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Rationale: The adverse consequences of human addictive drug use could be the result of either addictive drug consumption resulting in punishment (e.g., incarceration) or failure to engage in negative-reinforced behaviors that might compete with drug-maintained behaviors (e.g., contingency management strategies that reset payment amounts for drug free urines). Objective: The goal of the present study was to establish a discrete-trial cocaine-vs-negative reinforcer (SNR) choice procedure where rats were presented with a simplified model of this conflict: choose negative reinforcement (i.e., escape or avoid foot shock) or choose an intravenous (IV) cocaine infusion followed by an inescapable shock. Methods: Responding was maintained in male and female rats by IV cocaine infusions (0.32–1.8 mg/kg/inf) and a SNR (0.1–0.7 mA shock) under a discrete-trial concurrent "choice" schedule during daily sessions. Following parametric reinforcer magnitude and response requirement experiments, the effects of 12 h extended access cocaine self-administration and acute diazepam (0.32–10 mg/kg, IP) pretreatment were determined on cocaine-vs-SNR choice. Results: Negative reinforcement was chosen over all cocaine doses. Lowering shock magnitude or increasing SNR response requirement failed to promote behavioral reallocation towards cocaine. Extended access cocaine self-administration sessions resulted in high daily cocaine intakes but failed to significantly increase cocaine choice in all (19) but one rat. Acute diazepam pretreatment also did not alter choice behavior up to doses that produced behavioral depression. Conclusions: These results suggest that SNRs may be a source of reinforcement that effectively compete with and mitigate maladaptive addictive drug-maintained behaviors in the general population. [ABSTRACT FROM AUTHOR]

Rodent models are useful for understanding the mechanisms that underlie opioid addiction, but most preclinical studies have focused on rewarding and consummatory aspects of opioids without components of dependence-induced escalation of drug taking or seeking. We characterized several opioid-related behaviors in mice using a model of vaporized fentanyl self-administration. Male and female C57BL/6J mice were assigned to short-access (ShA; 1 h, nondependent) or long-access (LgA; 6 h, dependent) fentanyl vapor self-administration and subsequently tested in a battery of behavioral tests, followed by blood collection during withdrawal. Compared with mice in the ShA group, mice in the LgA group escalated their fentanyl intake, were more motivated to work to obtain the drug, exhibited greater hyperalgesia, and exhibited greater signs of naloxone-precipitated withdrawal. Principal component analysis indicated the emergence of two independent behavioral constructs: “intake/motivation” and “hyperalgesia/punished seeking.” In mice in the LgA condition only, “hyperalgesia/punished seeking” was associated with plasma levels of proinflammatory interleukin-17 (IL-17), chemokine (C-C motif) ligand 4 (CCL-4), and tumor necrosis factor α (TNF-α). Overall, the results suggest that extended access to opioids leads to addiction-like behavior, and some constructs that are associated with addiction-like behavior may be associated with levels of the proinflammatory cytokines/chemokines IL-17, TNF-α, and CCL-4 in blood.

RationaleAcute cocaine administration produces an initial rewarding state followed by a dysphoric/anxiogenic "crash."ObjectiveThe objective of this study was to determine whether individual differences in the relative value of cocaine's positive and negative effects would account for variations in subsequent drug self-administration.MethodsThe dual actions of cocaine were assessed using a conditioned place test (where animals formed preferences for environments paired with the immediate rewarding effects of 1.0mg/kg i.v. cocaine or aversions of environments associated with the anxiogenic effects present 15-min postinjection) and a runway test (where animals developed approach-avoidance "retreat" behaviors about entering a goal box associated with cocaine delivery). Ranked scores from these two tests were then correlated with each other and with the escalation in the operant responding of the same subjects observed over 10 days of 1- or 6-h/day access to i.v. (0.4 mg/inj) cocaine self-administration.ResultsLarger place preferences were associated with faster runway start latencies (r s = -0.64), but not with retreat frequency or run times; larger place aversions predicted slower runway start times (r s = 0.62), increased run times (r s = 0.65), and increased retreats (r s = 0.62); response escalation was observed in both the 1- and 6-h self-administration groups and was associated with increased CPPs (r s = 0.58) but not CPAs, as well as with faster run times (r s = -0.60).ConclusionsTogether, these data suggest that animals exhibiting a greater positive than negative response to acute (single daily injections of) cocaine are at the greatest risk for subsequent escalated cocaine self-administration, a presumed indicator of cocaine addiction.

Rationale: Women meet criteria for substance use disorder after fewer years of drug use than men; this accelerated time course, or telescoping effect, has been observed for multiple drugs, including cocaine. Preclinical findings similarly indicate an enhanced vulnerability in females to developing an addiction-like phenotype; however, it is not yet known if this phenotype develops faster in females versus males. Objectives: The goal of this study was to determine using a rat model whether two key features of addiction in humans, an enhanced motivation for cocaine and compulsive use, emerge sooner during withdrawal from extended access cocaine self-administration in females versus males. Methods: Motivation for cocaine, as assessed under a progressive-ratio reinforcement schedule, was determined prior to and following extended access cocaine self-administration (24 h/day, 96 infusions/day, 10 days) and after 7, 14, or 60 days of withdrawal. Compulsive use, or use despite punishment, was evaluated once progressive-ratio responding stabilized by adding histamine, an aversive stimulus, to the cocaine solutions. Results: Motivation for cocaine increased from baseline sooner during withdrawal in females than males (at 7 versus 14 days); motivation was also highest in the 60-day group. Histamine decreased progressive-ratio responding for cocaine in both sexes, although effects were greatest in males in the 7-day withdrawal group; males reached the female-level of resistance to histamine punishment by 14 days of withdrawal. Conclusions: Female rats developed addition-like features sooner during withdrawal than male rats indicating that the telescoping effect observed in humans is biologically based. Additionally, like drug-seeking/craving, motivation for cocaine and measures of compulsive use incubate over withdrawal. [ABSTRACT FROM AUTHOR]

Rationale: The development of addiction is accompanied by a shift in the mechanisms motivating cocaine use from nucleus accumbens (NAc) dopamine D1 receptor (D1R) signaling to glutamate AMPA-kainate receptor (AMPA-R) signaling. Objective: Here, we determined whether similar shifts occur for NAc-D2R signaling and following systemic manipulation of D1R, D2R, and AMPA-R signaling. Methods: Male rats were given short-access (20 infusions/day) or extended-access to cocaine (24 h/day, 96 infusions/day, 10 days). Motivation for cocaine was assessed following 14 days of abstinence using a progressive-ratio schedule. Once responding stabilized, the effects of NAc-D2R antagonism (eticlopride; 0–10.0 μg/side) and systemic D1R (SCH-23390; 0–1.0 mg/kg), D2R (eticlopride; 0–0.1 mg/kg), and AMPA-R (CNQX; 0–1.5 mg/kg) antagonism, and NAc-dopamine-R gene expression (Drd1/2/3) were examined. Results: Motivation for cocaine was markedly higher in the extended- versus short-access group confirming the development of an addiction-like phenotype in the extended-access group. NAc-infused eticlopride decreased motivation for cocaine in both the short- and extended-access groups although low doses (0.1–0.3 μg) were more effective in the short-access group and high doses (3–10 μg/side) tended to be more effective in the extended-access group. Systemic administration of eticlopride (0.1 mg/kg) was more effective in the extended-access group, and systemic administration of CNQX was effective in the extended- but not short-access group. NAc-Drd2 expression was decreased in both the short- and extended-access groups. Conclusion: These findings indicate that in contrast to NAc-D1R, D2R remain critical for motivating cocaine use with the development of an addiction-like phenotype. These findings also indicate that shifts in the mechanisms motivating cocaine use impact the response to both site-specific and systemic pharmacological treatment. [ABSTRACT FROM AUTHOR]

Hamilton Public Library's northernmost rural branch in Ontario's Greater Toronto and Hamilton Area (GTHA) leveraged technology to offer customers Extended Access to the library, a valued community resource. Using a unique model of virtual assistance to support customers remotely, customers connect with information staff at the system's Central Library, when needed. Library hours increased from 17 to 60 hours per week: customer visits and programming participation subsequently increased. This successful pilot encouraged a second Extended Access Branch, with early data suggesting similar positive results. Now, with careful planning and attention to the pilot principles, additional locations are planned. [ABSTRACT FROM AUTHOR]

Synthetic cathinones are designer psychostimulants that are derivatives of the natural alkaloid cathinone, and produce effects similar to more traditional illicit stimulants such as cocaine and methamphetamine. The pyrovalerone cathinones methylenedioxypyrovalerone (MDPV) and α-pyrrolidinopropiophenone (α-PPP) exert their effects via inhibition of presynaptic dopamine and norepinephrine reuptake transporters. While the reinforcing effects of MDPV in rodents are well-established, very few studies have examined self-administration patterns of α-PPP. Users of synthetic cathinones often engage in repeated binge episodes of drug intake that last several days. We therefore sought to determine the reinforcing effects of three doses of α-PPP (0.05, 0.1 and 0.32 mg/kg/infusion) under conditions of prolonged binge-like access conditions, with three 96-h periods of drug access interspersed with 72 h of abstinence. MDPV (0.05 mg/kg/infusion) was used as a comparison drug. Our results show that both MDPV and the high (0.32 mg/kg/infusion) dose of α-PPP are readily self-administered at high levels across all three extended access periods, whereas lower doses of α-PPP produce variable and less robust levels of self-administration. These results indicate that higher doses of α-PPP have reinforcing effects under conditions of extended access, suggesting the potential for abuse and a need for consideration in drug control policies. [ABSTRACT FROM AUTHOR]

Women become addicted sooner after initiating cocaine use as compared to men. Preclinical studies reveal a similar vulnerability in females, with findings from ovariectomized rats suggesting that estradiol mediates the enhanced vulnerability. However, since ovariectomy depletes not only estradiol, but all ovarian hormones, its role in a physiological context is not clear. Thus, the goal of this study was to determine the role of estradiol in the development of an addiction-like phenotype in ovary-intact females treated chronically with the selective estrogen receptor (ER) modulator tamoxifen. We hypothesized that tamoxifen, by antagonizing ERs, would block the development of an addiction-like phenotype as defined by an enhanced motivation for cocaine (assessed under a progressive-ratio schedule), and a heightened vulnerability to relapse (assessed under an extinction/cue-induced reinstatement procedure). Effects were examined following extended access cocaine self-administration (24-h/day; 4-discrete trials/h; 1.5 mg/kg/infusion) and 14-days of abstinence, conditions optimized for inducing an addiction-like phenotype. As predicted, motivation for cocaine was increased following extended-access self-administration and protracted abstinence in the vehicle (sesame oil) and no-injection control groups, but not in the tamoxifen group indicating that ER signaling is critical for the development of this feature of an addiction-like phenotype. Surprisingly, the increase in motivation for cocaine following abstinence was also attenuated in the vehicle group as compared to no-injection controls suggesting that oil/injections also affected its development. Contrary to our hypothesis, tamoxifen did not decrease vulnerability to relapse as this group responded at similar levels during initial extinction sessions and cue-induced reinstatement testing as compared to controls. Tamoxifen did, however, impair extinction learning as this group took longer to extinguish as compared to controls. Taken together, these findings indicate that estradiol is critical for the extinction of drug-associated cues and the development of motivational features of addiction.

Women become addicted sooner after initiating cocaine use as compared to men. Preclinical studies reveal a similar vulnerability in females, with findings from ovariectomized rats suggesting that estradiol mediates the enhanced vulnerability. However, since ovariectomy depletes not only estradiol, but all ovarian hormones, its role in a physiological context is not clear. Thus, the goal of this study was to determine the role of estradiol in the development of an addiction-like phenotype in ovary-intact females treated chronically with the selective estrogen receptor (ER) modulator tamoxifen. We hypothesized that tamoxifen, by antagonizing ERs, would block the development of an addiction-like phenotype as defined by an enhanced motivation for cocaine (assessed under a progressive-ratio schedule), and a heightened vulnerability to relapse (assessed under an extinction/cue-induced reinstatement procedure). Effects were examined following extended access cocaine self-administration (24-h/day; 4-discrete trials/h; 1.5 mg/kg/infusion) and 14-days of abstinence, conditions optimized for inducing an addiction-like phenotype. As predicted, motivation for cocaine was increased following extended-access self-administration and protracted abstinence in the vehicle (sesame oil) and no-injection control groups, but not in the tamoxifen group indicating that ER signaling is critical for the development of this feature of an addiction-like phenotype. Surprisingly, the increase in motivation for cocaine following abstinence was also attenuated in the vehicle group as compared to no-injection controls suggesting that oil/injections also affected its development. Contrary to our hypothesis, tamoxifen did not decrease vulnerability to relapse as this group responded at similar levels during initial extinction sessions and cue-induced reinstatement testing as compared to controls. Tamoxifen did, however, impair extinction learning as this group took longer to extinguish as compared to controls. Taken together, these findings indicate that estradiol is critical for the extinction of drug-associated cues and the development of motivational features of addiction. [ABSTRACT FROM AUTHOR]

Behavioral economics is a powerful, translational approach for measuring drug demand in both humans and animals. Here, we asked if demand for cocaine in rats with limited drug experience could be used to identify individuals most at risk of expressing an addiction phenotype following either long‐ or intermittent access self‐administration schedules, both of which model the transition to uncontrolled drug‐seeking. Because the orexin‐1 receptor antagonist SB‐334867 (SB) is particularly effective at reducing drug‐seeking in highly motivated individuals, we also asked whether demand measured after prolonged drug experience could predict SB efficacy. Demand elasticity (α) measured immediately following acquisition of cocaine self‐administration ('baseline α') was positively correlated with α assessed after 2w of long‐ or intermittent access. Baseline α also predicted the magnitude of compulsive responding for cocaine, drug‐seeking in initial abstinence and cued reinstatement following long‐, intermittent‐ or standard short access. When demand was measured after these differential access conditions, α predicted the same addiction endophenotypes predicted by baseline α, as well as primed reinstatement and the emergence of negative emotional mood behavior following abstinence. α also predicted the efficacy of SB, such that high demand rats showed greater reductions in motivation for cocaine following SB compared to low demand rats. Together, these findings indicate that α might serve as a behavioral biomarker to predict individuals most likely to progress from controlled to uncontrolled drug use, and to identify individuals most likely to benefit from orexin‐based therapies for the treatment of addiction. [ABSTRACT FROM AUTHOR]

Rationale: Epidemiological data suggest that menthol may increase vulnerability to cigarette/nicotine use and relapse. While menthol's sensory properties are often attributed as the underlying cause of the enhanced vulnerability, an alternative possibility is that they are mediated via pharmacological interactions with nicotine. Objective: This study addressed the possibility that menthol enhances nicotine intake and relapse vulnerability via pharmacological interactions with nicotine using a concurrent intravenous menthol/nicotine self-administration procedure. Methods: Following acquisition, adolescent rats were given 23-h/day access to nicotine (0.01 mg/kg/infusion), nicotine plus menthol (0.16, 0.32, or 0.64 mg/kg/infusion), or menthol alone (0.16, 0.32, 0.64 mg/kg/infusion) for a total of 10 days. Nicotine-seeking was assessed using an extinction/cue-induced reinstatement procedure following 10 days of forced abstinence. We also assessed the effect of menthol (0.32 mg/kg/infusion) on progressive ratio responding for nicotine (0.01 mg/kg/infusion). Results: Menthol decreased PR responding for nicotine but did not affect self-administration under extended access conditions. The low dose of menthol tended to decrease subsequent extinction responding, and was not different from menthol alone, whereas the high dose decreased reinstatement responding. Although not significant, the highest levels of extinction responding were observed in a minority of rats in the moderate and high menthol–nicotine groups; rats in these groups also took longer to extinguish. Conclusions: Taken together, these results demonstrate that pharmacological interactions of menthol with nicotine reduce, rather than increase, nicotine's reinforcing effects and some measures of relapse vulnerability. Importantly, however, moderate and high menthol doses may increase some aspects of relapse vulnerability in a minority of individuals. [ABSTRACT FROM AUTHOR]

Background: Cocaine use disorder is characterized by compulsive drug-seeking that persists long into abstinence. Work using rodent models of cocaine addiction has found evidence for reversal learning deficits 21 days after non-contingent cocaine administration and 60 days after self-administration. Here we sought to determine if a deficit in reversal learning is present 3-4 weeks after cessation of cocaine self-administration, when relapse to cocaine-seeking is robust. Conversely, we hypothesized that reversal learning training would protect against relapse, similar to other forms of environmental enrichment.Methods: Male rats underwent short access (ShA, 2 h/10d) or long access (LgA, 1 h/7d then 6 h/10d) cocaine self-administration, followed by 21-29 days of abstinence. During abstinence, a subset of rats underwent training in a plus-maze that required an egocentric strategy to earn a sucrose reward. Following response acquisition and retention, the ability to reverse the spatial navigation strategy was tested.Results: Total trials to criteria and total errors made did not differ between the groups during response acquisition, retention, or reversal. On the first reversal test, ShA rats performed better than LgA and control rats. ShA rats' performance worsened over time. There were no effects of cognitive training or length of cocaine access on context-primed relapse of cocaine-seeking.Conclusions: The present data indicate that perhaps LgA cocaine self-administration does not produce adaptations to regions mediating context-primed relapse as it does for cocaine and cocaine-associated cue-induced reinstatement of drug-seeking. A time-dependent deficit in reversal learning was found only in ShA rats. Reversal learning training did not protect against cocaine relapse. [ABSTRACT FROM AUTHOR]

In rats trained to self-administer methamphetamine, extinction responding in the presence of drug-associated contextual and discrete cues progressively increases after withdrawal (incubation of methamphetamine craving). The conditioning factors underlying this incubation are unknown. Here, we studied incubation of methamphetamine craving under different experimental conditions to identify factors contributing to this incubation. We also determined whether the rats' response to methamphetamine priming incubates after withdrawal. We trained rats to self-administer methamphetamine in a distinct context (context A) for 14 days (6 hours/day). Lever presses were paired with a discrete light cue. We then tested groups of rats in context A or a different non-drug context (context B) after 1 day, 1 week or 1 month for extinction responding with or without the discrete cue. Subsequently, we tested the rats for reinstatement of drug seeking induced by exposure to contextual, discrete cue, or drug priming (0, 0.25 and 0.5 mg/kg). Operant responding in the extinction sessions in contexts A or B was higher after 1 week and 1 month of withdrawal than after 1 day; this effect was context-independent. Independent of the withdrawal period, operant responding in the extinction sessions was higher when responding led to contingent delivery of the discrete cue. After extinction, discrete cue-induced reinstatement, but not context- or drug priming-induced reinstatement, progressively increased after withdrawal. Together, incubation of methamphetamine craving, as assessed in extinction tests, is primarily mediated by time-dependent increases in non-reinforced operant responding, and this effect is potentiated by exposure to discrete, but not contextual, cues. [ABSTRACT FROM AUTHOR]

Background Cue-induced methamphetamine craving increases after prolonged forced (experimenter-imposed) abstinence from the drug (incubation of methamphetamine craving). Here, we determined whether this incubation phenomenon would occur under conditions that promote voluntary (self-imposed) abstinence. We also determined the effect of the novel metabotropic glutamate receptor 2 positive allosteric modulator, AZD8529, on incubation of methamphetamine craving after forced or voluntary abstinence. Methods We trained rats to self-administer palatable food (6 sessions) and then to self-administer methamphetamine under two conditions: 12 sessions (9 hours/day) or 50 sessions (3 hours/day). We then assessed cue-induced methamphetamine seeking in extinction tests after 1 or 21 abstinence days. Between tests, the rats underwent either forced abstinence (no access to the food- or drug-paired levers) or voluntary abstinence (achieved via a discrete choice procedure between methamphetamine and palatable food; 20 trials per day) for 19 days. We also determined the effect of subcutaneous injections of AZD8529 (20 and 40 mg/kg) on cue-induced methamphetamine seeking 1 day or 21 days after forced or voluntary abstinence. Results Under both training and abstinence conditions, cue-induced methamphetamine seeking in the extinction tests was higher after 21 abstinence days than after 1 day (incubation of methamphetamine craving). AZD8529 decreased cue-induced methamphetamine seeking on day 21 but not day 1 of forced or voluntary abstinence. Conclusions We introduce a novel animal model to study incubation of drug craving and cue-induced drug seeking after prolonged voluntary abstinence, mimicking the human condition of relapse after successful contingency management treatment. Our data suggest that positive allosteric modulators of metabotropic glutamate receptor 2 should be considered for relapse prevention. [ABSTRACT FROM AUTHOR]

Recent studies have shown that when given a mutually exclusive choice between cocaine and palatable foods, most rats prefer the non-drug rewards over cocaine. Here, we used a discrete choice procedure to assess whether palatable food preference generalizes to rats with a history of limited (3 hours/day) or extended (6 or 9 hours/day) access to methamphetamine self-administration. On different daily sessions, we trained rats to lever-press for either methamphetamine (0.1-0.2 mg/kg/infusion) or palatable food (five pellets per reward delivery) for several weeks; regular food was freely available. We then assessed food-methamphetamine preference either during training, after priming methamphetamine injections (0.5-1.0 mg/kg), following a satiety manipulation (palatable food exposure in the home cage) or after 21 days of withdrawal from methamphetamine. We also assessed progressive ratio responding for palatable food and methamphetamine. We found that independent of the daily drug access conditions and the withdrawal period, the rats strongly preferred the palatable food over methamphetamine, even when they were given free access to the palatable food in the home cage. Intake of methamphetamine and progressive ratio responding for the drug, both of which increased or escalated over time, did not predict preference in the discrete choice test. Results demonstrate that most rats strongly prefer palatable food pellets over intravenous methamphetamine, confirming previous studies using discrete choice procedures with intravenous cocaine. Results also demonstrate that escalation of drug self-administration, a popular model of compulsive drug use, is not associated with a cardinal feature of human addiction of reduced behavioral responding for non-drug rewards. [ABSTRACT FROM AUTHOR]

Background While dopamine signaling in the nucleus accumbens (NAc) plays a well-established role in motivating cocaine use in early nonaddicted stages, recent evidence suggests that other signaling pathways may be critical once addiction has developed. Given the importance of glutamatergic signaling in the NAc for drug seeking and relapse, here we examined its role in motivating cocaine self-administration under conditions known to produce either a nonaddicted or an addicted phenotype. Methods Following acquisition, male and female Sprague Dawley rats were given either short access (three fixed-ratio 1 sessions, 20 infusions/day) or extended 24-hour access (10 days; 4 trials/hour; up to 96 infusions/day) to cocaine. Following a 14-day abstinence period, motivation for cocaine was assessed under a progressive-ratio schedule, and once stable, the effects of intra-NAc infusions of the glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate/kainate receptor antagonist CNQX (0, .01, .03, .1 μg/side) were determined. As an additional measure for the development of an addicted phenotype, separate groups of rats were screened under an extinction/cue-induced reinstatement procedure following abstinence from short-access versus extended-access self-administration. Results Motivation for cocaine and levels of extinction and reinstatement responding were markedly higher following extended-access versus short-access self-administration, confirming the development of an addicted phenotype in the extended-access group. CNQX dose-dependently reduced motivation for cocaine in the extended-access group but was without effect in the short-access group. Conclusions These results suggest that the role of glutamatergic signaling in the NAc, though not essential for motivating cocaine use in nonaddicted stages, becomes critical once addiction has developed. [ABSTRACT FROM AUTHOR]

Background: Although considerable evidence implicates dopamine D1-receptor signaling in the nucleus accumbens in motivation for cocaine during early stages of addiction, less is known with regard to its role after the development of addiction. Here, we examined its role in the development of an addicted phenotype in intact male and female rats, and in female rats that were either resistant or vulnerable to developing this phenotype. Methods: Intact males, females, and ovariectomized (OVX) females with and without estradiol (vulnerable, OVX+E; resistant, OVX+Veh) were given either short access (ShA) (three fixed-ratio 1 sessions, maximum of 20 infusions) or 24-hour extended access (ExA) to cocaine for 10 days (4 trials/hour). Motivation for cocaine was assessed after a 14-day abstinence period with a progressive-ratio schedule. Once responding stabilized, the effects of intra-accumbens infusion of the D1-receptor antagonist, SCH-23390 (0, .3, 1.0, 3.0 µg), were examined. Results: Motivation for cocaine was markedly higher after abstinence from ExA versus ShA self-administration in intact males and females, indicating the development of an addicted phenotype in these groups. Motivation for cocaine was also higher than ShA control subjects in OVX+E but not OVX+Veh females after ExA self-administration, confirming the categorization of these groups as vulnerable versus resistant. After ExA self-administration, intact males and females and OVX+E but not OVX+Veh females were less sensitive to the effects of D1-receptor antagonism as compared with their ShA counterparts. Conclusions: These results suggest that the role of D1-receptor signaling, although critical in “nonaddicted” stages, becomes diminished once addiction has developed. [ABSTRACT FROM AUTHOR]

Reports of abuse and toxic effects of synthetic cathinones, frequently sold as 'bath salts' or 'legal highs', have increased dramatically in recent years. One of the most widely used synthetic cathinones is 3,4-methylenedioxypyrovalerone (MDPV). The current study evaluated the abuse potential of MDPV by assessing its ability to support intravenous self-administration and to lower thresholds for intracranial self-stimulation (ICSS) in rats. In the first experiment, the rats were trained to intravenously self-administer MDPV in daily 2-hour sessions for 10 days at doses of 0.05, 0.1 or 0.2 mg/kg per infusion. The rats were then allowed to self-administer MDPV under a progressive ratio (PR) schedule of reinforcement. Next, the rats self-administered MDPV for an additional 10 days under short access (ShA; 2 hours/day) or long access (LgA; 6 hours/day) conditions to assess escalation of intake. A separate group of rats underwent the same procedures, with the exception of self-administering methamphetamine (0.05 mg/kg per infusion) instead of MDPV. In the second experiment, the effects of MDPV on ICSS thresholds following acute administration (0.1, 0.5, 1 and 2 mg/kg, i.p.) were assessed. MDPV maintained self-administration across all doses tested. A positive relationship between MDPV dose and breakpoints for reinforcement under PR conditions was observed. LgA conditions led to escalation of drug intake at 0.1 and 0.2 mg/kg doses, and rats self-administering methamphetamine showed similar patterns of escalation. Finally, MDPV significantly lowered ICSS thresholds at all doses tested. Together, these findings indicate that MDPV has reinforcing properties and activates brain reward circuitry, suggesting a potential for abuse and addiction in humans. [ABSTRACT FROM AUTHOR]

Abstract: Rationale: Increased appetite and weight gain after cessation are deterrents for quitting smoking. Pharmacotherapies that can reduce this weight gain in ex-smokers would be invaluable, and yet are not well studied in this context. Objective: To examine the effects of extended daily exposure to intravenous cytisine, an alpha4beta2 nAChR partial agonist used for smoking cessation in some European countries, on body weight and patterns of food intake in rats. Methods: In the first experiment, programmed infusions of cytisine were administered over 15h per day. Food intake, meal patterns, and weight change were examined relative to a vehicle-infused group during treatment, and in a post-cytisine phase. The second experiment examined the effects of cytisine on food intake, meal patterns, and weight change when substituted for nicotine in a self-administration protocol. Rats self-administered nicotine and cytisine during alternating four day periods, and changes in body weight, drug infusions, and meal patterns were compared between drugs and during an extinction phase. Results: In the first experiment, cytisine-treated rats ate less and gained less weight than those that received the vehicle. This occurred primarily by a reduced frequency of meals. In the 12day post-cytisine phase, animals maintained a lower body weight relative to controls throughout. In the second experiment, total pellet intake increased during cytisine substitution relative to nicotine and animals self-administered cytisine significantly less than nicotine. However, cytisine substitution maintained decreases in food intake and weight gain compared to baseline via decreases in total pellet intake and meal size. Conclusion: Cytisine administration results in decreased weight gain and changes in meal patterns dependent upon mode and pattern of administration and a previous history of nicotine administration. [Copyright &y& Elsevier]

Rationale: Adolescence marks a period of increased vulnerability to the development of substance use disorders. High sweet preference is a genetically mediated behavioral trait that also predicts vulnerability to substances of abuse. Previous research has shown that while adolescent rats selectively bred for high (HiS) saccharin intake acquire cocaine self-administration at the same rate as adult HiS rats, adolescent rats bred for low saccharin intake (LoS) acquire cocaine self-administration faster than adult LoS rats. Objectives: This study was conducted to investigate the interaction of the addiction vulnerability factors of peri-adolescence and saccharin preference on cocaine intake using an animal model of escalation of cocaine consumption over 6-h/day sessions. Methods: Peri -adolescent and adult HiS and LoS female rats self-administered i.v. cocaine (0.4 mg/kg/inf) during short-access (2-h/day) sessions for 2 days. Next, a long-access (6-h/day) period (LgA) commenced and lasted 16 days. Following LgA, session length was returned to 2-h/day for a second short access phase. Results: LoS peri-adolescent rats escalated cocaine intake over the LgA period and consumed more drug than LoS adult rats; however, peri-adolescent and adult HiS rats consumed similar amounts of cocaine during this period. Additionally, adult HiS rats self-administered more cocaine than adult LoS rats during the LgA period, while there was no phenotypic difference between the rat lines during peri-adolescence for the LgA period. During the first short-access phase, peri-adolescent rats self-administered more cocaine than adult rats. Conclusions: These results emphasize the importance of adolescent drug abuse prevention by illustrating that phenotypic protection from addiction may not be expressed until adulthood. [ABSTRACT FROM AUTHOR]

Abstract: Despite increasing rates of opioid abuse by human adolescents, few laboratory experiments address adolescent vulnerability to opiates. We examined intravenous morphine self-administration after adolescent- vs. adult-onset, followed by extinction and cue-induced reinstatement. Adolescent male Sprague–Dawley rats [postnatal day (P) 35 at start] and adults (P91) acquired lever pressing maintained by 0.375 mg/kg/infusion morphine on a fixed ratio one schedule of reinforcement. Subjects were subsequently divided into short or long daily access conditions (ShAcc, 1-h vs. LgAcc, 8-h; 18 sessions). After extinction, cue-induced reinstatement was recorded over 1 h. During the first six 1-h acquisition sessions and continuing throughout ShAcc conditions, adolescent-onset rats self-administered less morphine than adults, an effect commonly interpreted as higher drug sensitivity. In contrast under LgAcc conditions, escalation of morphine intake was similar across ages. Extinction of drug-seeking was similar across ages, although rats from LgAcc conditions pressed more than ShAcc conditions. Notably, cue-induced reinstatement was less robust in rats that began morphine self-administration during adolescence vs. adulthood. Although increased sensitivity of younger rats to morphine reinforcement under ShAcc conditions might help explain opioid abuse by human adolescents, lower rates of reinstatement in younger rats might suggest that adolescent development includes some protective factors that dampen the long-term impact of early drug intake. [Copyright &y& Elsevier]

Background: Chronic abuse of methamphetamine produces deficits in hippocampal function, perhaps by altering hippocampal neurogenesis and plasticity. We examined how intravenous methamphetamine self-administration modulates active division, proliferation of late progenitors, differentiation, maturation, survival, and mature phenotype of hippocampal subgranular zone (SGZ) progenitors. Methods: Adult male Wistar rats were given access to methamphetamine 1 hour twice weekly (intermittent short), 1 hour daily (short), or 6 hours daily (long). Rats received one intraperitoneal injection of bromodeoxyuridine (BrdU) to label progenitors in the synthesis (S) phase, and 28-day-old surviving BrdU-immunoreactive (IR) cells were quantified. Ki-67, doublecortin (DCX), and activated caspase-3 (AC-3) were used to visualize and quantify proliferating, differentiating, maturing, and apoptotic cells. Terminal corticosterone was measured to determine changes in adrenal steroids. Results: Intermittent access to methamphetamine increased Ki-67 and DCX-IR cells, but opposing effects on late progenitors and postmitotic neurons resulted in no overall change in neurogenesis. Daily access to methamphetamine decreased all studied aspects of neurogenesis and reduced hippocampal granule neurons and volume, changes that likely are mediated by decreased proliferative and neurogenic capacity of the SGZ. Furthermore, methamphetamine self-administration relative to the amount of methamphetamine intake produced a biphasic effect on hippocampal apoptosis and reduced corticosterone levels. Conclusions: Intermittent (occasional access) and daily (limited and extended access) self-administration of methamphetamine impact different aspects of neurogenesis, the former producing initial pro-proliferative effects and the latter producing downregulating effects. These findings suggest that altered hippocampal integrity by even modest doses of methamphetamine could account for pronounced pathology linked to methamphetamine abuse. [Copyright &y& Elsevier]

Rationale: The prevalence of cocaine use in opioid-dependent individuals is reportedly high, and the associated negative health and social consequences are severe and well documented. Sensitization of the reinforcing effects of cocaine has been demonstrated following noncontingent opioid exposure in animals; however, no preclinical studies have investigated the impact of opioid self-administration on cocaine's reinforcing effects. Objective: Experiments were designed to investigate whether access to heroin self-administration altered the subsequent reinforcing effects of cocaine. Methods: Baseline responding for cocaine under a progressive ratio schedulewas first established. Heroin was then selfadministered under a 24-h discrete-trials procedure (DT5; access to heroin five times per hour). Subsequently, cocainemaintained responding was reassessed. Results: Here we demonstrate that 10 days of DT5 heroin self-administration (50 μg/kg per infusion) resulted in an increase in cocaine's reinforcing effects at several doses across the cocaine dose-effect curve (0.38-3.0 mg/kg per infusion). These increases were relatively long lasting, exceeding the time course of a mild withdrawal syndrome. Conclusions: The DT5x10-day history of heroin self-administration resulted in an upward shift in the cocaine dose--effect curve, suggesting that DT5 heroin self-administration produced an increase in potency and sensitization of the maximal effectiveness with which cocaine functions as a reinforcer. The present experiments contribute to a growing amount of preclinical evidence suggesting an impact of opioid exposure on the reinforcing effects of cocaine, which may partially explain the high incidence of cocaine use in opioid-dependent individuals. [ABSTRACT FROM AUTHOR]

Rationale. Most nicotine self-administration (NSA) studies in rats are performed under limited-access conditions. Few studies have examined the relationship between nicotine dependence and NSA. Objectives. To determine how NSA access conditions affect NSA and the duration of nicotine dependence during abstinence, as reflected in somatic signs of withdrawal precipitated by administration of the nicotinic receptor antagonist mecamylamine. Methods. The effects of different NSA access conditions (zero, 1 h/5 days, 1 h/7 days and 6 h/7 days per week) and non-contingent nicotine administration on NSA and somatic signs were examined. Results. Daily NSA access (30 days) resulted in spontaneous and mecamylamine-induced somatic signs. Both daily access groups (1 h/day and 6 h/day, 7 days/week) exhibited spontaneous somatic signs on day 25 of NSA (17 h post-NSA) and sensitivity to mecamylamine up to 2 and 4 weeks of abstinence, respectively. In contrast, the 1 h/day, 5 days/week access group exhibited mecamylamine-induced somatic signs only up to 1 week of abstinence. NSA behavior was stable in rats with 1 h/day 5 days/week and 1 h/day 7 days/week access, but decreased from initially high rates in the 6 h/day 7 days/week access group, and decreased in rats receiving non-contingent nicotine. In contrast, extended cocaine self-administration access resulted in a gradual escalation in cocaine intake. Conclusion. There was no escalation in nicotine intake with extended access conditions, unlike cocaine self-administration. Nevertheless, daily nicotine self-administration seven days per week, for either 1 or 6 h per day, was sufficient to induce long-lasting adaptations in nicotinic acetylcholine receptor activity reflected in spontaneous and antagonist-precipitated somatic signs of withdrawal, possibly reflecting aspects of nicotine dependence. [ABSTRACT FROM AUTHOR]

An increasing emphasis has been placed on the development and use of animal models of addiction that capture defining features of human drug addiction, including escalation/binge drug use, enhanced motivation for the drug, preference for the drug over other reward options, use despite negative consequences, and enhanced drug-seeking/relapse vulnerability. The need to examine behavior in both males and females has also become apparent given evidence demonstrating that the addiction process occurs differently in males and females. This review discusses the procedures that are used to model features of addiction in animals, as well as factors that influence their development. Individual differences are also discussed, with a particular focus on sex differences. While no one procedure consistently produces all characteristics, different models have been developed to focus on certain characteristics. A history of escalating/binge patterns of use appears to be critical for producing other features characteristic of addiction, including an enhanced motivation for the drug, enhanced drug seeking, and use despite negative consequences. These characteristics tend to emerge over abstinence, and appear to increase rather than decrease in magnitude over time. In females, these characteristics develop sooner during abstinence and/or following less drug exposure as compared to males, and for psychostimulant addiction, may require estradiol. Although preference for the drug over other reward options has been demonstrated in non-human primates, it has been more difficult to establish in rats. Future research is needed to define the parameters that optimally induce each of these features of addiction in the majority of animals. Such models are essential for advancing our understanding of human drug addiction and its treatment in men and women., (Copyright © 2017 Elsevier Inc. All rights reserved.)