacos , Serina-Treonina Quinasas TOR/fisiología , Animales , Autofagia/efectos de los fármacos , Conducta/efectos de los fármacos , Humanos , Inmunosupresores , Diana Mecanicista del Complejo 1 de la Rapamicina , Complejos Multiproteicos/genética , Neuronas/efectos de los fármacos , Biosíntesis de Proteínas/efectos de los fármacos , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Transducción de Señal/genética , Transducción de Señal/fisiología , Sirolimus , Trastornos Relacionados con Sustancias/genética , Trastornos Relacionados con Sustancias/fisiopatología , Trastornos Relacionados con Sustancias/psicología , Transmisión Sináptica/efectos de los fármacos , Serina-Treonina Quinasas TOR/genéticaRESUMEN
Glial cell line-derived neurotrophic factor (GDNF) is a potent inhibitor of ethanol consumption and relapse, and GDNF heterozygous knockout mice display increased reward sensitivity to ethanol and consume more ethanol after a period of abstinence than their wild-type littermates. Here, we tested whether ethanol alters GDNF expression in the ventral tegmental area (VTA; GDNF's site of action) and/or the nucleus accumbens (NAc; the main source of GDNF), and if so, determine the role of the endogenous growth factor in the regulation of ethanol consumption. Systemic administration of ethanol increased GDNF expression and protein levels in the VTA, but not the NAc. Additionally, GDNF levels were elevated after an ethanol-drinking session in rats that consumed ethanol in the intermittent-access two-bottle choice procedure for 1 week, but not 7 weeks. Deprivation following 7 weeks of excessive ethanol intake reduced GDNF levels, while a short ethanol binge drinking period following deprivation upregulated GDNF expression. Importantly, knockdown of GDNF within the VTA using adenovirus expressing short hairpin RNA facilitated the escalation of ethanol drinking by ethanol-naïve rats, but not by rats with a history of excessive ethanol consumption. These results suggest that during initial ethanol-drinking experiences, GDNF in the VTA is increased and protects against the development of excessive ethanol intake. However, the growth factor's protective response to ethanol breaks down after protracted excessive ethanol intake and withdrawal, resulting in persistent, excessive ethanol consumption.
Asunto(s)
Trastornos Relacionados con Alcohol/genética , Factor Neurotrófico Derivado de la Línea Celular Glial/genética , Área Tegmental Ventral/metabolismo , Consumo de Bebidas Alcohólicas/genética , Trastornos Relacionados con Alcohol/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Western Blotting/métodos , Depresores del Sistema Nervioso Central/administración & dosificación , Depresores del Sistema Nervioso Central/farmacología , Condicionamiento Operante , Modelos Animales de Enfermedad , Etanol/administración & dosificación , Etanol/farmacología , Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Masculino , Datos de Secuencia Molecular , Núcleo Accumbens/metabolismo , Ratas , Ratas Long-Evans , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Recompensa , AutoadministraciónRESUMEN
Alcohol abuse and dependence have a staggering socioeconomic impact, yet current therapeutic strategies are largely inadequate to treat these disorders. Thus, the development of new strategies that can effectively prevent alcohol use disorders (AUDs) is of paramount importance. Currently approved medications attempt to deter alcohol intake by blocking ethanol metabolism or by targeting the neurochemical systems downstream of the cascades leading to craving and dependence. Unfortunately, these medications have provided only limited success as indicated by the continued high rates of alcohol abuse and alcoholism. The lack of currently available effective treatment strategies is highlighted by the urgent call by the NIAAA to find new and paradigm-changing therapeutics to either prevent or treat alcohol-related problems. This mini-review highlights recent findings from 4 laboratories with a focus on compounds that have the potential to be novel therapeutic agents that can be developed for the prevention and/or treatment of AUDs.
Asunto(s)
Trastornos Inducidos por Alcohol/tratamiento farmacológico , Fármacos del Sistema Nervioso Central/farmacología , Agonistas de Receptores de GABA-A/farmacología , Canales Iónicos Activados por Ligandos/efectos de los fármacos , Trastornos Inducidos por Alcohol/prevención & control , Animales , Antiparasitarios/farmacología , Evaluación Preclínica de Medicamentos , Factor Neurotrófico Derivado de la Línea Celular Glial/efectos de los fármacos , Medicina de Hierbas , Humanos , Ivermectina/farmacología , Terapia Molecular Dirigida , Preparaciones de Plantas/farmacologíaRESUMEN
Relapse to alcohol seeking and drinking is a major clinical challenge in alcohol use disorder and is frequently brought about by cue-induced craving, caused by exposure to cues that evoke alcohol-related memories. It has been postulated that memories become labile for manipulation shortly after their retrieval and then restabilize in a "memory reconsolidation" process. Disruption or interference with the reconsolidation of drug-associated memories has been suggested as a possible strategy to reduce or even prevent cue-induced craving and relapse. Here, we review literature demonstrating the capacity of behavioral or pharmacological manipulations to reduce relapse in animal models and humans when applied after a short retrieval of memories associated with alcohol, suggestively disrupting the reconsolidation of such memories. We suggest that while there is a clear potential of using post-retrieval manipulations to target specific relapse-evoking memories, future research should be more systematic, standardized, and translational. Specifically, we discuss several critical limitations and boundary conditions, which should be addressed to improve consistency and replicability in the field and lead to the development of an efficient reconsolidation-based relapse prevention therapy.
RESUMEN
Relapse, a critical issue in alcohol addiction, can be attenuated by disruption of alcohol-associated memories. Memories are thought to temporarily destabilize upon retrieval during the reconsolidation process. Here, we provide evidence for unique transcriptional dynamics underpinning alcohol memory reconsolidation. Using a mouse place-conditioning procedure, we show that alcohol-memory retrieval increases the mRNA expression of immediate-early genes in the dorsal hippocampus and medial prefrontal cortex, and that alcohol seeking is abolished by post-retrieval non-specific inhibition of gene transcription, or by downregulating ARC expression using antisense-oligodeoxynucleotides. However, since retrieval of memories for a natural reward (sucrose) also increased the same immediate-early gene expression, we explored for alcohol-specific transcriptional changes using RNA-sequencing. We revealed a unique transcriptional fingerprint activated by alcohol memories, as the expression of this set of plasticity-related genes was not altered by sucrose-memory retrieval. Our results suggest that alcohol memories may activate two parallel transcription programs: one is involved in memory reconsolidation in general, and another is specifically activated during alcohol-memory processing.
Asunto(s)
Etanol , Memoria , Humanos , Memoria/fisiología , Etanol/farmacología , Hipocampo , RecurrenciaRESUMEN
Fibroblast growth factor 2 (FGF2) is involved in the development and maintenance of the brain dopamine system. We previously showed that alcohol exposure alters the expression of FGF2 and its receptor, FGF receptor 1 (FGFR1) in mesolimbic and nigrostriatal brain regions, and that FGF2 is a positive regulator of alcohol drinking. Here, we determined the effects of FGF2 and of FGFR1 inhibition on alcohol consumption, seeking and relapse, using a rat operant self-administration paradigm. In addition, we characterized the effects of FGF2-FGFR1 activation and inhibition on mesolimbic and nigrostriatal dopamine neuron activation using in vivo electrophysiology. We found that recombinant FGF2 (rFGF2) increased the firing rate and burst firing activity of dopaminergic neurons in the mesolimbic and nigrostriatal systems and led to increased operant alcohol self-administration. In contrast, the FGFR1 inhibitor PD173074 suppressed the firing rate of these dopaminergic neurons, and reduced operant alcohol self-administration. Alcohol seeking behavior was not affected by PD173074, but this FGFR1 inhibitor reduced post-abstinence relapse to alcohol consumption, albeit only in male rats. The latter was paralleled by the increased potency and efficacy of PD173074 in inhibiting dopamine neuron firing. Together, our findings suggest that targeting the FGF2-FGFR1 pathway can reduce alcohol consumption, possibly via altering mesolimbic and nigrostriatal neuronal activity.
Asunto(s)
Dopamina , Factor 2 de Crecimiento de Fibroblastos , Ratas , Masculino , Animales , Dopamina/metabolismo , Factor 2 de Crecimiento de Fibroblastos/farmacología , Etanol/farmacología , Etanol/metabolismo , Consumo de Bebidas Alcohólicas/genética , Recurrencia , Área Tegmental VentralRESUMEN
We previously showed that infusion of glial cell line-derived neurotrophic factor (GDNF) into the ventral tegmental area (VTA) rapidly reduces alcohol intake and relapse (Carnicella et al., 2008, 2009a), and increases dopamine (DA) levels in the nucleus accumbens (NAc) of alcohol-naive rats (Wang et al., 2010). Withdrawal from excessive alcohol intake is associated with a reduction in NAc DA levels, whereas drug-induced increases in NAc DA levels are associated with reward. We therefore tested whether GDNF in the VTA reverses alcohol withdrawal-associated DA deficiency and/or possesses rewarding properties. Rats were trained for 7 weeks to consume high levels of alcohol (5.47 ± 0.37 g/kg/24 h) in intermittent access to 20% alcohol in a two-bottle choice procedure. Using in vivo microdialysis, we show that 24 h withdrawal from alcohol causes a substantial reduction in NAc DA overflow, which was reversed by intra-VTA GDNF infusion. Using conditioned place preference (CPP) paradigm, we observed that GDNF on its own does not induce CPP, suggesting that the growth factor is not rewarding. However, GDNF blocked acquisition and expression of alcohol-CPP. In addition, GDNF induced a downward shift in the dose-response curve for operant self-administration of alcohol, further suggesting that GDNF suppresses, rather than substitutes for, the reinforcing effects of alcohol. Our findings suggest that GDNF reduces alcohol-drinking behaviors by reversing an alcohol-induced allostatic DA deficiency in the mesolimbic system. In addition, as it lacks abuse liability, the study further highlights GDNF as a promising target for treatment of alcohol use/abuse disorders.