RESUMEN
Oxycodone is one of the most widely prescribed and misused opioid painkillers in the United States. Evidence suggests that biological sex and hormonal status can impact drug reward in humans and rodents, but the extent to which these factors can influence the rewarding effects of oxycodone is unclear. The purpose of this study was to utilize place conditioning to determine the effects of sex and female hormonal status on the expression of oxycodone conditioned reward in rats. Gonadally intact adult Sprague-Dawley male and female rats were used to test: (1) whether both sexes express conditioned reward to oxycodone at similar doses, (2) the impact of conditioning session length on oxycodone conditioned reward expression in both sexes, and (3) the influence of female estrous cycle stage on oxycodone conditioned reward expression. Both sexes expressed conditioned reward at the same doses of oxycodone. Increasing the length of conditioning sessions did not reveal an effect of sex and resulted in lower magnitude conditioned reward expression. Importantly however, female stage of estrous cycle significantly influenced oxycodone conditioned reward expression. These results suggest that female hormonal status can impact the rewarding effects of opioids and thus have important implications for prescription opioid treatment practices.
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Analgésicos Opioides , Oxicodona , Adulto , Humanos , Ratas , Femenino , Masculino , Animales , Ratas Sprague-Dawley , Oxicodona/farmacología , Analgésicos Opioides/farmacología , Ciclo Estral , RecompensaRESUMEN
Introduction: Rates of relapse to drug use during abstinence are among the highest for opioid use disorder (OUD). In preclinical studies, reinstatement to drug-seeking has been extensively studied as a model of relapse-but the work has been primarily in males. We asked whether biological sex contributes to behaviors comprising self-administration of the prescription opioid oxycodone in rats, and we calculated the relative contribution of these behavioral measures to reinstatement in male and female rats. Materials and methods: Rats were trained to self-administer oxycodone (8 days, training phase), after which we examined oxycodone self-administration behaviors for an additional 14 days under three conditions in male and female rats: short access (ShA, 1 h/d), long access (LgA, 6 h/d), and saline self-administration. All rats were then tested for cue-induced reinstatement of drug-seeking after a 14-d forced abstinence period. We quantified the # of infusions, front-loading of drug intake, non-reinforced lever pressing, inter-infusion intervals, escalation of intake, and reinstatement responding on the active lever. Results: Both male and female rats in LgA and ShA conditions escalated oxycodone intake to a similar extent. However, males had higher levels of non-reinforced responding than females under LgA conditions, and females had greater levels of reinstatement responding than males. We then correlated each addiction-related measure listed above with reinstatement responding in males and females and ranked their respective relative contributions. Although the majority of behavioral measures associated with oxycodone self-administration did not show sex differences on their own, when analyzed together using partial least squares regression, their relative contributions to reinstatement were sex-dependent. Front-loading behavior was calculated to have the highest relative contribution to reinstatement in both sexes, with long and short inter-infusion intervals having the second greatest contribution in females and males, respectively. Discussion: Our results demonstrate sex differences in some oxycodone self-administration measures. More importantly, we demonstrate that a sex- dependent constellation of self-administration behaviors can predict the magnitude of reinstatement, which holds great promise for relapse prevention in people.
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The current opioid epidemic has dramatically increased the number of children who are prenatally exposed to opioids, including oxycodone. A number of social and cognitive abnormalities have been documented in these children as they reach young adulthood. However, little is known about the mechanisms underlying developmental effects of prenatal opioid exposure. Microglia, the resident immune cells of the brain, respond to acute opioid exposure in adulthood. Moreover, microglia are known to sculpt neural circuits during typical development. Indeed, we recently found that microglial phagocytosis of dopamine D1 receptors (D1R) in the nucleus accumbens (NAc) is required for the natural developmental decline in NAc-D1R that occurs between adolescence and adulthood in rats. This microglial pruning occurs only in males, and is required for the normal developmental trajectory of social play behavior. However, virtually nothing is known as to whether this developmental program is altered by prenatal exposure to opioids. Here, we show in rats that maternal oxycodone self-administration during pregnancy leads to reduced adolescent microglial phagocytosis of D1R and subsequently higher D1R density within the NAc in adult male, but not female, offspring. Finally, we show prenatal and adult behavioral deficits in opioid-exposed offspring, including impaired extinction of oxycodone-conditioned place preference in males. This work demonstrates for the first time that microglia play a key role in translating prenatal opioid exposure to changes in neural systems and behavior.
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Analgésicos Opioides , Efectos Tardíos de la Exposición Prenatal , Analgésicos Opioides/farmacología , Animales , Dopamina/farmacología , Femenino , Humanos , Masculino , Microglía/metabolismo , Núcleo Accumbens , Oxicodona/farmacología , Embarazo , Ratas , Receptores de Dopamina D1/metabolismo , RecompensaRESUMEN
OBJECTIVES: Gender differences in the prevalence of opioid misuse continue to evolve and have not been well characterized in recent years. Our objective was to investigate gender differences in the prevalence of opioid misuse and use disorder in the US over the 5-year period from 2015 to 2019. METHODS: We used annual survey data from the 2015-2019 National Survey on Drug Use and Health to estimate gender differences in the prevalence of opioid misuse. We examined past-year opioid analgesic misuse initiation, opioid analgesic misuse, heroin use, opioid analgesic use disorder and heroin use disorder. Logistic regression models were used to test gender differences, adjusting for sociodemographic variables. RESULTS: In adjusted analyses, women had higher odds of having initiated opioid analgesic misuse in the past year compared to men. In contrast, men had higher odds of misuse of opioid analgesics, heroin use, and an opioid analgesic or heroin use disorder. CONCLUSIONS: Although opioid misuse has historically been more prevalent in men, the gender difference in opioid analgesic misuse continues to narrow, with more women initiating misuse than men including higher rates of misuse in adolescent girls. Heroin use continues to be approximately twice as common in men as women.
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Trastornos Relacionados con Opioides , Mal Uso de Medicamentos de Venta con Receta , Adolescente , Analgésicos Opioides , Femenino , Heroína , Humanos , Masculino , Trastornos Relacionados con Opioides/epidemiología , Prevalencia , Factores Sexuales , Estados Unidos/epidemiologíaRESUMEN
RATIONALE: Methamphetamine (MA) addiction is a major public health issue in the USA, with a poorly understood genetic component. We previously identified heterogeneous nuclear ribonucleoprotein H1 (Hnrnph1; H1) as a quantitative trait gene underlying sensitivity to MA-induced behavioral sensitivity. Mice heterozygous for a frameshift deletion in the first coding exon of H1 (H1+/-) showed reduced MA phenotypes including oral self-administration, locomotor activity, dopamine release, and dose-dependent differences in MA conditioned place preference. However, the effects of H1+/- on innate and MA-modulated reward sensitivity are not known. OBJECTIVES: We examined innate reward sensitivity and facilitation by MA in H1+/- mice via intracranial self-stimulation (ICSS). METHODS: We used intracranial self-stimulation (ICSS) of the medial forebrain bundle to assess shifts in reward sensitivity following acute, ascending doses of MA (0.5-4.0 mg/kg, i.p.) using a within-subjects design. We also assessed video-recorded behaviors during ICSS testing sessions. RESULTS: H1+/- mice displayed reduced normalized maximum response rates in response to MA. H1+/- females had lower normalized M50 values compared to wild-type females, suggesting enhanced reward facilitation by MA. Finally, regardless of genotype, there was a dose-dependent reduction in distance to the response wheel following MA administration, providing an additional measure of MA-induced reward-driven behavior. CONCLUSIONS: H1+/- mice displayed a complex ICSS phenotype following MA, displaying indications of both blunted reward magnitude (lower normalized maximum response rates) and enhanced reward sensitivity specific to H1+/- females (lower normalized M50 values).
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Dopaminérgicos/administración & dosificación , Ribonucleoproteínas Nucleares Heterogéneas/genética , Metanfetamina/administración & dosificación , Recompensa , Autoestimulación/efectos de los fármacos , Autoestimulación/fisiología , Animales , Relación Dosis-Respuesta a Droga , Femenino , Locomoción/efectos de los fármacos , Locomoción/fisiología , Masculino , Haz Prosencefálico Medial/efectos de los fármacos , Haz Prosencefálico Medial/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , AutoadministraciónRESUMEN
Withdrawal from opioid painkillers can produce short-lived physical symptoms and protracted psychological symptoms including anxiety and depressive-like states that often lead to opioid misuse and opioid use disorder (OUD). Studies testing the hypothesis that opioid withdrawal potentiates the reinforcing effects of opioid self-administration (SA) are largely inconclusive and have focused on males. Although some clinical evidence indicates that women are more likely than men to misuse opioids to self-medicate, preclinical studies in both sexes are lacking. Based on clinical reports, we hypothesized that withdrawal from escalating-dose morphine injections that approximates a prescription painkiller regimen would lead to increased oxycodone SA to a greater extent in female compared to male rats. After escalating-dose morphine (5-30 mg/kg or vehicle, twice/day for 12 days), rats underwent a 2-week abstinence period during which withdrawal signs were measured. The impact of this treatment was assessed on oxycodone SA acquisition, maintenance, dose response, and progressive ratio responding, with additional analyses to compare sexes. We found that both sexes expressed somatic withdrawal, whereas only males demonstrated hyperalgesia in the warm water tail flick assay. During SA acquisition, males with prior morphine exposure took significantly more oxycodone than females. Finally, females with prior morphine exposure demonstrated the lowest motivation to SA oxycodone in the progressive ratio test. Contrary to our initial hypothesis, our findings suggest that prior opioid exposure increases vulnerability to initiate misuse more in males and decreases the reinforcing efficacy of oxycodone in females.
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Morfina/administración & dosificación , Narcóticos/administración & dosificación , Trastornos Relacionados con Opioides/tratamiento farmacológico , Oxicodona/administración & dosificación , Animales , Femenino , Masculino , Ratas , Ratas Sprague-Dawley , Refuerzo en Psicología , Autoadministración , Síndrome de Abstinencia a Sustancias/psicologíaRESUMEN
Drugs of abuse and highly palatable foods (e.g. high fat or sweet foods) have powerful reinforcing effects, which can lead to compulsive and addictive drives to ingest these substances to the point of psychopathology and self-harm--specifically the development of Substance Use Disorder (SUD) and obesity. Both SUD and binge-like overeating can be defined as disorders in which the salience of the reward (food or drug) becomes exaggerated relative to, and at the expense of, other rewards that promote well-being. A major roadblock in the treatment of these disorders is high rates of relapse after periods of abstinence. It is common, although not universal, for cue-induced craving to increase over time with abstinence, often triggered by cues previously paired with the reinforcing substance. Accumulating evidence suggests that similar neural circuits and cellular mechanisms contribute to abstinence-induced and cue-triggered seeking of drugs and palatable food. Although much research has focused on the important role of corticolimbic circuitry in drug-seeking, our goal is to expand focus to the more recently explored hypothalamic-thalamic-striatal circuitry. Specifically, we review how connections, and neurotransmitters therein, among the lateral hypothalamus, paraventricular nucleus of the thalamus, and the nucleus accumbens contribute to abstinence-induced opioid- and (high fat or sweet) food-seeking. Given that biological sex and gonadal hormones have been implicated in addictive behavior across species, another layer to this review is to compare behaviors and neural circuit-based mechanisms of abstinence-induced opioid- or food-seeking between males and females when such data is available.
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Analgésicos Opioides/efectos adversos , Conducta Adictiva/metabolismo , Alimentos/efectos adversos , Neurobiología/métodos , Síndrome de Abstinencia a Sustancias/metabolismo , Animales , Ansia/efectos de los fármacos , Señales (Psicología) , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Conducta Alimentaria , Femenino , Humanos , Hipotálamo/metabolismo , Masculino , Núcleos Talámicos de la Línea Media/metabolismo , Núcleo Accumbens/efectos de los fármacos , Recurrencia , Recompensa , Caracteres Sexuales , Trastornos Relacionados con Sustancias/metabolismo , Sacarosa/efectos adversosRESUMEN
Neuropathy is major source of chronic pain that can be caused by mechanically or chemically induced nerve injury. Intraplantar formalin injection produces local necrosis over a two-week period and has been used to model neuropathy in rats. To determine whether neuropathy alters dopamine (DA) receptor responsiveness in mesolimbic brain regions, we examined dopamine D1-like and D2-like receptor (D1/2R) signaling and expression in male rats 14 days after bilateral intraplantar formalin injections into both rear paws. D2R-mediated G-protein activation and expression of the D2R long, but not short, isoform were reduced in nucleus accumbens (NAc) core, but not in NAc shell, caudate-putamen or ventral tegmental area of formalin- compared to saline-treated rats. In addition, D1R-stimulated adenylyl cyclase activity was also reduced in NAc core, but not in NAc shell or prefrontal cortex, of formalin-treated rats, whereas D1R expression was unaffected. Other proteins involved in dopamine neurotransmission, including dopamine uptake transporter and tyrosine hydroxylase, were unaffected by formalin treatment. In behavioral tests, the potency of a D2R agonist to suppress intracranial self-stimulation (ICSS) was decreased in formalin-treated rats, whereas D1R agonist effects were not altered. The combination of reduced D2R expression and signaling in NAc core with reduced suppression of ICSS responding by a D2R agonist suggest a reduction in D2 autoreceptor function. Altogether, these results indicate that intraplantar formalin produces attenuation of highly specific DA receptor signaling processes in NAc core of male rats and suggest the development of a neuropathy-induced allostatic state in both pre- and post-synaptic DA receptor function.
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Formaldehído/toxicidad , Neuralgia/metabolismo , Núcleo Accumbens/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Transducción de Señal/fisiología , Animales , Condicionamiento Operante/efectos de los fármacos , Condicionamiento Operante/fisiología , Modelos Animales de Enfermedad , Agonistas de Dopamina/farmacología , Antagonistas de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Masculino , Neuralgia/inducido químicamente , Núcleo Accumbens/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/antagonistas & inhibidores , Receptores de Dopamina D2/agonistas , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND: New treatments for stress-related disorders including depression, anxiety, and substance use disorder are greatly needed. Kappa opioid receptors are expressed in the central nervous system, including areas implicated in analgesia and affective state. Although kappa opioid receptor agonists share the antinociceptive effects of mu opioid receptor agonists, they also tend to produce negative affective states. In contrast, selective kappa opioid receptor antagonists have antidepressant- and anxiolytic-like effects, stimulating interest in their therapeutic potential. The prototypical kappa opioid receptor antagonists (e.g., norBNI, JDTic) have an exceptionally long duration of action that complicates their use in humans, particularly in tests to establish safety. This study was designed to test dose- and time-course effects of novel kappa opioid receptor antagonists with the goal of identifying short-acting lead compounds for future medication development. METHODS: We screened 2 novel, highly selective kappa opioid receptor antagonists (CYM-52220 and CYM-52288) with oral efficacy in the warm water tail flick assay in rats to determine initial dose and time course effects. For comparison, we tested existing kappa opioid receptor antagonists JDTic and LY-2456302 (also known as CERC-501 or JNJ-67953964). RESULTS: In the tail flick assay, the rank order of duration of action for the antagonists was LY-2456302 < CYM-52288 < CYM-52220 << JDTic. Furthermore, LY-2456302 blocked the depressive (anhedonia-producing) effects of the kappa opioid receptor agonist U50,488 in the intracranial self-stimulation paradigm, albeit at a higher dose than that needed for analgesic blockade in the tail flick assay. CONCLUSIONS: These results suggest that structurally diverse kappa opioid receptor antagonists can have short-acting effects and that LY-2456302 reduces anhedonia as measured in the intracranial self-stimulation test.
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3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/farmacología , Analgésicos no Narcóticos/farmacología , Ansiolíticos/farmacología , Antidepresivos/farmacología , Conducta Animal/efectos de los fármacos , Benzamidas/farmacología , Antagonistas de Narcóticos/farmacología , Piperidinas/farmacología , Pirrolidinas/farmacología , Receptores Opioides kappa/antagonistas & inhibidores , Tetrahidroisoquinolinas/farmacología , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/administración & dosificación , Analgésicos no Narcóticos/administración & dosificación , Animales , Ansiolíticos/administración & dosificación , Antidepresivos/administración & dosificación , Benzamidas/administración & dosificación , Desarrollo de Medicamentos , Evaluación Preclínica de Medicamentos , Masculino , Antagonistas de Narcóticos/administración & dosificación , Piperidinas/administración & dosificación , Pirrolidinas/administración & dosificación , Ratas , Ratas Sprague-Dawley , Receptores Opioides kappa/agonistas , Tetrahidroisoquinolinas/administración & dosificaciónRESUMEN
Anxiety disorders disproportionately affect women compared to men, which may arise from sex differences in stress responses. MiRNAs are small non-coding RNAs known to regulate gene expression through actions on mRNAs. MiRNAs are regulated, in part, by factors such as stress and gonadal sex, and they have been implicated in the pathophysiology of multiple psychiatric disorders. Here, we assessed putative sex differences in miRNA expression in the bed nucleus of the stria terminalis (BNST) - a sexually dimorphic brain region implicated in anxiety - of adult male and female rats that had been exposed to social isolation (SI) stress throughout adolescence. To assess the translational utility of our results, we assessed if childhood trauma in humans resulted in changes in blood miRNA expression that are similar to those observed in rats. Male and female Sprague-Dawley rats underwent SI during adolescence or remained group housed (GH) and were tested for anxiety-like behavior in the elevated plus maze as adults. Small RNA sequencing was performed on tissue extracted from the BNST. Furthermore, we re-analyzed an already available small RNA sequencing data set from the Grady Trauma Project (GTP) from men and women to identify circulating miRNAs that are associated with childhood trauma exposure. Our results indicated that there were greater anxiogenic-like effects and changes in BNST miRNA expression in SI versus GH females compared to SI versus GH males. In addition, we found nine miRNAs that were regulated in both the BNST from SI compared to GH rats and in blood samples from humans exposed to childhood trauma. These studies emphasize the utility of rodent models in studying neurobiological mechanisms underlying psychiatric disorders and suggest that rodent models could be used to identify novel sex-specific pharmacotherapies for anxiety disorders.
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BACKGROUND: There is an urgent need to identify factors that increase vulnerability to opioid addiction to help stem the opioid epidemic and develop more efficient pharmacotherapeutics. MicroRNAs are small non-coding RNAs that regulate gene expression at a posttranscriptional level and have been implicated in chronic drug-taking in humans and in rodent models. Recent evidence has shown that chronic opioid treatment regulates the microRNA miR-9. The present study was designed to test the hypothesis that miR-9 in the nucleus accumbens potentiates oxycodone addictive-like behavior. METHODS: We utilized adeno-associated virus (AAV) to overexpress miR-9 in the nucleus accumbens of male rats and tested the effects on intravenous self-administration of the highly abused prescription opioid, oxycodone, in 1-hour short-access followed by 6-h long-access sessions, the latter of which leads to escalation of drug intake. In separate rats, we assessed the effects of nucleus accumbens miR-9 overexpression on mRNA targets including RE1-silencing transcription factor (REST) and dopamine D2 receptor (DRD2), which have been shown to be regulated by drugs of abuse. RESULTS: Overexpression of miR-9 in the nucleus accumbens significantly increased oxycodone self-administration compared with rats expressing a control, scrambled microRNA. Analysis of the pattern of oxycodone intake revealed that miR-9 overexpression increased "burst" episodes of intake and decreased the inter-infusion interval. Furthermore, miR-9 overexpression decreased the expression of REST and increased DRD2 in the nucleus accumbens at time points that coincided with behavioral effects. CONCLUSIONS: These results suggest that nucleus accumbens miR-9 regulates oxycodone addictive-like behavior as well as the expression of genes that are involved in drug addiction.
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Conducta Adictiva/fisiopatología , MicroARNs/biosíntesis , MicroARNs/fisiología , Núcleo Accumbens/metabolismo , Oxicodona/farmacología , Animales , Conducta Adictiva/inducido químicamente , Dependovirus/genética , Vectores Genéticos/administración & dosificación , Masculino , Microinyecciones , Ratas , Receptores de Dopamina D2/biosíntesis , Proteínas Represoras/biosíntesis , AutoadministraciónRESUMEN
The neuropeptide dynorphin (DYN) activates kappa opioid receptors (KORs) in the brain to produce depressive-like states and decrease motivation. KOR-mediated suppression of dopamine release in the nucleus accumbens (NAc) is considered one underlying mechanism. We previously showed that, regardless of estrous cycle stage, female rats are less sensitive than males to KOR agonist-mediated decreases in motivation to respond for brain stimulation reward, measured with intracranial self-stimulation (ICSS). However, the explicit roles of KORs, circulating gonadal hormones, and their interaction with dopamine signaling in motivated behavior are not known. As such, we measured the effects of the KOR agonist U50,488 on ICSS stimulation thresholds before and after gonadectomy (or sham surgery). We found that ovariectomized females remained less sensitive than sham or castrated males to KOR-mediated decreases in brain stimulation reward, indicating that circulating gonadal hormones do not play a role. We used qRT-PCR to examine whether sex differences in gene expression in limbic brain regions are associated with behavioral sex differences. We found no sex differences in Pdyn or Oprk1 mRNA in the NAc and ventral tegmental area (VTA), but tyrosine hydroxylase (Th) mRNA was significantly higher in female compared to male VTA. To further explore sex-differences in KOR-mediated suppression of dopamine, we used fast scan cyclic voltammetry (FSCV) and demonstrated that U50,488 was less effective in suppressing evoked NAc dopamine release in females compared to males. These data raise the possibility that females are protected from KOR-mediated decreases in motivation by an increased capacity to produce and release dopamine.
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Dopamina/metabolismo , Motivación/efectos de los fármacos , Receptores Opioides kappa/agonistas , Receptores Opioides kappa/metabolismo , Autoestimulación/efectos de los fármacos , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero , Anhedonia , Animales , Castración , Dinorfinas/metabolismo , Femenino , Masculino , Modelos Animales , Motivación/fisiología , Núcleo Accumbens/efectos de los fármacos , Ratas , Ratas Long-Evans , Ratas Sprague-Dawley , Recompensa , Autoestimulación/fisiología , Factores Sexuales , Tirosina 3-Monooxigenasa/metabolismo , Área Tegmental Ventral/metabolismoRESUMEN
There is increasing evidence in humans and laboratory animals for biologically based sex differences in every phase of drug addiction: acute reinforcing effects, transition from occasional to compulsive use, withdrawal-associated negative affective states, craving, and relapse. There is also evidence that many qualitative aspects of the addiction phases do not differ significantly between males and females, but one sex may be more likely to exhibit a trait than the other, resulting in population differences. The conceptual framework of this review is to focus on hormonal, chromosomal, and epigenetic organizational and contingent, sex-dependent mechanisms of four neural systems that are known-primarily in males-to be key players in addiction: dopamine, mu-opioid receptors (MOR), kappa opioid receptors (KOR), and brain-derived neurotrophic factor (BDNF). We highlight data demonstrating sex differences in development, expression, and function of these neural systems as they relate-directly or indirectly-to processes of reward and addictive behavior, with a focus on psychostimulants and opioids. We identify gaps in knowledge about how these neural systems interact with sex to influence addictive behavior, emphasizing throughout that the impact of sex can be highly nuanced and male/female data should be reported regardless of the outcome.
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Conducta Adictiva/metabolismo , Encéfalo/metabolismo , Dopamina/metabolismo , Receptores Opioides/metabolismo , Recompensa , Caracteres Sexuales , Trastornos Relacionados con Sustancias/metabolismo , Animales , Conducta Adictiva/fisiopatología , Encéfalo/fisiopatología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Femenino , Humanos , Masculino , Receptores Dopaminérgicos/metabolismo , Trastornos Relacionados con Sustancias/fisiopatologíaRESUMEN
RATIONALE: Mood disorders can be triggered by stress and are characterized by deficits in reward processing, including disrupted reward learning (the ability to modulate behavior according to past rewards). Reward learning is regulated by the anterior cingulate cortex (ACC) and striatal circuits, both of which are implicated in the pathophysiology of mood disorders. OBJECTIVES: Here, we assessed in rats the effects of a potent stressor (social defeat) on reward learning and gene expression in the ACC, ventral tegmental area (VTA), and striatum. METHODS: Adult male Wistar rats were trained on an operant probabilistic reward task (PRT) and then exposed to 3 days of social defeat before assessment of reward learning. After testing, the ACC, VTA, and striatum were dissected, and expression of genes previously implicated in stress was assessed. RESULT: Social defeat blunted reward learning (manifested as reduced response bias toward a more frequently rewarded stimulus) and was associated with increased nociceptin/orphanin FQ (N/OFQ) peptide mRNA levels in the striatum and decreased Fos mRNA levels in the VTA. Moreover, N/OFQ peptide and nociceptin receptor mRNA levels in the ACC, VTA and striatum were inversely related to reward learning. CONCLUSIONS: The behavioral findings parallel previous data in humans, suggesting that stress similarly disrupts reward learning in both species. Increased striatal N/OFQ mRNA in stressed rats characterized by impaired reward learning is consistent with accumulating evidence that antagonism of nociceptin receptors, which bind N/OFQ, has antidepressant-like effects. These results raise the possibility that nociceptin systems represent a molecular substrate through which stress produces reward learning deficits in mood disorders.
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Cuerpo Estriado/metabolismo , Aprendizaje/fisiología , Péptidos Opioides/biosíntesis , ARN Mensajero/biosíntesis , Recompensa , Estrés Psicológico/metabolismo , Animales , Femenino , Humanos , Relaciones Interpersonales , Masculino , Trastornos del Humor/genética , Trastornos del Humor/metabolismo , Trastornos del Humor/psicología , Péptidos Opioides/genética , ARN Mensajero/genética , Ratas , Ratas Long-Evans , Ratas Wistar , Estrés Psicológico/psicología , Área Tegmental Ventral/metabolismo , NociceptinaRESUMEN
RATIONALE: Oxycodone is one of the most widely prescribed painkillers in the USA. However, its use is complicated by high abuse potential. As sex differences have been described in drug addiction, the present study tested for sex differences in intravenous oxycodone self-administration in rats. METHODS: Male and female Sprague-Dawley rats were implanted with jugular vein catheters and trained to self-administer oxycodone (0.03 mg/kg/infusion) under fixed ratio 1 (FR1), FR2, and FR5 schedules of reinforcement followed by a dose-response study to assess sensitivity to the reinforcing effects of oxycodone. In separate rats, sucrose pellet self-administration was assessed under an FR1 schedule to determine whether sex differences in oxycodone self-administration could be generalized across reinforcers. In separate rats, oxycodone distribution to plasma and brain was measured after intravenous drug delivery. RESULTS: In the first 3 trials under an FR1 schedule of reinforcement, male rats self-administered more oxycodone than females. In contrast, females self-administered more sucrose pellets. Under FR2 and FR5 schedules, no significant sex differences in oxycodone intake were observed, although female rats had significantly more inactive lever presses. Male and female rats showed similar inverted U-shaped dose-effect functions, with females tending to self-administer more oxycodone than males at higher doses. No significant sex differences were observed in plasma or brain oxycodone levels, suggesting that sex differences in oxycodone self-administration behavior were not due to pharmacokinetics. CONCLUSION: Our results suggest subtle sex differences in oxycodone self-administration, which may influence the abuse liability of oxycodone and have ramifications for prescription opioid addiction treatment.
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Condicionamiento Psicológico , Narcóticos/administración & dosificación , Oxicodona/administración & dosificación , Sacarosa/administración & dosificación , Edulcorantes/administración & dosificación , Animales , Femenino , Infusiones Intravenosas , Masculino , Ratas , Ratas Sprague-Dawley , Esquema de Refuerzo , Refuerzo en Psicología , Autoadministración , Factores SexualesRESUMEN
UNLABELLED: Dependence is a hallmark feature of opiate addiction and is defined by the emergence of somatic and affective withdrawal signs. The nucleus accumbens (NAc) integrates dopaminergic and glutamatergic inputs to mediate rewarding and aversive properties of opiates. Evidence suggests that AMPA glutamate-receptor-dependent synaptic plasticity within the NAc underlies aspects of addiction. However, the degree to which NAc AMPA receptors (AMPARs) contribute to somatic and affective signs of opiate withdrawal is not fully understood. Here, we show that microinjection of the AMPAR antagonist NBQX into the NAc shell of morphine-dependent rats prevented naloxone-induced conditioned place aversions and decreases in sensitivity to brain stimulation reward, but had no effect on somatic withdrawal signs. Using a protein cross-linking approach, we found that the surface/intracellular ratio of NAc GluA1, but not GluA2, increased with morphine treatment, suggesting postsynaptic insertion of GluA2-lacking AMPARs. Consistent with this, 1-naphthylacetyl spermine trihydrochloride (NASPM), an antagonist of GluA2-lacking AMPARs, attenuated naloxone-induced decreases in sensitivity to brain stimulation reward. Naloxone decreased the surface/intracellular ratio and synaptosomal membrane levels of NAc GluA1 in morphine-dependent rats, suggesting a compensatory removal of AMPARs from synaptic zones. Together, these findings indicate that chronic morphine increases synaptic availability of GluA1-containing AMPARs in the NAc, which is necessary for triggering negative-affective states in response to naloxone. This is broadly consistent with the hypothesis that activation of NAc neurons produces acute aversive states and raises the possibility that inhibiting AMPA transmission selectively in the NAc may have therapeutic value in the treatment of addiction. SIGNIFICANCE STATEMENT: Morphine dependence and withdrawal result in profound negative-affective states that play a major role in the maintenance of addiction. However, the underlying neurobiological mechanisms are not fully understood. We use a rat model of morphine dependence to show that GluA1 subunits of AMPA glutamate receptors in the nucleus accumbens (NAc), a brain region critical for modulating affective states, are necessary for aversive effects of morphine withdrawal. Using biochemical methods in NAc tissue, we show that morphine dependence increases cell surface expression of GluA1, suggesting that neurons in this area are primed for increased AMPA receptor activation upon withdrawal. This work is important because it suggests that targeting AMPA receptor trafficking and activation could provide novel targets for addiction treatment.
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Trastornos del Humor/inducido químicamente , Trastornos del Humor/metabolismo , Dependencia de Morfina/metabolismo , Morfina/envenenamiento , Núcleo Accumbens/metabolismo , Receptores AMPA/metabolismo , Síndrome de Abstinencia a Sustancias/metabolismo , Animales , Masculino , Ratas , Ratas Sprague-Dawley , Distribución TisularRESUMEN
Negative affective states can increase the rewarding value of drugs of abuse and promote drug taking. Chronic cocaine exposure increases levels of the neuropeptide dynorphin, an endogenous ligand at kappa opioid receptors (KOR) that suppresses dopamine release in the nucleus accumbens (NAc) and elicits negative affective states upon drug withdrawal. However, there is evidence that the effects of KOR activation on affective state are biphasic: immediate aversive effects are followed by delayed increases in reward. The impact of KOR-induced affective states on reward-related effects of cocaine over time is not known. We hypothesize that the initial aversive effects of KOR activation increase, whereas the delayed rewarding effects decrease, the net effects of cocaine on reward and dopamine release. We treated rats with cocaine at various times (15 min to 48 h) after administration of the selective KOR agonist salvinorin A (salvA). Using intracranial self-stimulation and fast scan cyclic voltammetry, we found that cocaine-induced increases in brain stimulation reward and evoked dopamine release in the NAc core were potentiated when cocaine was administered within 1 h of salvA, but attenuated when administered 24 h after salvA. Quantitative real-time PCR was used to show that KOR and prodynorphin mRNA levels were decreased in the NAc, whereas tyrosine hydroxylase and dopamine transporter mRNA levels and tissue dopamine content were increased in the ventral tegmental area 24 h post-salvA. These findings raise the possibility that KOR activation-as occurs upon withdrawal from chronic cocaine-modulates vulnerability to cocaine in a time-dependent manner.
Asunto(s)
Afecto/fisiología , Cocaína/administración & dosificación , Dopamina/metabolismo , Núcleo Accumbens/metabolismo , Receptores Opioides kappa/fisiología , Recompensa , Área Tegmental Ventral/metabolismo , Afecto/efectos de los fármacos , Animales , Diterpenos de Tipo Clerodano/administración & dosificación , Dopamina/genética , Masculino , Núcleo Accumbens/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Receptores Opioides kappa/agonistas , Receptores Opioides kappa/metabolismo , Autoestimulación/efectos de los fármacos , Factores de Tiempo , Área Tegmental Ventral/efectos de los fármacosRESUMEN
Unconditioned rewarding stimuli evoke phasic increases in dopamine concentration in the nucleus accumbens (NAc) while discrete aversive stimuli elicit pauses in dopamine neuron firing and reductions in NAc dopamine concentration. The unconditioned effects of more prolonged aversive states on dopamine release dynamics are not well understood and are investigated here using the malaise-inducing agent lithium chloride (LiCl). We used fast-scan cyclic voltammetry to measure phasic increases in NAc dopamine resulting from electrical stimulation of dopamine cell bodies in the ventral tegmental area (VTA). Systemic LiCl injection reduced electrically evoked dopamine release in the NAc of both anesthetized and awake rats. As some behavioral effects of LiCl appear to be mediated through glucagon-like peptide-1 receptor (GLP-1R) activation, we hypothesized that the suppression of phasic dopamine by LiCl is GLP-1R dependent. Indeed, peripheral pretreatment with the GLP-1R antagonist exendin-9 (Ex-9) potently attenuated the LiCl-induced suppression of dopamine. Pretreatment with Ex-9 did not, however, affect the suppression of phasic dopamine release by the kappa-opioid receptor agonist, salvinorin A, supporting a selective effect of GLP-1R stimulation in LiCl-induced dopamine suppression. By delivering Ex-9 to either the lateral or fourth ventricle, we highlight a population of central GLP-1 receptors rostral to the hindbrain that are involved in the LiCl-mediated suppression of NAc dopamine release.