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Hypocretin receptor 2 antagonism dose-dependently reduces escalated heroin self-administration in rats.

ABSTRACT: The hypocretin/orexin (HCRT) system has been associated with both positive and negative drug reinforcement, implicating HCRT receptor 1 (HCRT-R1) signaling in drug-related behaviors for all major drug classes, including opioids. However, to date there are limited studies investigating the role of HCRT receptor 2 (HCRT-R2) signaling in compulsive-like drug seeking. Escalation of drug intake with extended access has been suggested to model the transition from controlled drug use to compulsive-like drug seeking/taking. The current study examined the effects of a HCRT-R2 antagonist, NBI-80713, on heroin self-administration in rats allowed short- (1 h; ShA) or long- (12 h; LgA) access to intravenous heroin self-administration. Results indicate that systemically administered NBI-80713 dose-dependently decreased heroin self-administration in LgA, but not in ShA, animals. Quantitative PCR analyses showed an increase in Hcrtr2 mRNA levels in the central amygdala, a stress-related brain region, of LgA rats. These observations suggest a functional role for HCRT-R2 signaling in compulsive-like heroin self-administration associated with extended access and indicate HCRT-R2 antagonism as a potential pharmacological target for the treatment of heroin dependence.

SUBMITTER: Schmeichel BE

PROVIDER: S-EPMC4367454 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Hypocretin receptor 2 antagonism dose-dependently reduces escalated heroin self-administration in rats.

Schmeichel Brooke E BE Barbier Estelle E Misra Kaushik K KK Contet Candice C Schlosburg Joel E JE Grigoriadis Dimitri D Williams John P JP Karlsson Camilla C Pitcairn Caleb C Heilig Markus M Koob George F GF Vendruscolo Leandro F LF

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20150313 5

The hypocretin/orexin (HCRT) system has been associated with both positive and negative drug reinforcement, implicating HCRT receptor 1 (HCRT-R1) signaling in drug-related behaviors for all major drug classes, including opioids. However, to date there are limited studies investigating the role of HCRT receptor 2 (HCRT-R2) signaling in compulsive-like drug seeking. Escalation of drug intake with extended access has been suggested to model the transition from controlled drug use to compulsive-like ...[more]

PMID: 25367502

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Project description:RATIONALE:Drug addiction is a complex disease that is impacted by numerous factors. One such factor, time of day, influences drug intake, but there have been no investigations of how time of day affects the amount of drug taken and the development of addiction-like behavior. Previous data from our group show circadian disruption in rats given access to heroin during the light phase, which is important because circadian disruption, itself, can increase drug intake. Thus, the goal of this experiment was to determine how time of day of access affects heroin self-administration and the development of addiction-like behaviors including escalation of heroin intake, willingness to work for heroin on a progressive ratio schedule of reinforcement, seeking during extinction, incubation of seeking, and reinstatement of heroin-seeking behavior. MATERIALS AND METHODS:Male Sprague Dawley rats were given the opportunity to self-administer heroin for 6 h per trial during the second half of either the light or dark phase for 18 trials, including one progressive ratio challenge. Rats then underwent 14 days of abstinence, with a 5-h extinction test occurring on both the first and the 14th days of abstinence. The second extinction test was followed by a heroin prime and 1 h of reinstatement testing. On the following day, a subset of rats were tested in an additional extinction test where rats were tested either at the same time of the day as their previous self-administration sessions or during the opposite light/dark phase. RESULTS:Relative to Light Access rats, Dark Access rats took more heroin, exhibited more goal-directed behavior, exhibited more seeking during the dark phase, failed to extinguish seeking during the 5-h extinction test in the dark phase, and exhibited greater incubation of heroin seeking following abstinence. However, Dark Access rats did not escalate drug taking over trials, work harder for drug, or seek more during drug-induced reinstatement than Light Access rats. CONCLUSIONS:These results show that time of access to heroin affects overall heroin intake and seeking in extinction, but does not affect other addiction-like behaviors in rats.

Project description:UNLABELLED: BACKGROUND: Animal studies show that diets containing resistant starch (RS) at levels not achievable in the human diet result in lower body weight and/or adiposity in rodents. We aimed to determine whether RS dose-dependently reduces adiposity in obesity-prone (OP) and obesity-resistant (OR) rats. METHODS: Male Sprague-Dawley rats (n=120) were fed a moderate-fat, high-energy diet for 4 wk. Rats that gained the most weight (40%) were classified as obesity-prone (OP) and obesity-resistant (OR) rats were the 40% that gained the least weight. OP and OR rats were randomly allocated to one of six groups (n=8 for each phenotype). One group was killed for baseline measurements, the other five groups were allocated to AIN-93 based diets that contained 0, 4, 8, 12 and 16% RS (as high amylose maize starch) for 4 wk. These diets were matched for total carbohydrate content. At 0, 4 and 7 wk from the start of the study insulin sensitivity was calculated by homeostasis model assessment of insulin resistance (HOMA-IR) and adiposity was determined by dual-energy X-ray absorptiometry (DXA). At 8 wk, rats were euthanized and fat pad weights, intestinal digesta short chain fatty acid (SCFA) pools and plasma gut hormone levels were determined. RESULTS: Obesity prone rats gained less weight with 4, 12 and 16% RS compared to 0% RS, but the effect in OR animals was significant only at 16% RS. Irrespective of phenotype, diets containing ?8% RS reduced adiposity compared to 0% RS. Energy intake decreased by 9.8 kJ/d for every 4% increase in RS. All diets containing RS increased total SCFA pools in the caecum and lowered plasma GIP concentrations compared to the 0% RS, whereas plasma GLP-1 and PYY were increased when the diet contained at least 8% RS. Insulin sensitivity was not affected by RS. CONCLUSION: RS in amounts that could be potentially consumed by humans were effective in reducing adiposity and weight gain in OP and OR rats, due in part to a reduction in energy intake, and changes in gut hormones and large bowel carbohydrate fermentation.

Project description:BackgroundChronic exposure to ethanol (EtOH) and other drugs of abuse can alter the expression and activity of cyclin-dependent kinase 5 (CDK5) and its cofactor p35, but the functional implication of CDK5 signaling in the regulation of EtOH-related behaviors remains unknown. In the present study, we sought to determine whether CDK5 activity plays a role in the escalation of EtOH self-administration triggered by dependence.MethodsWe tested the effect of systemically administered (S)-CR8, a nonselective CDK inhibitor, on operant responding for EtOH or saccharin, a highly palatable reinforcer, in adult male Wistar rats. Half of the rats were made EtOH-dependent via chronic intermittent EtOH inhalation (CIE). We then sought to identify a possible neuroanatomical locus for the behavioral effect of (S)-CR8 by quantifying protein levels of CDK5 and p35 in subregions of the extended amygdala and prefrontal cortex from EtOH-naïve, nondependent, and dependent rats at the expected time of EtOH self-administration. We also analyzed the phosphorylation of 4 CDK5 substrates and of the CDK substrate consensus motif.Results(S)-CR8 dose-dependently reduced EtOH self-administration in dependent rats. It had no effect on water or saccharin self-administration, nor in nondependent rats. The abundance of CDK5 or p35 was not altered in any of the brain regions analyzed. In the bed nucleus of the stria terminalis, CDK5 abundance was negatively correlated with intoxication levels during EtOH vapor exposure but there was no effect of dependence on the phosphorylation ratio of CDK5 substrates. In contrast, EtOH dependence increased the phosphorylation of low-molecular-weight CDK substrates in the basolateral amygdala (BLA).ConclusionsThe selective effect of (S)-CR8 on excessive EtOH intake has potential therapeutic value for the treatment of alcohol use disorders. Our data do not support the hypothesis that this effect would be mediated by the inhibition of up-regulated CDK5 activity in the extended amygdala nor prefrontal cortex. However, increased activity of CDKs other than CDK5 in the BLA may contribute to excessive EtOH consumption in alcohol dependence. Other (S)-CR8 targets may also be implicated.

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Hypocretin receptor 2 antagonism dose-dependently reduces escalated heroin self-administration in rats.

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Hypocretin receptor 2 antagonism dose-dependently reduces escalated heroin self-administration in rats.

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