Deep brain stimulation of the nucleus accumbens shell attenuates cocaine withdrawal but increases cocaine self-administration, cocaine-induced locomotor activity, and GluR1/GluA1 in the central nucleus of the amygdala in male cocaine-dependent rats.

BACKGROUND: Cocaine addiction is a major public health problem. Despite decades of intense research, no effective treatments are available. Both preclinical and clinical studies strongly suggest that deep brain stimulation of the nucleus accumbens (NAcc) is a viable target for the treatment of cocaine use disorder (CUD). OBJECTIVE: Although previous studies have shown that DBS of the NAcc decreases cocaine seeking and reinstatement, the effects of DBS on cocaine intake in cocaine-dependent animals have not yet been investigated. METHODS: Rats were made cocaine dependent by allowing them to self-administer cocaine in extended access conditions (6 h/day, 0.5 mg/kg/infusion). The effects of monophasic bilateral high-frequency DBS (60 µs pulse width and 130 Hz frequency) stimulation with a constant current of 150 µA of the NAcc shell on cocaine intake was then evaluated. Furthermore, cocaine-induced locomotor activity, irritability-like behavior during cocaine abstinence, and the levels of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits 1 and 2 (GluR1/GluA1 and GluR2/GluA2) after DBS were investigated. RESULTS: Contrary to our expectations, DBS of the NAcc shell induced a slight increase in cocaine self-administration, and increased cocaine-induced locomotion after extended access of cocaine self-administration. In addition, DBS decreased irritability-like behavior 18 h into cocaine withdrawal. Finally, DBS increased both cytosolic and synaptosomal levels of GluR1, but not GluR2, in the central nucleus of the amygdala but not in other brain regions. CONCLUSIONS: These preclinical results with cocaine-dependent animals support the use of high-frequency DBS of the NAcc shell as a therapeutic approach for the treatment of the negative emotional state that emerges during cocaine abstinence, but also demonstrate that DBS does not decrease cocaine intake in active, long-term cocaine users. These data, together with the existing evidence that DBS of the NAcc shell reduces the reinstatement of cocaine seeking in abstinent animals, suggest that NAcc shell DBS may be beneficial for the treatment of the negative emotional states and craving during abstinence, although it may worsen cocaine use if individuals continue drug use.

The Cocaine and Oxycodone Biobanks, Two Repositories from Genetically Diverse and Behaviorally Characterized Rats for the Study of Addiction.

The rat oxycodone and cocaine biobanks contain samples that vary by genotypes (by using genetically diverse genotyped HS rats), phenotypes (by measuring addiction-like behaviors in an advanced SA model), timepoints (samples are collected longitudinally before, during, and after SA, and terminally at three different timepoints in the addiction cycle: intoxication, withdrawal, and abstinence or without exposure to drugs through age-matched naive rats), samples collected (organs, cells, biofluids, feces), preservation (paraformaldehyde-fixed, snap-frozen, or cryopreserved) and application (proteomics, transcriptomics, microbiomics, metabolomics, epigenetics, anatomy, circuitry analysis, biomarker discovery, etc.Substance use disorders (SUDs) are pervasive in our society and have substantial personal and socioeconomical costs. A critical hurdle in identifying biomarkers and novel targets for medication development is the lack of resources for obtaining biological samples with a detailed behavioral characterization of SUD. Moreover, it is nearly impossible to find longitudinal samples. As part of two ongoing large-scale behavioral genetic studies in heterogeneous stock (HS) rats, we have created two preclinical biobanks using well-validated long access (LgA) models of intravenous cocaine and oxycodone self-administration (SA) and comprehensive characterization of addiction-related behaviors. The genetic diversity in HS rats mimics diversity in the human population and includes individuals that are vulnerable or resilient to compulsive-like responding for cocaine or oxycodone. Longitudinal samples are collected throughout the experiment, before exposure to the drug, during intoxication, acute withdrawal, and protracted abstinence, and include naive, age-matched controls. Samples include, but are not limited to, blood plasma, feces and urine, whole brains, brain slices and punches, kidney, liver, spleen, ovary, testis, and adrenal glands. Three preservation methods (fixed in formaldehyde, snap-frozen, or cryopreserved) are used to facilitate diverse downstream applications such as proteomics, metabolomics, transcriptomics, epigenomics, microbiomics, neuroanatomy, biomarker discovery, and other cellular and molecular approaches. To date, >20,000 samples have been collected from over 1000 unique animals and made available free of charge to non-profit institutions through https://www.cocainebiobank.org/ and https://www.oxycodonebiobank.org/.

Oxycodone self-administration and withdrawal behaviors in male and female Wistar rats.

RATIONALE: Over the last decade, oxycodone has become one of the most widely abused drugs in the USA. Oxycodone use disorder (OUD) is a serious health problem that has prompted a need to develop animal models of OUD that have both face and predictive validity. Oxycodone use in humans is more prevalent in women and leads to pronounced hyperalgesia and irritability during withdrawal. However, unclear is whether current animal models of oxycodone self-administration recapitulate these characteristics in humans. OBJECTIVES: We assessed the face validity of a model of extended-access oxycodone self-administration in rats by examining the escalation of oxycodone intake and behavioral symptoms of withdrawal, including irritability-like behavior and mechanical nociception, in male and female Wistar rats. RESULTS: Both male and female rats escalated their oxycodone intake over fourteen 12-h self-administration sessions. After escalation, female rats administered more drug than male rats. No differences in plasma oxycodone levels were identified, but males had a significantly higher level of oxycodone in the brain at 30 min. Extended access to oxycodone significantly decreased aggressive-like behavior and increased defensive-like behaviors when tested immediately after a 12-h self-administration session, followed by a rebound increase in aggressive-like behavior 12 h into withdrawal. Tests of mechanical nociception thresholds during withdrawal indicated pronounced hyperalgesia. No sex differences in irritability-like behavior or pain sensitivity were observed. CONCLUSIONS: The present study demonstrated the face validity of the extended access model of oxycodone self-administration by identifying sex differences in the escalation of oxycodone intake and pronounced changes in pain and affective states.

Nociceptin attenuates the escalation of oxycodone self-administration by normalizing CeA-GABA transmission in highly addicted rats.

Approximately 25% of patients who are prescribed opioids for chronic pain misuse them, and 5 to 10% develop an opioid use disorder. Although the neurobiological target of opioids is well known, the molecular mechanisms that are responsible for the development of addiction-like behaviors in some but not all individuals are poorly known. To address this issue, we used a unique outbred rat population (heterogeneous stock) that better models the behavioral and genetic diversity that is found in humans. We characterized individual differences in addiction-like behaviors using an addiction index that incorporates the key criteria of opioid use disorder: escalated intake, highly motivated responding, and hyperalgesia. Using in vitro electrophysiological recordings in the central nucleus of the amygdala (CeA), we found that rats with high addiction-like behaviors (HA) exhibited a significant increase in γ-aminobutyric acid (GABA) transmission compared with rats with low addiction-like behaviors (LA) and naive rats. The superfusion of CeA slices with nociceptin/orphanin FQ peptide (N/OFQ; 500 nM), an endogenous opioid-like peptide, normalized GABA transmission in HA rats. Intra-CeA levels of N/OFQ were lower in HA rats than in LA rats. Intra-CeA infusions of N/OFQ (1 µg per site) reversed the escalation of oxycodone self-administration in HA rats but not in LA rats. These results demonstrate that the downregulation of N/OFQ levels in the CeA may be responsible for hyper-GABAergic tone in the CeA that is observed in individuals who develop addiction-like behaviors. Based on these results, we hypothesize that small molecules that target the N/OFQ system might be useful for the treatment of opioid use disorder.

Healthcare resource utilization and treatment costs of Finnish chronic inflammatory bowel disease patients treated with infliximab.

Objectives: Inflammatory bowel disease (IBD) is associated with a high economic burden to society due to its early onset and chronic character. Here, we set out to characterize healthcare resource utilization and associated costs in Crohn's disease (CD) and ulcerative colitis (UC) patients with infliximab treatment, the most widely used first-line biologic agent in Finland, in a real-world clinical setting. Methods: This was a retrospective, non-interventional single-center study. Infliximab was administered in routine care, and data were collected retrospectively from electronic health records. All adult anti-TNF naïve CD or UC patients whose infliximab treatment was initiated at the Hospital District of Southwest Finland between the years of 2014 and 2016 were included in the study. Each patient was followed-up for 12 months after the initiation of infliximab treatment. Results: A total of 155 patients were included (45 CD, 110 UC). Altogether, 60.0% (n = 27) of all CD patients and 43.6% (n = 48) of all UC patients persisted on infliximab therapy 12 months after treatment initiation. The total cost was similar for both CD and UC cohorts (CD, €10,243; UC, €10,770), infliximab treatment being the highest individual cost (60.3% of the total cost in CD; 53.4% in UC). The mean number of infliximab infusions during the 12-month follow-up was 7.0 for CD and 6.5 for UC patients. Conclusions: IBD causes a significant burden to the Finnish healthcare system. This study provides a detailed characterization of the cost landscape of IBD and contributes to optimizing treatment strategies and healthcare resource use in the biosimilar era.

Adolescent cannabinoid exposure induces irritability-like behavior and cocaine cross-sensitization without affecting the escalation of cocaine self-administration in adulthood.

Cannabis use is typically initiated during adolescence and is a significant risk factor for the development of cocaine use in adulthood. However, no preclinical studies have examined the effects of adolescent cannabinoid exposure on cocaine dependence in adulthood using the escalation model of cocaine self-administration and the assessment of negative emotional states. In the present study, we found that exposure to the cannabinoid receptor agonist WIN55,212-2 (WIN) in adolescence produced irritability-like behavior and psychomotor cross-sensitization to cocaine in adolescence. In adulthood, rats were allowed to self-administer cocaine. The acquisition of cocaine self-administration was lower in rats with adolescent WIN exposure compared with controls. However, both WIN-exposed and control rats escalated their cocaine intake at the same rate, had similar responding under a progressive-ratio schedule of reinforcement, and had similar psychomotor responses to cocaine. Interestingly, the increase in irritability-like behavior that was previously observed in adolescence after WIN exposure persisted into adulthood. Whether the persisting increase in irritability-like behavior after WIN exposure has translational relevance remains to be studied. In summary, these results suggest that psychoactive cannabinoid exposure during adolescence is unlikely to have a major effect on the escalation of cocaine intake or the development of compulsive-like responding per se in adulthood in a rat model of cocaine self-administration. However, whether the persisting irritability-like behavior may predispose an individual to mood-related impairments in adulthood or predict such impairments warrants further investigation.

Systemic and Intra-Habenular Activation of the Orphan G Protein-Coupled Receptor GPR139 Decreases Compulsive-Like Alcohol Drinking and Hyperalgesia in Alcohol-Dependent Rats.

GPR139 is an orphan G protein-coupled receptor (GPCR) that is expressed mainly in the brain, with the highest expression in the medial habenula. The modulation of GPR139 receptor function has been hypothesized to be beneficial in the treatment of some mental disorders, but behavioral studies have not yet provided causal evidence of the role of GPR139 in brain dysfunction. Because of the high expression of GPR139 in the habenula, a critical brain region in addiction, we hypothesized that GPR139 may play role in alcohol dependence. Thus, we tested the effect of GPR139 receptor activation using the selective, brain-penetrant receptor agonist JNJ-63533054 on addiction-like behaviors in alcohol-dependent male rats. Systemic administration of JNJ-63533054 (30 mg/kg but not 10 mg/kg, p.o.) reversed the escalation of alcohol self-administration in alcohol-dependent rats, without affecting water or saccharin intake in dependent rats or alcohol intake in nondependent rats. Moreover, systemic JNJ-63533054 administration decreased withdrawal-induced hyperalgesia, without affecting somatic signs of alcohol withdrawal. Further analysis demonstrated that JNJ-63533054 was effective only in a subgroup of dependent rats that exhibited compulsive-like alcohol drinking. Finally, site-specific microinjection of JNJ-63533054 in the habenula but not interpeduncular nucleus (IPN) reduced both alcohol self-administration and withdrawal-induced hyperalgesia in dependent rats. These results provide robust preclinical evidence that GPR139 receptor activation reverses key addiction-like behaviors in dependent animals, suggest that GPR139 may be a novel target for the treatment of alcohol use disorder, and demonstrate that GPR139 is functionally relevant in regulating mammalian behavior.

CRF1 Receptor-Dependent Increases in Irritability-Like Behavior During Abstinence from Chronic Intermittent Ethanol Vapor Exposure.

BACKGROUND: In humans, emotional and physical signs of withdrawal from ethanol are commonly seen. Many of these symptoms, including anxiety-like and depression-like behavior, have been characterized in animal models of ethanol dependence. One issue with several current behavioral tests that measure withdrawal in animal models is that they are often not repeatable within subjects over time. Additionally, irritability, one of the most common symptoms of ethanol withdrawal in humans, has not been well characterized in animal models. The corticotropin-releasing factor (CRF)-CRF1 receptor system has been suggested to be critical for the emergence of anxiety-like behavior in ethanol dependence, but the role of this system in irritability-like behavior has not been characterized. METHODS: The present study compared the effects of chronic intermittent ethanol (CIE) vapor exposure-induced ethanol dependence on irritability-like behavior in rats using the bottle-brush test during acute withdrawal and protracted abstinence. Rats were trained to self-administer ethanol in operant chambers and then either left in a nondependent state or made dependent via CIE. Naïve, nondependent, and dependent rats were tested for irritability-like behavior in the bottle-brush test 8 hours and 2 weeks into abstinence from ethanol. Separate cohorts of dependent and nondependent rats were used to examine the effect of the specific CRF1 receptor antagonist R121919 on irritability-like behavior. RESULTS: Dependent rats exhibited escalated ethanol intake compared with their own pre-CIE baseline and nondependent rats. At both time points of abstinence, ethanol-dependent rats exhibited increased aggressive-like responses compared with naïve and nondependent rats. R121919 reduced irritability-like behavior in both dependent and nondependent rats, but dependent rats were more sensitive to R121919. CONCLUSIONS: Irritability-like behavior is a clinically relevant and reliable measure of negative emotional states that is partially mediated by activation of the CRF-CRF1 system and remains elevated during protracted abstinence in ethanol-dependent rats.

Cebranopadol Blocks the Escalation of Cocaine Intake and Conditioned Reinstatement of Cocaine Seeking in Rats.

Cebranopadol is a novel agonist of nociceptin/orphanin FQ peptide (NOP) and opioid receptors with analgesic properties that is being evaluated in clinical Phase 2 and Phase 3 trials for the treatment of chronic and acute pain. Recent evidence indicates that the combination of opioid and NOP receptor agonism may be a new treatment strategy for cocaine addiction. We sought to extend these findings by examining the effects of cebranopadol on cocaine self-administration (0.5 mg/kg/infusion) and cocaine conditioned reinstatement in rats with extended access to cocaine. Oral administration of cebranopadol (0, 25, and 50 µg/kg) reversed the escalation of cocaine self-administration in rats that were given extended (6 hour) access to cocaine, whereas it did not affect the self-administration of sweetened condensed milk (SCM). Cebranopadol induced conditioned place preference but did not affect locomotor activity during the conditioning sessions. Finally, cebranopadol blocked the conditioned reinstatement of cocaine seeking. These results show that oral cebranopadol treatment prevented addiction-like behaviors (i.e., the escalation of intake and reinstatement), suggesting that it may be a novel strategy for the treatment of cocaine use disorder. However, the conditioned place preference that was observed after cebranopadol administration suggests that this compound may have some intrinsic rewarding effects.