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Cocaine use disorder is a condition that leads to tremendous morbidity and mortality for which there are currently no FDA-approved pharmacotherapies. Previous research has demonstrated an important role for the resident population of bacteria of the large intestine, collectively dubbed the gut microbiome, in modulating brain and behavior in models of cocaine and other substance use disorders. Importantly, previous work has repeatedly shown that depletion of the gut microbiome leads to increased cocaine taking and seeking behaviors in multiple models. While the precise mechanism of these gut-brain signaling pathways in models of cocaine use is not fully clear, and intriguing possibility is through gut microbiome influences on innate immune system function. In this manuscript we identify the cytokine colony stimulating factor 2 (CSF2) as an immune factor that is increased by cocaine in a gut microbiome dependent manner. Peripherally injected CSF2 crosses the blood-brain barrier into the nucleus accumbens, a brain region central to behavioral responses to cocaine. Treatment with peripheral CSF2 reduces acute and sensitized locomotor responses to cocaine as well as reducing cocaine place preference at high doses. On a molecular level, we find that peripheral injections of CSF2 alter the transcriptional response to both acute and repeated cocaine in the nucleus accumbens. Finally, treatment of microbiome depleted mice with CSF2 reverses the behavioral effects of microbiome depletion on the conditioned place preference assay. Taken together, this work identifies an innate immune factor that represents a novel gut-brain signaling cascade in models of cocaine use and lays the foundations for further translational work targeting this pathway.
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Opioid use disorder is a public health crisis that causes tremendous suffering for patients as well as substantial social and economic costs for society. There are currently available treatments for patients with opioid use disorder, but they remain intolerable or ineffective for many. Thus the need to develop new avenues for therapeutics development in this space is great. Substantial work in models of substance use disorders, including opioid use disorder, demonstrates that prolonged exposure to drugs of abuse leads to marked transcriptional and epigenetic dysregulation in limbic substructures. It is widely believed that these changes in gene regulation in response to drugs are a key driving factor in the perpetuation of drug taking and seeking behaviors. Thus, development of interventions that could shape transcriptional regulation in response to drugs of abuse would be of high value. Over the past decade there has been a surge in research demonstrating that the resident bacteria of the gastrointestinal tract, collectively the gut microbiome, can have tremendous influence on neurobiological and behavioral plasticity. Previous work from our group and others has demonstrated that alterations in the gut microbiome can alter behavioral responses to opioids in multiple paradigms. Additionally, we have previously reported that depletion of the gut microbiome with antibiotics markedly shifts the transcriptome of the nucleus accumbens following prolonged morphine exposure. In this manuscript we present a comprehensive analysis of the effects of the gut microbiome on transcriptional regulation of the nucleus accumbens following morphine by utilizing germ-free, antibiotic treated, and control mice. This allows for detailed understanding of the role of the microbiome in regulating baseline transcriptomic control, as well as response to morphine. We find that germ-free status leads to a marked gene dysregulation in a manner distinct to adult mice treated with antibiotics, and that altered gene pathways are highly related to cellular metabolic processes. These data provide additional insight into the role of the gut microbiome in modulating brain function and lay a foundation for further study in this area.
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Morfina , Trastornos Relacionados con Opioides , Ratones , Animales , Morfina/efectos adversos , Transcriptoma , Núcleo Accumbens , AntibacterianosRESUMEN
Psychostimulant use disorder is a major public health issue, and despite the scope of the problem there are currently no Food and Drug Administration (FDA)-approved treatments. There would be tremendous utility in development of a treatment that could help patients both achieve and maintain abstinence. Previous work from our group has identified granulocyte-colony stimulating factor (G-CSF) as a neuroactive cytokine that alters behavioral response to cocaine, increases synaptic dopamine release, and enhances cognitive flexibility. Here, we investigate the role of G-CSF in affecting extinction and reinstatement of cocaine-seeking and perform detailed characterization of its proteomic effects in multiple limbic substructures. Male Sprague Dawley rats were injected with PBS or G-CSF during (1) extinction or (2) abstinence from cocaine self-administration, and drug seeking behavior was measured. Quantitative assessment of changes in the proteomic landscape in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) were performed via data-independent acquisition (DIA) mass spectrometry analysis. Administration of G-CSF during extinction accelerated the rate of extinction, and administration during abstinence attenuated cue-induced cocaine-seeking. Analysis of global protein expression demonstrated that G-CSF regulated proteins primarily in mPFC that are critical to glutamate signaling and synapse maintenance. Taken together, these findings support G-CSF as a viable translational research target with the potential to reduce drug craving or seeking behaviors. Importantly, recombinant G-CSF exists as an FDA-approved medication which may facilitate rapid clinical translation. Additionally, using cutting-edge multiregion discovery proteomics analyses, these studies identify a novel mechanism underlying G-CSF effects on behavioral plasticity.SIGNIFICANCE STATEMENT Pharmacological treatments for psychostimulant use disorder are desperately needed, especially given the disease's chronic, relapsing nature. However, there are currently no Food and Drug Administration (FDA)-approved pharmacotherapies. Emerging evidence suggests that targeting the immune system may be a viable translational research strategy; preclinical studies have found that the neuroactive cytokine granulocyte-colony stimulating factor (G-CSF) alters cocaine reward and reinforcement and can enhance cognitive flexibility. Given this basis of evidence we studied the effects of G-CSF treatment on extinction and reinstatement of cocaine seeking. We find that administration of G-CSF accelerates extinction and reduces cue-induced drug seeking after cocaine self-administration. In addition, G-CSF leads to downregulation of synaptic glutamatergic proteins in medial prefrontal cortex (mPFC), suggesting that G-CSF influences drug seeking via glutamatergic mechanisms.
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Trastornos Relacionados con Cocaína/tratamiento farmacológico , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Glutamatos/fisiología , Factor Estimulante de Colonias de Granulocitos/farmacología , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Sinapsis/efectos de los fármacos , Sinapsis/metabolismo , Animales , Trastornos Relacionados con Cocaína/psicología , Ansia/efectos de los fármacos , Señales (Psicología) , Extinción Psicológica/efectos de los fármacos , Sistema Límbico/efectos de los fármacos , Masculino , Proteínas del Tejido Nervioso/biosíntesis , Proteínas del Tejido Nervioso/genética , Proteómica , Ratas , Ratas Sprague-Dawley , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Síndrome de Abstinencia a Sustancias/psicologíaRESUMEN
Deficits in motivation and cognition are hallmark symptoms of multiple psychiatric diseases. These symptoms are disruptive to quality of life and often do not improve with available medications. In recent years there has been increased interest in the role of the immune system in neuropsychiatric illness, but to date no immune-related treatment strategies have come to fruition. The cytokine granulocyte-colony stimulating factor (G-CSF) is known to have trophic and neuroprotective properties in the brain, and we recently identified it as a modulator of neuronal and behavioral plasticity. By combining operant tasks that assess discrete aspects of motivated behavior and decision-making in male mice and rats with subsecond dopamine monitoring via fast-scan cyclic voltammetry, we defined the role of G-CSF in these processes as well as the neural mechanism by which it modulates dopamine function to exert these effects. G-CSF enhanced motivation for sucrose as well as cognitive flexibility as measured by reversal learning. These behavioral outcomes were driven by mesolimbic dopamine system plasticity, as systemically administered G-CSF increased evoked dopamine release in the nucleus accumbens independent of clearance mechanisms. Importantly, sustained increases in G-CSF were required for these effects as acute exposure did not enhance behavioral outcomes and decreased dopamine release. These effects seem to be a result of the ability of G-CSF to alter local inflammatory signaling cascades, particularly tumor necrosis factor α. Together, these data show G-CSF as a potent modulator of the mesolimbic dopamine circuit and its ability to appropriately attend to salient stimuli.SIGNIFICANCE STATEMENT Emerging evidence has highlighted the importance of the immune system in psychiatric diseases states. However, the effects of peripheral cytokines on motivation and cognitive function are largely unknown. Here, we report that granulocyte-colony stimulating factor (G-CSF), a pleiotropic cytokine with known trophic and neuroprotective properties in the brain, acts directly on dopaminergic circuits to enhance their function. These changes in dopaminergic dynamics enhance reward learning and motivation for natural stimuli. Together, these results suggest that targeting immune factors may provide a new avenue for therapeutic intervention in the multiple psychiatric disorders that are characterized by motivational and cognitive deficits.
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Condicionamiento Operante/fisiología , Dopamina/fisiología , Factor Estimulante de Colonias de Granulocitos/fisiología , Motivación/fisiología , Núcleo Accumbens/fisiología , Recompensa , Animales , Toma de Decisiones/fisiología , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Masculino , Ratones Endogámicos C57BL , Núcleo Accumbens/inmunología , Ratas Sprague-Dawley , Aprendizaje Inverso/fisiología , Sacarosa/administración & dosificaciónRESUMEN
Substance use disorders are global health problems with few effective treatment options. Unfortunately, most potential pharmacological treatments are hindered by abuse potential of their own, limited efficacy, or adverse side effects. As a consequence, there is a pressing need for the development of addiction treatments with limited abuse potential and fewer off target effects. Given the difficulties in developing new pharmacotherapies for substance use disorders, there has been growing interest in medications that act on non-traditional targets. Recent evidence suggests a role for dysregulated immune signaling in the pathophysiology of multiple psychiatric diseases. While there is evidence that immune responses in the periphery and the central nervous system are altered by exposure to drugs of abuse, the contributions of neuroimmune interactions to addictive behaviors are just beginning to be appreciated. In this review, we discuss the data on immunological changes seen in clinical populations with substance use disorders, as well as in translational animal models of addiction. Importantly, we highlight those mechanistic findings showing causal roles for central or peripheral immune mediators in substance use disorder and appropriate animal models. Based on the literature reviewed here, it is clear that brain-immune system interactions in substance use disorders are much more complex and important than previously understood. While much work remains to be done, there are tremendous potential therapeutic implications for immunomodulatory treatments in substance use disorders.
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Encéfalo/inmunología , Estimulantes del Sistema Nervioso Central/efectos adversos , Microbioma Gastrointestinal/inmunología , Neuroinmunomodulación/inmunología , Trastornos Relacionados con Opioides/inmunología , Animales , Encéfalo/efectos de los fármacos , Microbioma Gastrointestinal/efectos de los fármacos , Humanos , Factores Inmunológicos/farmacología , Factores Inmunológicos/uso terapéutico , Mediadores de Inflamación/inmunología , Neuroinmunomodulación/efectos de los fármacos , Trastornos Relacionados con Opioides/tratamiento farmacológicoRESUMEN
Substance use disorders are a set of recalcitrant neuropsychiatric conditions that cause tremendous morbidity and mortality and are among the leading causes of loss of disability-adjusted life years worldwide. While each specific substance use disorder is driven by problematic use of a different substance, they all share a similar pattern of escalating and out-of-control substance use, continued use despite negative consequences, and a remitting/relapsing pattern over time. Despite significant advances in our understanding of the neurobiology of these conditions, current treatment options remain few and are ineffective for too many individuals. In recent years, there has been a rapidly growing body of literature demonstrating that the resident population of microbes in the gastrointestinal tract, collectively called the gut microbiome, plays an important role in modulating brain and behavior in preclinical and clinical studies of psychiatric disease. While these findings have not yet been translated into clinical practice, this remains an important and exciting avenue for translational research. In this review, we highlight the current state of microbiome-brain research within the substance use field with a focus on both clinical and preclinical studies. We also discuss potential neurobiological mechanisms underlying microbiome effects on models of substance use disorder and propose future directions to bring these findings from bench to bedside.
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Microbioma Gastrointestinal , Trastornos Relacionados con Sustancias , Humanos , Encéfalo , Tracto GastrointestinalRESUMEN
Opioid use disorder (OUD) is a public health crisis currently being exacerbated by increased rates of use and overdose of synthetic opioids, primarily fentanyl. Therefore, the identification of novel biomarkers and treatment strategies to reduce problematic fentanyl use and relapse to fentanyl taking is critical. In recent years, there has been a growing body of work demonstrating that the gut microbiome can serve as a potent modulator of the behavioral and transcriptional responses to both stimulants and opioids. Here, we advance this work to define how manipulations of the microbiome drive fentanyl intake and fentanyl-seeking in a translationally relevant drug self-administration model. Depletion of the microbiome of male rats with broad spectrum antibiotics leads to increased drug administration on increased fixed ratio, progressive ratio, and drug seeking after abstinence. Utilizing 16Sâ sequencing of microbiome contents from these animals, specific populations of bacteria from the gut microbiome correlate closely with levels of drug taking. Additionally, global proteomic analysis of the nucleus accumbens following microbiome manipulation and fentanyl administration to define how microbiome status alters the functional proteomic landscape in this key limbic substructure. These data demonstrate that an altered microbiome leads to marked changes in the synaptic proteome in response to repeated fentanyl treatment. Finally, behavioral effects of microbiome depletion are reversible by upplementation of the microbiome derived short-chain fatty acid metabolites. Taken together, these findings establish clear relevance for gut-brain signaling in models of OUD and lay foundations for further translational work in this space.
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Microbioma Gastrointestinal , Trastornos Relacionados con Opioides , Masculino , Ratas , Animales , Fentanilo , Proteoma , Proteómica , Analgésicos Opioides , Trastornos Relacionados con Opioides/tratamiento farmacológicoRESUMEN
Cocaine use disorder represents a public health crisis with no FDA-approved medications for its treatment. A growing body of research has detailed the important connections between the brain and the resident population of bacteria in the gut, the gut microbiome, in psychiatric disease models. Acute depletion of gut bacteria results in enhanced reward in a mouse cocaine place preference model, and repletion of bacterially-derived short-chain fatty acid (SCFA) metabolites reverses this effect. However, the role of the gut microbiome and its metabolites in modulating cocaine-seeking behavior after prolonged abstinence is unknown. Given that relapse prevention is the most clinically challenging issue in treating substance use disorders, studies examining the effects of microbiome manipulations in relapse-relevant models are critical. Here, male Sprague-Dawley rats received either untreated water or antibiotics to deplete the gut microbiome and its metabolites. Rats were trained to self-administer cocaine and subjected to either within-session threshold testing to evaluate motivation for cocaine or 21 days of abstinence followed by a cue-induced cocaine-seeking task to model relapse behavior. Microbiome depletion did not affect cocaine acquisition on an fixed-ratio 1 schedule. However, microbiome-depleted rats exhibited significantly enhanced motivation for low dose cocaine on a within-session threshold task. Similarly, microbiome depletion increased cue-induced cocaine-seeking following prolonged abstinence and altered transcriptional regulation in the nucleus accumbens. In the absence of a normal microbiome, repletion of bacterially-derived SCFA metabolites reversed the behavioral and transcriptional changes associated with microbiome depletion. These findings suggest that gut bacteria, via their metabolites, are key regulators of drug-seeking behaviors, positioning the microbiome as a potential translational research target.
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Trastornos Relacionados con Cocaína , Cocaína , Ratones , Ratas , Masculino , Animales , Ratas Sprague-Dawley , Comportamiento de Búsqueda de Drogas , Trastornos Relacionados con Cocaína/metabolismo , Núcleo Accumbens , Recurrencia , Autoadministración , Señales (Psicología) , Extinción PsicológicaRESUMEN
Social/peer influences are among the strongest predictors of adolescent drug use. However, this important subject does not get much attention in pre-clinical studies. We recently observed that exposure to different social partners modulates morphine locomotor sensitization. Sensitivity to the hyper-locomotor response of drugs of abuse is a predictor of sensitivity to other drug-induced behaviors. Thus, this study examined how exposure to different social partners affected the rewarding properties of morphine. All animals were group-housed four per cage in one of two conditions referred to as 'only' and 'cage-mates'. In the mixed treatment condition, morphine- and saline-treated mice were housed together. These groups are referred to as 'morphine cage-mates' and 'saline cage-mates', respectively. In the separated treatment conditions, all mice in the cage received morphine (i.e. 'morphine only') or saline (i.e. 'saline only'), and cages were visually separated from each other. All animals were subsequently individually tested for the acquisition of morphine conditioned place preference (CPP) following one conditioning session with 10, 20 or 40 mg/kg morphine or saline. As expected, one conditioning session established morphine CPP in the morphine only animals, but not in the saline only animals. Notably, morphine CPP was not acquired by the morphine cage-mate animals. Additionally, 40 mg/kg morphine was sufficient to establish morphine CPP in the saline cage-mate animals. These results indicate that social environment has an effect on the rewarding properties of morphine. It suggests that exposure to different peers can alter the abuse potential of opioids and potentially other illicit drugs.
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Analgésicos Opioides/farmacología , Conducta de Elección/efectos de los fármacos , Condicionamiento Psicológico/efectos de los fármacos , Morfina/farmacología , Medio Social , Trastornos Relacionados con Sustancias/psicología , Adolescente , Analgésicos Opioides/administración & dosificación , Análisis de Varianza , Animales , Corticosterona/sangre , Relación Dosis-Respuesta a Droga , Vivienda para Animales , Humanos , Masculino , Ratones , Modelos Animales , Morfina/administración & dosificación , Grupo Paritario , Distribución Aleatoria , Recompensa , Cloruro de Sodio/administración & dosificación , Estrés Psicológico/sangre , Factores de Tiempo , Adulto JovenRESUMEN
Opioid Use Disorder (OUD) is associated with tremendous morbidity and mortality. Despite this burden, current pharmacotherapies for OUD are ineffective or intolerable for many patients. As such, interventions aimed at promoting resilience against OUD are of immense clinical interest. Treatment with a Bioactive Dietary Polyphenol Preparation (BDPP) promotes resilience and adaptive neuroplasticity in multiple models of neuropsychiatric disease. Here, we assessed effects of BDPP treatment on behavioral and molecular responses to repeated morphine treatment in male mice. BDPP pre-treatment alters responses for both locomotor sensitization and conditioned place preference. Most notably, polyphenol treatment consistently reduced formation of preference at low dose (5 mg/kg) morphine but enhanced it at high dose (15 mg/kg). In parallel, we performed transcriptomic profiling of the nucleus accumbens, which again showed a dose × polyphenol interaction. We also profiled microbiome composition and function, as polyphenols are metabolized by the microbiome and can act as prebiotics. The profile revealed polyphenol treatment markedly altered microbiome composition and function. Finally, we investigated involvement of the SIRT1 deacetylase, and the role of polyphenol metabolites in behavioral responses. These results demonstrate polyphenols have robust dose-dependent effects on behavioral and physiological responses to morphine and lay the foundation for future translational work.
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Morfina , Núcleo Accumbens , Ratones , Masculino , Animales , Núcleo Accumbens/metabolismo , Polifenoles/metabolismoRESUMEN
Given that social influences are among the strongest predictors of adolescents' drug use, this study examines the effects of social interactions on morphine sensitization in both adolescent and adult rats. Rats treated with morphine (twice daily, 6 days, 2.5-10 mg/kg, subcutaneously, s.c.) or saline were group-housed in two different conditions. Thus, four experimental groups were examined for each age group: (1) morphine-treated rats housed physically and visually separate from saline-injected rats ('morphine only'); (2) morphine-treated rats housed together with saline-injected rats ('morphine cage-mates'); (3) saline-injected rats housed together with morphine-treated rats ('saline cage-mates'); and (4) saline-injected rats housed physically and visually separate from morphine-treated rats ('saline only'). Starting 9 days following the last morphine injection, rats were individually examined once daily for 5 consecutive days for their locomotor response to 2.5 mg/kg of morphine. For both age groups, there were no significant differences in morphine-induced hyper-locomotion between saline cage-mates and saline only rats. Morphine only rats exhibited morphine locomotor sensitization as compared to both the saline only and saline cage-mates rats. Notably, a significant difference was observed between the adolescent morphine cage-mates and morphine only rats. The adolescent morphine cage-mates did not exhibit the enhanced locomotor response as compared to the saline only and saline cage-mate rats. A trend of reduced morphine locomotor sensitization was observed in the adult morphine cage-mates as compared to morphine only but it did not reach statistical significance. Thus, this study demonstrates social influences on morphine sensitization which are more prevalent in adolescents as compared to adults.
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Morfina/farmacología , Narcóticos/farmacología , Trastornos Relacionados con Opioides/psicología , Conducta Social , Envejecimiento/fisiología , Análisis de Varianza , Animales , Locomoción/efectos de los fármacos , Morfina/administración & dosificación , Actividad Motora/efectos de los fármacos , Narcóticos/administración & dosificación , Ratas , Ratas Sprague-Dawley , Medio SocialRESUMEN
RATIONALE: In rodents, environmental enrichment (EE) produces both preventive and curative effects on drug addiction, and this effect is believed to depend at least in part on EE's actions on the stress system. OBJECTIVES: This study investigated whether exposure to EE during abstinence reduces methamphetamine seeking after extended self-administration. In addition, we investigated whether these effects are associated with alterations in the levels of glucocorticoid receptors (GR) in the brain and whether administration of GR antagonists blocks methamphetamine relapse. METHODS: We allowed rats to self-administer methamphetamine for twenty 14-h sessions. After 3 weeks of abstinence either in standard (SE) or EE conditions, we measured methamphetamine seeking in a single 3-h session. Then, we used western blot techniques to measure GR levels in several brain areas. Finally, in an independent group of rats, after methamphetamine self-administration and abstinence in SE, we administered the GR antagonist mifepristone, and we investigated methamphetamine seeking. RESULTS: Exposure to EE reduced methamphetamine seeking and reversed methamphetamine-induced increases in GR levels in the ventral and dorsal hippocampus. In addition, EE decreased GR levels in the amygdala in drug-naive animals, but this effect was prevented by previous exposure to methamphetamine. Administration of mifepristone significantly decreased methamphetamine seeking. CONCLUSIONS: The anti-craving effects of EE are paralleled by restoration of methamphetamine-induced dysregulation of GR in the hippocampus. These results provide support for the hypothesis that the effect of EE on methamphetamine relapse is at least in part mediated by EE's action on the brain stress system.
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Metanfetamina , Animales , Comportamiento de Búsqueda de Drogas , Metanfetamina/farmacología , Mifepristona/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Glucocorticoides , Recurrencia , AutoadministraciónRESUMEN
Differences in overall cocaine intake can directly affect neuroadaptations, and this relationship can make it difficult to interpret neurobiological changes seen in drug-choice studies, since drug intake varies between subjects. Herein, a choice procedure that controls for cocaine intake was utilized to explore if neuronal activity, measured as cFos expression in the orbitofrontal cortex (OFC) and nucleus accumbens (NAc), was reflective of preference. Results demonstrated that cFos expression, in both the OFC and NAc, was independent of cocaine preference when cocaine intake was kept constant across individuals. However, when cocaine intake was systematically varied, the expression of cFos associated with cocaine preference was related to overall cocaine intake in the OFC, but not the NAc. Altogether, these results demonstrate that cocaine intake during choice can affect neurobiological outcome measures; thus, the neurobehavioral mechanisms underlying cocaine preference may be better isolated when controlling for cocaine frequency and intake. In all, some caution is warranted when interpreting results from choice studies evaluating the neurobehavioral mechanisms that underlie drug preference when drug frequency and intake are uncontrolled, and future research is needed to determine the role of drug frequency and intake on neurobiological measures associated with drug choice.
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Encéfalo/efectos de los fármacos , Conducta de Elección/efectos de los fármacos , Cocaína/administración & dosificación , Neuronas/efectos de los fármacos , Refuerzo en Psicología , Animales , Encéfalo/metabolismo , Conducta de Elección/fisiología , Condicionamiento Operante/efectos de los fármacos , Condicionamiento Operante/fisiología , Masculino , Neuronas/metabolismo , Ratas , Ratas Sprague-Dawley , AutoadministraciónRESUMEN
Recent evidence has demonstrated that the gut microbiome has marked effects on neuronal function and behavior. Disturbances to microbial populations within the gut have been linked to myriad models of neuropsychiatric disorders. However, the role of the microbiome in substance use disorders remains understudied. Here we show that male mice with their gut microbiome depleted by nonabsorbable antibiotics (Abx) exhibit decreased formation of morphine conditioned place preference across a range of doses (2.5-15 mg/kg), have decreased locomotor sensitization to morphine, and demonstrate marked changes in gene expression within the nucleus accumbens (NAc) in response to high-dose morphine (20 mg/kg × 7 days). Replacement of short-chain fatty acid (SCFA) metabolites, which are reduced by microbiome knockdown, reversed the behavioral and transcriptional effects of microbiome depletion. This identifies SCFA as the crucial mediators of microbiome-brain communication responsible for the effects on morphine reward caused by microbiome knockdown. These studies add important new behavioral, molecular, and mechanistic insight to the role of gut-brain signaling in substance use disorders.
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Microbioma Gastrointestinal , Morfina , Animales , Condicionamiento Clásico , Masculino , Ratones , Morfina/farmacología , Núcleo Accumbens , RecompensaRESUMEN
Given that social influences are among the strongest predictors of adolescents' drug use, this study examined the effect of social interaction on morphine-induced hyperlocomotion in both adolescent and adult mice. Three experimental groups of adolescent and adult male mice were examined (i) morphine-treated mice (twice daily, 10-40 mg/kg, subcutaneous), (ii) saline-injected mice housed together with the morphine-treated mice ('saline cage-mates'), and (iii) saline-injected mice housed physically and visually separated from the morphine-treated mice ('saline alone'). After the treatment period, mice were tested individually for their locomotor response to 10 mg/kg morphine (subcutaneous). Adolescent saline cage-mates, though administered morphine for the very first time, exhibited an enhanced hyperlocomotion response similar to the locomotor sensitization response exhibited by the morphine-treated mice. This was not observed in adults. In adults, there were no significant differences in morphine-induced hyperlocomotion between saline alone and saline cage-mates. As expected, morphine-treated adults and adolescents both exhibited locomotor sensitization. These results show a vulnerability to social influences in adolescent mice, which does not exist in adult mice.
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Envejecimiento/efectos de los fármacos , Relaciones Interpersonales , Morfina/farmacología , Actividad Motora/efectos de los fármacos , Narcóticos/farmacología , Animales , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Social peers influence human drug use at every stage of addiction. Using a dual-compartment apparatus that allows for limited social contact, recent work has shown that cocaine self-administration is enhanced when two rats are trained to self-administer at the same time compared to rats trained alone or trained in the presence of a saline self-administration control peer. The current study measured social influence on self-administration of the short-acting opioid remifentanil using a dual-compartment operant conditioning chamber. METHODS: Adult male rats were placed in one of five groups: (1) REMI-REMI group, in which both rats self-administered remifentanil; (2) REMI-SAL group, in which rats self-administered remifentanil in the presence of a peer that self-administered saline; (3) SAL-REMI group, in which rats self-administered saline in the presence of a peer that self-administered remifentanil; and (4) REMI ALONE and (5) SAL ALONE groups, in which rats administered their respective drugs alone (no peer). Self-administration was measured using a 2-lever procedure during acquisition, maintenance, increasing fixed-ratio, and dose-response phases. RESULTS: The presence of a social peer enhanced drug intake during acquisition, regardless of the drug exposure of their peer. Additionally, active lever position significantly affected remifentanil intake during acquisition and maintenance, with the greatest influence occurring when the active lever was close to the peer. CONCLUSION: The presence of a social peer in the drug-taking context potentiates remifentanil self-administration, regardless of the peer's drug access. Future studies utilizing the dual-compartment apparatus will help elucidate the neural mechanisms underlying social influence on opioid abuse.
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BACKGROUND: Individuals with opioid use disorder (OUD) exhibit high levels of economic demand for opioids, with high levels of consumption and relative insensitivity to changes in price. Because the medications used to treat OUD in medication-assisted therapy (MAT) act as antagonists or agonists at µ opioid receptors, they may alter the relationship between price and opioid intake. METHODS: This study examined demand for a commonly abused synthetic prescription opioid, fentanyl, in male rats following s.c. pre-treatment with naltrexone (0.1-1.0â¯mg/kg), morphine (0.3-3.0â¯mg/kg) or buprenorphine (0.3-3.0â¯mg/kg). We normalized demand curves to intake at the lowest price and estimated effects on elasticity (sensitivity to changes in price). Rats were first trained to earn fentanyl (5⯵g/kg/infusion) on a fixed ratio schedule, then they underwent daily training under a threshold procedure designed to produce within-session demand curve estimates. Rats received 14 threshold sessions before undergoing a series of tests encompassing each drug, at each dose. RESULTS: Elasticity was increased by pretreatment with naltrexone, morphine or buprenorphine. Morphine also decreased initial intake, when the price for fentanyl was lowest. In contrast, initial intake was increased by naltrexone (according to an inverted-U shaped curve). The effects of naltrexone did not persist after the test session, but morphine and buprenorphine continued affecting demand elasticity 24â¯h or 48â¯h after the test, respectively. CONCLUSIONS: These results indicate that fentanyl demand is sensitive to blockade or activation of opioid receptors by the drug classes used for MAT in humans.
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Buprenorfina/farmacología , Fentanilo/farmacología , Morfina/farmacología , Naltrexona/farmacología , Animales , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Masculino , Ratas , Receptores Opioides , Receptores Opioides mu/antagonistas & inhibidores , Esquema de Refuerzo , AutoadministraciónRESUMEN
This study examined whether activation of extracellular signal-regulated kinase (ERK) contributes to the increased open-arm time observed in the elevated plus maze (EPM) during opioid withdrawal. We applied SL327, a selective ERK kinase (MEK) inhibitor, to specific limbic areas and examined the effect on EPM behaviors of controls and during naloxone-precipitated morphine withdrawal. We next confirmed that ERK activation increased in limbic areas of mice undergoing naloxone-precipitated morphine withdrawal. Direct injection of SL327 into the amygdala blocked the withdrawal-induced increase in open-arm time; however, injecting SL327 into the septum had no effect. Consistent with these results, both 0.2 and 2 mg/kg naloxone increased ERK activation in the central amygdala of morphine-dependent mice. In drug-naive mice, 2 mg/kg naloxone, but not 0.2 mg/kg, increased ERK activation in the central amygdala. During withdrawal, increased ERK activation was also observed in the lateral septum. In the locus coeruleus, a significant increase was observed only in morphine-dependent mice receiving 2 mg/kg, but not 0.2 mg/kg naloxone. In conclusion, ERK activation in limbic areas is likely involved in both the aversive properties of naloxone and in the affective/emotional symptoms of opioid withdrawal, including mediating EPM behaviors.
Asunto(s)
Amígdala del Cerebelo/enzimología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Aprendizaje por Laberinto/fisiología , Tabique del Cerebro/enzimología , Síndrome de Abstinencia a Sustancias/metabolismo , Aminoacetonitrilo/análogos & derivados , Aminoacetonitrilo/farmacología , Amígdala del Cerebelo/efectos de los fármacos , Animales , Activación Enzimática , Masculino , Ratones , Ratones Endogámicos C57BL , Morfina/antagonistas & inhibidores , Naloxona/farmacología , Tabique del Cerebro/efectos de los fármacosRESUMEN
AIMS: Drug withdrawal is suggested to play a role in precipitating mood disorders in individuals with familial predisposition. Age-related differences in affective responses to withdrawal might explain the increased risk of mental illnesses when drug use begins during adolescence. Since there is a lack of animal research examining the effects of opioid withdrawal during adolescence, the present study examined whether there are age-related differences in affective responses to opioid withdrawal. MAIN METHODS: Adolescent and adult mice were injected with two different morphine regimens, namely low and high, which differed in the dosage. Three and nine days following discontinuation of morphine administration, immobility time in the forced swim test (FST) and locomotion (total distance traveled) were evaluated. KEY FINDINGS: On withdrawal day 3 (WD3), adolescent mice exhibited a decrease in immobility as compared to controls. No significant differences in immobility were observed on withdrawal day 9 (WD9). This effect on FST behaviors was not due to changes in overall motor activity, since no differences in locomotion were observed on either WD3 or WD9 in adolescent mice. In adults, no differences in either FST or locomotor behaviors were observed on WD3. As expected, on WD9, adult mice exhibited an increase in immobility and a decrease in locomotion. SIGNIFICANCE: This study demonstrates age-dependent differences in both FST scores and locomotor behaviors during opioid withdrawal. FST behaviors are classically used to evaluate mood in rodents, thus this study suggests that opioid withdrawal might affect mood differentially across age.
Asunto(s)
Dependencia de Morfina/psicología , Síndrome de Abstinencia a Sustancias/psicología , Factores de Edad , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Morfina/farmacocinética , Actividad Motora , Receptores Opioides/fisiología , NataciónRESUMEN
Addiction to psychostimulants is a major public health crisis that leads to significant morbidity and mortality, for which there are currently no FDA-approved pharmacotherapies. Female subjects have increased propensity to develop pathological substance use disorders after initial use, suggesting the possibility of different pathophysiological mechanisms between males and females. Recently, we identified the neuroactive cytokine granulocyte-colony stimulating factor (G-CSF) as a key mediator of neuronal and behavioral plasticity in response to cocaine in male mice. Here, we found that G-CSF potentiated the rewarding effects of cocaine in female mice as well; however, the dopaminergic mechanism linked to these effects was highly dependent on the ovarian hormone cycle. G-CSF treatment enhanced the ability of cocaine to inhibit dopamine clearance; however, this effect was observed specifically during pro/estrus, when circulating ovarian hormone levels were high. These findings demonstrate important sex differences in the synaptic effects of this translationally relevant neuroimmune modulator.