Cannabinoid self-administration in rats: sex differences and the influence of ovarian function.
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ABSTRACT:
SUBMITTER: Fattore L
PROVIDER: S-EPMC2190022 | biostudies-other | 2007 Nov
REPOSITORIES: biostudies-other
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Project description:The opioid epidemic has become a severe public health problem, with approximately 130 opioid-induced deaths occurring each day in the United States. Prescription opioids are responsible for approximately 40% of these deaths. Oxycodone is one of the most commonly abused prescription opioids, but despite its prevalent misuse, the number of preclinical studies investigating oxycodone-seeking behaviors is relatively limited. Furthermore, preclinical oxycodone studies that include female subjects are even more scarce, and it is critical that future work includes both sexes. Additionally, the oral route of administration is one of the most common routes for recreational users, especially in the early stages of drug experimentation. However, currently, only two studies have been published investigating operant oral oxycodone self-administration in rodents. Therefore, the primary goal of the present study was to establish an oral oxycodone operant self-administration model in adult male and female rats, as well as to examine a potential mechanism of stress-primed reinstatement. We found that females consumed significantly more oral oxycodone than males in operant self-administration sessions. We also found that active oxycodone self-administration was reduced by mu opioid receptor antagonism and by substitution of water for oxycodone solution. Lastly, we induced stress-primed reinstatement and found that this behavior was significantly attenuated by antagonism of the neurokinin-1 receptor, consistent with our prior work examining stress-induced reinstatement of alcohol- and cocaine-seeking.
| S-EPMC7289656 | biostudies-literature
Project description:Sex differences in the sensitivity to nicotine may influence vulnerability to tobacco dependence. The goal of this study was to investigate the dose-response function for the reinforcing and subjective effects of intravenous nicotine in male and female smokers. Tobacco-dependent subjects (12 male and 14 female) participated in four experimental sessions in which they received sample infusions of saline and nicotine (0.1, 0.2, 0.3, or 0.4 mg doses) in a randomized double-blind crossover design. During each session, subjects first received the sample infusions, and heart rate (HR), blood pressure, and subjective stimulatory, pleasurable and aversive responses were monitored. Immediately following the sample infusions, subjects self-administered either nicotine or saline in six double-blind forced-choice trials. A sex by dose interaction was observed in the nicotine choice paradigm. Nicotine self-administration rate was negatively correlated with nicotine dose in males (males displayed choice preference for low doses of nicotine over high doses of nicotine), but no significant relationship between dose and choice preference was evident in females. Relative to placebo, sample doses of nicotine increased heart rate and blood pressure, and induced stimulatory, pleasurable, and aversive subjective effects. Diastolic blood pressure increased dose dependently in males, but not in females. These findings, which demonstrate sex differences in nicotine self-administration for doses that are near to the reinforcement threshold, suggest that male and female smokers may respond differently to the changes in nicotine doses available for self-administration.
| S-EPMC4908640 | biostudies-literature
Project description:The discovery of functional cannabinoid receptors 2 (CB2Rs) in brain suggests a potential new therapeutic target for neurological and psychiatric disorders. However, recent findings in experimental animals appear controversial. Here we report that there are significant species differences in CB2R mRNA splicing and expression, protein sequences, and receptor responses to CB2R ligands in mice and rats. Systemic administration of JWH133, a highly selective CB2R agonist, significantly and dose-dependently inhibited intravenous cocaine self-administration under a fixed ratio (FR) schedule of reinforcement in mice, but not in rats. However, under a progressive ratio (PR) schedule of reinforcement, JWH133 significantly increased breakpoint for cocaine self-administration in rats, but decreased it in mice. To explore the possible reasons for these conflicting findings, we examined CB2R gene expression and receptor structure in the brain. We found novel rat-specific CB2C and CB2D mRNA isoforms in addition to CB2A and CB2B mRNA isoforms. In situ hybridization RNAscope assays found higher levels of CB2R mRNA in different brain regions and cell types in mice than in rats. By comparing CB2R-encoding regions, we observed a premature stop codon in the mouse CB2R gene that truncated 13 amino-acid residues including a functional autophosphorylation site in the intracellular C-terminus. These findings suggest that species differences in the splicing and expression of CB2R genes and receptor structures may in part explain the different effects of CB2R-selective ligands on cocaine self-administration in mice and rats.
| S-EPMC4330519 | biostudies-literature
Project description:RationaleMale rats escalate methamphetamine (meth) intake during long-access meth self-administration, show enhanced reinstatement of meth-seeking, and exhibit meth-induced memory impairments. However, the impact of long-access daily meth self-administration on reinstatement and cognitive dysfunction has not been assessed in females, even though clinical studies on meth addiction have shown differences between men and women.ObjectivesThis study determined whether male and freely cycling female rats: (1) escalate meth intake in a 6-h daily-access period relative to 1-h access; (2) show different sensitivity to meth primed reinstatement after short- and long-access conditions; and (3) show deficits in novel object and object in place recognition memory.MethodsMale and female Long-Evans rats self-administered meth in limited (1-h/day) or extended (6-h/day) daily access sessions. After 21 days, meth access was discontinued, and rats entered an abstinence period. On the seventh and 14th days of abstinence, rats were assessed for recognition memory using tests for: (a) novel object recognition memory and (b) object-in-place memory. Rats were tested for reinstatement of meth-seeking following extinction of responding.ResultsFemale rats self-administered more meth and escalated intake faster than males during extended, but not limited, daily access. Both males and females in the extended, but not limited, access groups showed memory deficits on both tasks. Female rats showed greater reinstatement to meth-seeking with lower doses of meth priming injections than males.ConclusionsRelative to males, females were equally susceptible to meth-induced memory deficits but exhibited higher meth intake and greater relapse to meth-seeking.
| S-EPMC3698560 | biostudies-literature
Project description:Background and purposeStudies using intermittent-access drug self-administration show increased motivation to take and seek cocaine and fentanyl, relative to continuous access. In this study, we examined the effects of intermittent- and continuous-access self-administration on heroin intake, patterns of self-administration and cue-induced heroin-seeking, after forced or voluntary abstinence, in male and female rats. We also modelled brain levels of heroin and its active metabolites.Experimental approachRats were trained to self-administer a palatable solution and then heroin (0.075 mg·kg-1 per inf) either continuously (6 h·day-1 ; 10 days) or intermittently (6 h·day-1 ; 5-min access every 30-min; 10 days). Brain levels of heroin and its metabolites were modelled using a pharmacokinetic software. Next, heroin-seeking was assessed after 1 or 21 abstinence days. Between tests, rats underwent either forced or voluntary abstinence. The oestrous cycle was measured using a vaginal smear test.Key resultsIntermittent access exacerbated heroin self-administration and was characterized by a burst-like intake, yielding higher brain peaks of heroin and 6-monoacetylmorphine concentrations. Moreover, intermittent access increased cue-induced heroin-seeking during early, but not late abstinence. Heroin-seeking was higher in females after intermittent, but not continuous access, and this effect was independent of the oestrous cycle.Conclusions and implicationsIntermittent heroin access in rats resembles critical features of heroin use disorder: a self-administration pattern characterized by repeated large doses of heroin and higher relapse vulnerability during early abstinence. This has significant implications for refining animal models of substance use disorder and for better understanding of the neuroadaptations responsible for this disorder.Linked articlesThis article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc.
| S-EPMC9253203 | biostudies-literature
Project description:Cannabis is the most used illicit drug in the United States. With many states passing legislation to permit its recreational use, there is concern that cannabis use among adolescents could increase dramatically in the coming years. Historically, it has been difficult to model real-world cannabis use to investigate the causal relationship between cannabis use in adolescence and behavioral and neurobiological effects in adulthood. To this end, we used a novel volitional vapor administration model to investigate long-term effects of cannabis use during adolescence on the medial prefrontal cortex (mPFC) and mPFC-dependent behaviors in male and female rats. Adolescent (35-55 day old) female rats had significantly higher rates of responding for vaporized Δ9-tetrahydrocannabinol (THC)-dominant cannabis extract (CANTHC) compared to adolescent males. In adulthood (70-110 day old), female, but not male, CANTHC rats also took more trials to reach criterion and made more regressive errors in an automated attentional set-shifting task compared to vehicle rats. Similar set-shifting deficits were observed in males when they were exposed to a non-contingent CANTHC vapor dosing regimen that approximated CANTHC self-administration rates in females. No differences were observed in effort-based decision making in either sex. In the mPFC, female (but not male) CANTHC rats displayed more reactive microglia with no significant changes in myelin basic protein expression or dendritic spine density. Together, these data reveal important sex differences in rates of cannabis vapor self-administration in adolescence that confer enduring alterations to mPFC structure and function. Importantly, female-specific deficits in behavioral flexibility appear to be driven by elevated rates of CANTHC self-administration as opposed to a sex difference in the effects of CANTHC vapor per se.
| S-EPMC9882275 | biostudies-literature
Project description:Cannabis/cannabinoids are widely used for recreational and therapy purposes, but their risks are largely disregarded. However, cannabinoid-associated use disorders and dependence are alarmingly increasing and an effective treatment is lacking. Recently, the growth hormone secretagogue receptor (GHSR1A) antagonism was proposed as a promising mechanism for drug addiction therapy. However, the role of GHS-R1A and its endogenous ligand ghrelin in cannabinoid abuse remains unclear. Therefore, the aim of our study was to investigate whether the GHS-R1A antagonist JMV2959 could reduce the tetrahydrocannabinol (THC)-induced conditioned place preference (CPP) and behavioral stimulation, the WIN55,212-2 intravenous self-administration (IVSA), and the tendency to relapse. Following an ongoing WIN55,212-2 self-administration, JMV2959 3 mg/kg was administered intraperitoneally 20 min before three consequent daily 120-min IVSA sessions under a fixed ratio FR1, which significantly reduced the number of the active lever-pressing, the number of infusions, and the cannabinoid intake. Pretreatment with JMV2959 suggested reduction of the WIN55,212-2-seeking/relapse-like behavior tested in rats on the twelfth day of the forced abstinence period. On the contrary, pretreatment with ghrelin significantly increased the cannabinoid IVSA as well as enhanced the relapse-like behavior. Co-administration of ghrelin with JMV2959 abolished/reduced the significant efficacy of the GHS-R1A antagonist in the cannabinoid IVSA. Pretreatment with JMV2959 significantly and dose-dependently reduced the manifestation of THC-induced CPP. The THC-CPP development was reduced after the simultaneous administration of JMV2959 with THC during conditioning. JMV2959 also significantly reduced the THC-induced behavioral stimulation in the LABORAS cage. Our findings suggest that GHS-R1A importantly participates in the rewarding/reinforcing effects of cannabinoids.
| S-EPMC7957642 | biostudies-literature
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.
| S-EPMC6162178 | biostudies-literature
Project description:Individuals who begin drug use during early adolescence experience more adverse consequences compared to those initiating later, especially if they are female. The mechanisms for these age and gender differences remain obscure, but studies in rodents suggest that psychostimulants may disrupt the normal ontogeny of dopamine and glutamate systems in the prefrontal cortex (PFC). Here, we studied Sprague-Dawley rats of both sexes who began methamphetamine (METH, i.v.) self-administration in adolescence (postnatal [P] day 41) or adulthood (P91). Rats received seven daily 2-h self-administration sessions with METH or saccharin as the reinforcer, followed by 14 daily long access (LgA; 6 h) sessions. After 7 and 14 days of abstinence, novel object (NOR) or object-in-place (OiP) recognition was assessed. PFC and nucleus accumbens were collected 7 days after the final cognitive test and NMDA receptor subunits and dopamine D1 receptor expression was measured. We found that during LgA sessions, adolescent-onset rats escalated METH intake more rapidly than adult-onset rats, with adolescent-onset females earning the most infusions. Adolescent-onset rats with a history of METH self-administration exhibited modest deficits in OiP compared to their adult-onset counterparts, but there was no sex difference and self-administration groups did not differ from naïve control rats. All rats displayed intact novel object recognition memory. We found no group differences in D1 and NMDA receptor expression, suggesting no long-lasting alteration of ontogenetic expression profiles. Our findings suggest that adolescent-onset drug use is more likely to lead to compulsive-like patterns of drug-taking and modest dysfunction in PFC-dependent cognition.
| S-EPMC7307427 | biostudies-literature
Project description:BackgroundStudies using continuous-access drug self-administration showed that cocaine seeking increases during abstinence (incubation of cocaine craving). Recently, studies using intermittent-access self-administration showed increased motivation to self-administer and seek cocaine. We examined whether intermittent cocaine self-administration would potentiate incubation of craving in male and female rats and examined the estrous cycle's role in this incubation.MethodsIn experiment 1, male and female rats self-administered cocaine either continuously (8 hours/day) or intermittently (5 minutes ON, 25 minutes OFF × 16) for 12 days, followed by relapse tests after 2 or 29 days. In experiments 2 and 3, female rats self-administered cocaine intermittently for six, 12, or 18 sessions. In experiment 4, female rats self-administered cocaine continuously followed by relapse tests after 2 or 29 days. In experiments 3 and 4, the estrous cycle was measured using a vaginal smear test.ResultsIncubation of cocaine craving was observed in both sexes after either intermittent or continuous drug self-administration. Independent of access condition and abstinence day, cocaine seeking was higher in female rats than in male rats. In both sexes, cocaine seeking on both abstinence days was higher after intermittent drug access than after continuous drug access. In female rats, incubation of craving after either intermittent or continuous drug access was significantly higher during estrus than during non-estrus; for intermittent drug access, this effect was independent of the training duration.ConclusionsIn both sexes, intermittent cocaine access caused time-independent increases in drug seeking during abstinence. In female rats, the time-dependent increase in drug seeking (incubation) is critically dependent on the estrous cycle phase.
| S-EPMC6534474 | biostudies-literature