The effect of corticosterone on the acquisition of Pavlovian conditioned approach behavior is dependent on sex and vendor.

Cues in the environment become predictors of biologically relevant stimuli, such as food, through associative learning. These cues can not only act as predictors but can also be attributed with incentive motivational value and gain control over behavior. When a cue is imbued with incentive salience, it attains the ability to elicit maladaptive behaviors characteristic of psychopathology. We can capture the propensity to attribute incentive salience to a reward cue in rats using a Pavlovian conditioned approach paradigm, in which the presentation of a discrete lever-cue is followed by the delivery of a food reward. Upon learning the cue-reward relationship, some rats, termed sign-trackers, develop a conditioned response directed towards the lever-cue; whereas others, termed goal-trackers, approach the food cup upon lever-cue presentation. Here, we assessed the effects of systemic corticosterone (CORT) on the acquisition and expression of sign- and goal-tracking behaviors in male and female rats, while examining the role of the vendor (Charles River or Taconic) from which the rats originated in these effects. Male and female rats from Charles River had a greater tendency to sign-track than those from Taconic. Administration of CORT enhanced the acquisition of sign-tracking behavior in males from Charles River and females from both vendors. Conversely, administration of CORT had no effect on the expression of the conditioned response. These findings demonstrate a role for CORT in cue-reward learning and suggest that inherent tendencies towards sign- or goal-tracking may interact with this physiological mediator of motivated behavior. Highlights: Male and female rats from Charles River exhibit more sign-tracking relative to those from Taconic.Corticosterone increases the acquisition of sign-tracking in male rats from Charles River.Corticosterone increases the acquisition of sign-tracking in female rats, regardless of vendor.There is no effect of corticosterone on the expression of sign-tracking behavior in either male or female rats.

Sex Differences in Response-Contingent Cannabis Vapor Administration During Adolescence Mediate Enduring Effects on Behavioral Flexibility and Prefrontal Microglia Activation in Rats.

Introduction: 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. Materials and Methods: We used a response-contingent 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. Results: Adolescent (35- to 55-day-old) female rats had significantly higher rates of responding for vaporized Δ9-tetrahydrocannabinol (THC)-dominant cannabis extract (CANTHC) compared with adolescent males. In adulthood (70-110 days 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 with vehicle rats, thereby indicating sex differences in behavioral flexibility impairments. Notably, sex-treatment interactions were not observed when rats of each sex were exposed to a noncontingent CANTHC vapor dosing regimen that approximated CANTHC vapor deliveries earned by 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 changes in myelin basic protein expression or dendritic spine density. Conclusion: Altogether, these data reveal important sex differences in rates of responding for CANTHC vapor in adolescence that may confer enduring alterations to mPFC structure and function and suggest that there may be subtle differences in the effects of response-contingent versus noncontingent cannabis exposure that should be systematically examined in future studies.

Sex differences in adolescent cannabis vapor self-administration mediate enduring effects on behavioral flexibility and prefrontal microglia activation in rats.

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.

Effects of the GluN2B antagonist, Ro 25-6981, on extinction consolidation following adolescent- or adult-onset methamphetamine self-administration in male and female rats.

Previous work suggests adolescent rats have deficient extinction consolidation relative to adults. Although the mechanisms underlying this age difference are currently unknown, studies in adult rats have implicated GluN2B-containing N-methyl-d-aspartate (NMDA) receptor function in extinction consolidation of drug-associated memory. Importantly, GluN2B neurotransmission emerges during adolescent development, and drugs of abuse during adolescence may delay the development of extinction consolidation by disrupting the ontogeny of GluN2B function. Here, we trained Sprague-Dawley rats of both sexes to self-administer methamphetamine [METH, 0.1 mg/kg/infusion intravenous (i.v.)] beginning during adolescence [postnatal (P) day 41] or adulthood (P91). Rats were given short access (2 h) to self-administer METH in seven daily sessions followed by 14 sessions with long access (6 h). Subsequently, rats underwent four daily 30-minute extinction sessions with immediate postsession injections of either a GluN2B antagonist [Ro25-6981; 6 mg/kg, intraperitoneal (i.p.)] or a vehicle solution. After four daily 2-h extinction sessions, a priming injection (1 mg/kg METH, i.p.) was given prior to a final 2-h reinstatement session. During LgA, adolescent-onset rats earn more METH than adult-onset rats and display greater drug-loading behavior. Rats reduced their drug-seeking behavior across the extinction sessions, with no significant group differences. Rats reinstated drug-seeking following the METH-priming injection, with females displaying greater reinstatement than males. These results do not support our a priori hypothesis that adolescent-onset METH use disrupts the ontogeny of GluN2B transmission and contributes to age-of-onset differences in extinction of METH-seeking. However, our findings suggest that age-of-onset contributes to excessive METH-taking, while sex confers vulnerability to relapse to METH-seeking.

AMPed-up adolescents: The role of age in the abuse of amphetamines and its consequences on cognition and prefrontal cortex development.

Adolescent use of amphetamine and its closely related, methylated version methamphetamine, is alarmingly high in those who use drugs for nonmedical purposes. This raises serious concerns about the potential for this drug use to have a long-lasting, detrimental impact on the normal development of the brain and behavior that is ongoing during adolescence. In this review, we explore recent findings from both human and laboratory animal studies that investigate the consequences of amphetamine and methamphetamine exposure during this stage of life. We highlight studies that assess sex differences in adolescence, as well as those that are designed specifically to address the potential unique effects of adolescent exposure by including groups at other life stages (typically young adulthood). We consider epidemiological studies on age and sex as vulnerability factors for developing problems with the use of amphetamines, as well as human and animal laboratory studies that tap into age differences in use, its short-term effects on behavior, and the long-lasting consequences of this exposure on cognition. We also focus on studies of drug effects in the prefrontal cortex, which is known to be critically important for cognition and is among the later maturing brain regions. Finally, we discuss important issues that should be addressed in future studies so that the field can further our understanding of the mechanisms underlying adolescent use of amphetamines and its outcomes on the developing brain and behavior.

Extended access self-administration of methamphetamine is associated with age- and sex-dependent differences in drug taking behavior and recognition memory in rats.

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.

Age- and sex-dependent effects of methamphetamine on cognitive flexibility and 5-HT2C receptor localization in the orbitofrontal cortex of Sprague-Dawley rats.

Adolescents and females experience worse outcomes of drug use compared to adults and males. This could result from age- and sex-specific consequences of drug exposure on brain function and cognitive behavior. In the current study, we examined whether a history of intravenous methamphetamine (METH) self-administration impacted cognitive flexibility and 5-HT2CR localization in the orbitofrontal cortex (OFC) in an age- and sex-dependent manner. Strategy shifting was assessed in male and female Sprague-Dawley rats that had self-administered METH (0.08 mg/kg/inf) or received non-contingent infusions of saline during periadolescence or young adulthood. After all rats reached adulthood, they were tested in an operant strategy shifting task and their brains were subsequently analyzed using immunofluorescence to quantify co-localization of 5-HT2C receptors with parvalbumin interneurons in the OFC. We found that adolescent-onset females were the only group impaired during discrimination and reversal learning, but they did not exhibit changes in localization of 5-HT2C receptors. In contrast, adult-onset males exhibited a significant increase in co-localization of 5-HT2C receptors within parvalbumin interneurons in the left hemisphere of the OFC. These studies reveal that age and sex differences in drug-induced deficits in reversal learning and 5-HT2CR co-localization with parvalbumin interneurons are dissociable and can manifest independently. In addition, these data highlight the potential for certain treatment approaches to be more suitable in some populations compared to others, such as alleviating drug-induced cognitive deficits as a focus for treatment in adolescent females.

Sex differences in adolescent ethanol drinking to behavioral intoxication.

Rodent models have been especially useful for investigating adolescent ethanol exposure. However, there is a paucity of studies examining sex differences in behavioral intoxication from adolescent ethanol drinking. Here, we used an ethanol drinking model to investigate if adolescent rats of both sexes readily drink ethanol to measurable behavioral intoxication, indicated by increased impulsive action and motor incoordination. Beginning on postnatal day (P) 28, male and female Long-Evans rats were given 30-min access to a solution of sucrose (20%) or sweetened ethanol (20% sucrose +15% ethanol) every other day until P60 and once after 2 weeks of forced abstinence (on P75). On alternate (nondrinking) days, rats were reinforced with a food pellet for making a cued nosepoke response. Beginning on P56, rats were tested in this task after drinking sessions to assess ethanol-induced changes in impulsive action, defined as premature responding prior to cue presentation. Motor coordination was assessed before and after drinking sessions using an incline plane test. Adolescent male and female rats readily consumed ethanol to behavioral intoxication, measured as reduced motor coordination. Following forced abstinence, females displayed greater ethanol-induced impulsive action. These studies provide evidence for sex differences in behavioral intoxication following adolescent ethanol drinking.

Age and sex differences in behavioral flexibility, sensitivity to reward value, and risky decision-making.

Compared with adults, adolescent behavior is often characterized by reduced behavioral flexibility, increased sensitivity to reward, and increased likelihood to take risks. These traits, which have been hypothesized to confer heightened vulnerability to psychopathologies such as substance use disorders (SUDs), have been the focus of studies in laboratory animal models that seek to understand their neural underpinnings. However, rodent studies to date have typically used only males and have adopted standard methodological practices (e.g., weight loss inducing food restriction) that are likely to have a disparate impact on adolescents compared with adults. Here, we used adolescent and adult Sprague-Dawley rats of both sexes to study instrumental behavior tasks that assess behavioral flexibility (strategy shifting and reversal learning; Experiment 1), sensitivity to reward value (outcome devaluation; Experiment 2), and risky decision making (probability discounting; Experiment 3). In Experiment 1, we found that adolescents were faster to acquire reversal learning than adults but there were no differences in strategy shifting. In Experiments 2 and 3, adolescents and adults were equally sensitive to changes in reward value and exhibited similar reductions in preference for a large reward when reinforcement probability was decreased. However, adolescents responded more efficiently and earned reinforcers at a higher rate than their same-sex, adult counterparts. Together, these findings provide only limited support for the existence of an "adolescent-typical" phenotype in Sprague-Dawley rats and instead suggest that age differences in the expression of these behaviors may depend on conditions such as pubertal status and motivational state. (PsycINFO Database Record

Reduced sensitivity to reinforcement in adolescent compared to adult Sprague-Dawley rats of both sexes.

RATIONALE: Adolescence is a period of considerable development of brain and behavior and is the time during which most drug use is initiated. OBJECTIVE: Age-dependent differences in motivated behaviors may be one of the factors that contribute to heightened vulnerability to developing substance use disorders, so we sought to compare age differences in methamphetamine (METH) and saccharin seeking. METHODS: Beginning during adolescence or adulthood, male and female Sprague-Dawley rats were trained to self-administer 0.1% saccharin (via liquid dipper cup) or intravenous METH at one of three doses (0.02, 0.05, 0.08 mg/kg/inf) under increasing fixed ratio schedules of reinforcement. Subsequently, responding for METH (0.02, 0.05, 0.08, or 0.1 mg/kg/inf) under progressive ratio response requirements was assessed in rats that acquired METH self-administration at the highest dose (0.08 mg/kg/inf). RESULTS: We found that adult-onset rats acquired METH self-administration more readily and exhibited higher motivation compared to adolescent-onset rats, although there were no differences in METH intake during acquisition. Adult rats also acquired saccharin self-administration more readily, but in contrast to METH, there were age and sex differences in saccharin intake driven by high levels of responding in adult females. CONCLUSIONS: These findings challenge the prevailing notion that adolescents are hypersensitive to reward and instead raise questions about the potential role of methodological factors on which rodent studies often differ.

Ontogeny of object-in-context recognition in the rat.

The object-in-context recognition (OiC) task [19] is a spontaneous exploration task that serves as an index of incidental contextual learning and memory. During the test phase, rats prefer to explore the object mismatched to the testing context based on previous object-context pairings experienced during training. The mechanisms of OiC memory have been explored in adult rats [12,35]; however, little is known about its determinants during development. Thus, the present study examined the ontogeny of the OiC task in preweanling through adolescent rats. We demonstrate that postnatal day (PD) 17, 21, 26, and 31 rats can perform the OiC task (Experiment 1) and that preference for the novel target is eliminated when rats are tested in an alternate context not encountered during training (Experiment 2). Lastly, we show that PD26 but not PD17 rats can perform the OiC task when the training contexts only differed by distal spatial cues (Experiment 3). These data demonstrate for the first time that PD17 rats can acquire and retain short-term OiC memory, which involves associative learning of object and context information. However, we also provide evidence that preweanling rats' ability to utilize certain aspects of a context (i.e., distal spatial cues) in the OiC task is not equivalent to that of their older counterparts. Implications for the development of contextual memory and its related neural substrates are discussed.

Ontogeny of object versus location recognition in the rat: acquisition and retention effects.

Novel object and location recognition tasks harness the rat's natural tendency to explore novelty (Berlyne, 1950) to study incidental learning. The present study examined the ontogenetic profile of these two tasks and retention of spatial learning between postnatal day (PD) 17 and 31. Experiment 1 showed that rats ages PD17, 21, and 26 recognize novel objects, but only PD21 and PD26 rats recognize a novel location of a familiar object. These results suggest that novel object recognition develops before PD17, while object location recognition emerges between PD17 and PD21. Experiment 2 studied the ontogenetic profile of object location memory retention in PD21, 26, and 31 rats. PD26 and PD31 rats retained the object location memory for both 10-min and 24-hr delays. PD21 rats failed to retain the object location memory for the 24-hr delay, suggesting differential development of short- versus long-term memory in the ontogeny of object location memory.