Pharmacological activation of kappa opioid receptors: aversive effects in adolescent and adult male rats

Rationale

The dynorphin (DYN)/kappa opioid receptor (KOR) system is involved in the dysphoric properties of drugs of abuse. Given that adolescents show reduced sensitivity to aversive effects of many drugs, alterations in the DYN/KOR system may contribute to the prevalence of drug use during adolescence.

Objectives

The present study was designed to assess dysphoric properties of a selective kappa agonist, U62,066, in adolescent and adult rats using both conditioned taste aversion (CTA) and conditioned place aversion (CPA) paradigms.

Methods

For CTA, water-restricted rats were administered U62,066 following 30 min access to a saccharin solution, with subsequent saccharin consumption used to index aversion. For CPA, animals were allowed access to both compartments of a two-compartment chamber for a 15-min pre- and post-conditioning test. For conditioning, subjects were administered U62,066 prior to confinement to one side of the chamber and saline prior to confinement to the other side for a total of four pairings.

Results

Overall, adolescents displayed reduced sensitivity to the kappa agonist relative to adults. Adults demonstrated taste aversions to the 0.2 and 0.3 mg/kg doses of U62,066, whereas adolescents did not display aversions to any tested doses. Adults demonstrated a place aversion to the 0.1 and 0.2 mg/kg dose of U62,066 when paired with the preferred side of the conditioning chamber. Adolescents did not display aversions to any of the doses tested.

Conclusions

Reduced sensitivity to DYN/KOR system activation during adolescence may be a contributing factor to the age-typical insensitivity to aversive properties of drugs commonly abused by adolescents.     

Effect of sex on ethanol consumption and conditioned taste aversion in adolescent and adult rats

Rationale

Vulnerability to alcoholism is determined by many factors, including the balance of pleasurable vs. aversive alcohol-induced sensations: pleasurable sensations increase intake, while aversive sensations decrease it. Female sex and adolescent age are associated with lower sensitivity to intake-reducing effects and more rapid development of alcohol abuse.

Objectives

This study assessed voluntary drinking and the aversive effects of alcohol to determine whether these measures are inversely related across the sexes and development.

Methods

Voluntary drinking of 20 % ethanol in an every-other-day (EOD) availability pattern and the dose–response relationship of ethanol conditioned taste aversion (CTA) were assessed in male and female adolescent and adult rats.

Results

CTA was sex specific in adult but not adolescent rats, with adult females exhibiting less aversion. Voluntary ethanol consumption varied according to age and individual differences but was not sex specific. Adolescents initially drank more than adults, exhibited greater day-to-day variation in consumption, were more susceptible to the alcohol deprivation effect, and took longer to establish individual differences in consumption patterns.

Conclusions

These results show that the emergence of intake patterns differs between adolescents and adults. Adolescents as a group initiate drinking at high levels but decrease intake as they mature. A subset of adolescents maintained high drinking levels into adulthood. In contrast, most adults consumed at steady, low levels, but a small subset quickly established and maintained high-consumption patterns. Adolescents also showed marked deprivation-induced increases. Sex differences were not observed in EOD drinking during either adolescence or adulthood.     

The effects of an acute challenge with the NMDA receptor antagonists,MK-801, PEAQX,and ifenprodil,on social inhibition in adolescent and adult male rats

Rationale

NMDA antagonists consistently produce social inhibition in adult animals, although effects of these manipulations on social behavior of adolescents are relatively unknown.

Objectives

The aim of this study was to assess potential age differences in the socially inhibitory effects of the non-competitive NMDA antagonist, MK-801, as well as NR2 subunit selective effects, given the regional and developmental differences that exist for the NR2 subunit during ontogeny.

Methods

In separate experiments, adolescent and adult male Sprague–Dawley rats were treated acutely with MK-801 (0, 0.05, 0.1, 0.2 mg/kg, i.p.), the NR2A antagonist, PEAQX (2.5, 5, 10, 20 mg/kg, s.c.), or the NR2B antagonist, ifenprodil (1.5, 3, 6, 12 mg/kg, i.p.), 10 min prior to a social interaction test.

Results

Adolescents required higher doses of MK-801 (0.1 and 0.2 mg/kg) to induce social suppression, whereas adults demonstrated reductions in social activity after all doses. Likewise, adolescents required higher doses of ifenprodil (6 and 12 mg/kg) to produce social inhibitory effects relative to adults (all doses). In contrast, adults were less sensitive to PEAQX than adolescents, with adults showing social inhibition after 20 mg/kg whereas adolescents showed this effect following 10 and 20 mg/kg. Although locomotor activity was generally reduced at both ages by all drugs tested, ANCOVAs using locomotor activity as a covariate revealed similar patterns of social inhibitory effects.

Conclusions

Adolescents are less sensitive than adults to the disruption of social behavior by NMDA and NR2B-selective receptor antagonism, but not by an NR2A antagonist—age differences that may be related to different subunit expression patterns during development.     

Reinstatement of cocaine seeking induced by drugs, cues, and stress in adolescent and adult rats

Rationale

In human and animal studies, adolescence marks a period of increased vulnerability to the initiation and subsequent abuse of drugs. Adolescents may be especially vulnerable to relapse, and a critical aspect of drug abuse is that it is a chronically relapsing disorder. However, little is known of how vulnerability factors such as adolescence are related to conditions that induce relapse, triggered by the drug itself, drug-associated cues, or stress.

Objective

The purpose of this study was to compare adolescent and adult rats on drug-, cue-, and stress-induced reinstatement of cocaine-seeking behavior.

Methods

On postnatal days 23 (adolescents) and 90 (adults), rats were implanted with intravenous catheters and trained to lever press for i.v. infusions of cocaine (0.4 mg/kg) during two daily 2-h sessions. The rats then self-administered i.v. cocaine for ten additional sessions. Subsequently, visual and auditory stimuli that signaled drug delivery were unplugged, and rats were allowed to extinguish lever pressing for 20 sessions. Rats were then tested on cocaine-, cue-, and yohimbine (stress)-induced cocaine seeking using a within-subject multicomponent reinstatement procedure.

Results

Results indicated that adolescents had heightened cocaine seeking during maintenance and extinction compared to adults. During reinstatement, adolescents (vs adults) responded more following cocaine- and yohimbine injections, while adults (vs adolescents) showed greater responding following presentations of drug-associated cues.

Conclusion

These results demonstrated that adolescents and adults differed across several measures of drug-seeking behavior, and adolescents may be especially vulnerable to relapse precipitated by drugs and stress.     

Effect of age on methylphenidate-induced conditioned taste avoidance and related BDNF/TrkB signaling in the insular cortex of the rat

Rationale

Drug use and abuse is thought to be a function of the balance between its rewarding and aversive effects, such that the rewarding effects increase the likelihood of use while the drug’s dissociable aversive effects limit it. Adolescents exhibit a shift in this balance toward reward, which may ultimately lead to increased use. Importantly, recent work shows that adolescents are also protected from the aversive effects of many abusable drugs as measured by conditioned taste avoidance (CTA). However, such effects of methylphenidate (MPH, widely prescribed to adolescents with ADHD) have not been characterized.

Objectives

The effect of age on MPH-induced CTA was assessed. In addition, MPH-induced changes in brain-derived neurotrophic factor (BDNF) activity in the insular cortex (IC) and central nucleus of the amygdala (CeA), known to be important to CTA, were examined and related to CTAs in adolescents and adults.

Methods

CTAs induced by MPH (0, 10, 18, and 32 mg/kg) were assessed in adolescent (n = 34) and adult (n = 33) male Sprague Dawley rats. Following MPH CTA, IC and CeA tissue was probed for differences in BDNF and tropomyosin-related kinase receptor-B (TrkB) using Western blots.

Results

Blunted expression of MPH CTA was observed in the adolescents versus adults, which correlated with generally attenuated adolescent BDNF/TrkB activity in the IC, but the drug effects ran contrary to the expression of CTA.

Conclusions

Adolescents are protected from the aversive effects of MPH versus adults, but further work is needed to characterize the possible involvement of BDNF/TrkB.     

Higher long-lasting ethanol sensitization after adolescent ethanol exposure in mice

Rationale

Due to their maturing brain, adolescents are suggested to be more vulnerable to the long-term consequences of chronic alcohol use. Increased sensitization to the stimulant effects of ethanol is a possible consequence of ethanol exposure during adolescence.

Objectives

The aim of this study was to characterize the long-term alterations in the stimulant effects of ethanol and in the rate of ethanol sensitization in mice pre-exposed to ethanol during adolescence in comparison to mice pre-exposed to ethanol in adulthood.

Methods

Adolescent and adult female Swiss mice were injected with saline or ethanol (2.5 or 4 g/kg) during 14 consecutive days. After a 3-week period of ethanol abstinence, mice were tested as adults before and after a second exposure to daily repeated ethanol injections.

Results

All mice pre-exposed to ethanol as adults or adolescents showed higher stimulant effects when re-exposed to ethanol 3 weeks later. However, this enhanced sensitivity to the stimulant effects of ethanol was of significantly higher magnitude in mice repeatedly injected with high ethanol doses (4 g/kg) during adolescence. Furthermore, the increased expression of ethanol stimulant effects in these mice was maintained even after a second procedure of ethanol sensitization.

Conclusions

Adolescence is a critical period for the development of a sensitization to ethanol stimulant properties providing that high intermittent ethanol doses are administered. These results might contribute to explain the relationship between age at first alcohol use and risks of later alcohol problems and highlight the dangers of repeated consumption of high alcohol amounts in young adolescents.     

Chronic tolerance to the social consequences of ethanol in adolescent and adult Sprague-Dawley rats

Adolescence is a time when experimentation with ethanol becomes normative, with high levels of use becoming apparent in some adolescents. Little is known, however, as to whether ethanol adaptations emerging in adolescents with repeated ethanol use are similar to those emerging in adults. The presents study used a rodent model to investigate the development of chronic tolerance to ethanol-induced alterations in social behavior. The study focused both on ethanol-induced social facilitations, typically evident in adolescents but not adult animals at low doses of ethanol, as well as the inhibition of social behavior occurring at higher doses in both adolescent and adult rats. Adolescent and adult male and female Sprague-Dawley rats were injected intraperitoneally with either isotonic saline or 1 g/kg ethanol for 7 consecutive days: postnatal day (P) 27-33 for adolescents and P62-68 for adults. Acute effects of ethanol (0, 0.25, 0.5, 0.75, and 1 g/kg) on social behavior, social motivation (measured in terms of social preference), and locomotor activity were assessed 48 h after the last chronic exposure using a modified social interaction test in a familiar environment. Adolescents chronically exposed to ethanol developed tolerance to ethanol-induced social facilitation. Animals of both ages likewise developed chronic tolerance to ethanol-induced social inhibition. Metabolic tolerance emerged in adults, as indexed by a decrease in blood ethanol concentrations after chronic ethanol at this age, whereas only functional tolerance was evident in adolescents. Unexpectedly, chronic ethanol diminished baseline levels of social preference in adolescents, but made them more responsive to ethanol-induced enhancement of social preference. Chronic ethanol exposure in adulthood, however, only induced tolerance to the suppressing effects of higher ethanol doses on social preference. Thus, whereas adolescents and adult both develop adaptations following repeated exposure to ethanol, adolescents are more vulnerable to the disruptive effects of chronic ethanol exposure on social preference than their more mature counterparts.     

Molecular and behavioral characterization of adolescent protein kinase C following high dose ethanol exposure

Rationale

Ethanol is commonly used and abused during adolescence. Although adolescents display differential behavioral responses to ethanol, the mechanisms by which this occurs are not known. The protein kinase C (PKC) pathway has been implicated in mediating many ethanol-related effects in adults, as well as gamma-aminobutyric acid (GABA_A) receptor regulation.

Objectives

The present study was designed to characterize cortical PKC isoform and GABA_A receptor subunit expression during adolescence relative to adults as well as assess PKC involvement in ethanol action.

Results

Novel PKC isoforms were elevated, while PKCγ was lower during mid-adolescence relative to adults. Whole-cell lysate and synaptosomal preparations correlated for all isoforms except PKCδ. In parallel, synaptosomal GABA_A receptor subunit expression was also developmentally regulated, with GABA_AR δ and α₄ being lower while α₁ and γ₂ were higher or similar, respectively, in adolescents compared to adults. Following acute ethanol exposure, synaptosomal novel and atypical PKC isoform expression was decreased only in adolescents. Behaviorally, inhibiting PKC with calphostin C, significantly increased ethanol-induced loss of righting reflex (LORR) in adolescents but not adults, whereas activating PKC with phorbol dibutyrate was ineffective in adolescents but decreased LORR duration in adults. Further investigation revealed that inhibiting the cytosolic phospholipase A₂/arachidonic acid (cPLA₂/AA) pathway increased LORR duration in adolescents, but was ineffective in adults.

Conclusions

These data indicate that PKC isoforms are variably regulated during adolescence and may contribute to adolescent ethanol-related behavior. Furthermore, age-related differences in the cPLA₂/AA pathway may contribute to ethanol’s age-related effects on novel and atypical PKC isoform expression and behavior.     

Effects of repeated exposure to morphine in adolescent and adult male C57BL/6J mice: age-dependent differences in locomotor stimulation,sensitization, and body weight loss

Rationale

Given evidence for age-related differences in the effects of drugs of abuse, surprisingly few preclinical studies have explored effects of opioids in adolescents (versus adults).

Objectives

This study compared the motor stimulating and ataxic effects of repeatedly administered morphine in adolescent, late adolescent, and adult mice.

Methods

Mice were treated with saline or morphine (10–100 mg/kg, i.p.) once per day for 4 days, and morphine (3.2–56 mg/kg)-induced locomotion was assessed 3 days or 5 weeks later. Different mice were treated repeatedly with morphine and ataxia was measured.

Results

Acute administration of morphine increased locomotion more in adolescents than in adults. Repeated morphine enhanced morphine-induced locomotion, assessed 3 days later, to a similar extent in each age group (minimum effective dose 17.8 mg/kg). This sensitization was still evident 5 weeks later when the adolescents had become adult, but was smaller and occurred at a higher dose (56 mg/kg). In animals treated repeatedly with morphine as adults, sensitization was no longer apparent 5 weeks later. Intermittent morphine was at least 10-fold less potent to produce body weight loss in adolescents than in adults. Repeated morphine did not alter morphine-induced ataxia at any age.

Conclusions

Compared with adults, adolescents were more sensitive to the acute locomotor stimulating effects of morphine and to its long-lasting locomotor sensitizing effects, consistent with overactivity of dopamine systems during adolescence. In contrast, adolescents were less sensitive than adults to body weight loss induced by intermittent morphine, an effect indicative of morphine withdrawal in adult rodents.     

Effects of stressors on the reinforcing efficacy of nicotine in adolescent and adult rats

Rationale and objectives

Stress increases drug intake. This depends on the stressor, drug, and aspect of drug seeking assessed. The objectives of these experiments done in adolescent and adult male rats were to (1) examine social defeat effects on acquisition of nicotine self-administration (SA) and the reinforcing efficacy of nicotine and (2) determine the effects of acute exposure to intermittent footshock (FS) or yohimbine on the reinforcing efficacy of nicotine.

Methods

In experiment 1, rats received four defeat exposures prior to nicotine SA acquisition and progressive ratio (PR) SA sessions (30 μg/kg nicotine/infusion). Exposure to an olfactory cue previously paired with defeat was also tested on responding maintained by nicotine on the PR schedule. In experiments 2 and 3, the effects of FS (5 and 10 min) or yohimbine (0.625 and 1.25 mg/kg, i.p.) on PR responding for nicotine (15, 30, or 60 μg/kg/infusion) were assessed. Adolescents were aged PD34-36 and adults PD81-85 at the beginning of nicotine SA training.

Results

Defeat did not affect nicotine SA acquisition. Prior exposure to defeat or a defeat-paired olfactory cue did not affect PR responding for nicotine. FS modestly decreased PR responding in adolescents at the middle nicotine infusion dose. Yohimbine increased PR responding independent of nicotine infusion dose and age.

Conclusions

Together with previous work with other drugs, our data indicate that the effects of stress on the reinforcing efficacy of nicotine are stressor- and drug-dependent. This suggests that there is heterogeneity among stressors on how they affect neuronal systems underlying drug intake.     

Time-dependent decreases in nucleus accumbens AMPA/NMDA ratio and incubation of sucrose craving in adolescent and adult rats

Rationale and objective

There is evidence that cue-induced sucrose seeking progressively increases after cessation of oral sucrose self-administration (incubation of sucrose craving) in both adolescent and adult rats. The synaptic plasticity changes associated with this incubation at different age groups are unknown. We assessed whether incubation of sucrose craving in rats trained to self-administer sucrose as young adolescents, adolescents, or adults is associated with changes in 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA)/N-methyl-d-aspartate (NMDA) ratio (a measure of postsynaptic changes in synaptic strength) in nucleus accumbens.

Methods

Three age groups initiated oral sucrose self-administration training (10 days) on postnatal day (P) 35 (young adolescents), P42 (adolescents), or P70 (adults). They were then tested for cue-induced sucrose seeking (assessed in an extinction test) on abstinence days 1 and 21. Separate groups of rats were trained to self-administer sucrose or water (a control condition), and assessed for AMPA/NMDA ratio in nucleus accumbens on abstinence days 1–3 and 21.

Results

Adult rats earned more sucrose rewards, but sucrose intake per body weight was higher in young adolescent rats. Time-dependent increases in cue-induced sucrose seeking (incubation of sucrose craving) were more pronounced in adult rats, less pronounced in adolescents, and not detected in young adolescents. On abstinence day 21, but not days 1–3, AMPA/NMDA ratio in nucleus accumbens were decreased in rats that self-administered sucrose as adults and adolescents, but not young adolescents.

Conclusions

Our data demonstrate age-dependent changes in magnitude of incubation of sucrose craving and nucleus accumbens synaptic plasticity after cessation of sucrose self-administration.     

Differential alteration of the effects of MDMA (ecstasy) on locomotor activity and cocaine conditioned place preference in male adolescent rats by social and environmental enrichment

Rationale

Ecstasy (MDMA) is used predominately by adolescents and young adults. Young MDMA users are more likely than non-users to use other drugs, including cocaine. The response to stimulant drugs can be affected by environmental factors; however, little information exists about the role that housing plays in mediating effects of MDMA in adolescence.

Objectives

The present experiment examined whether social and environmental factors alter effects of MDMA on activity and cocaine reward.

Methods

Male adolescent rats were housed on PND 23. Isolated rats were housed alone (1 rat/cage) in an impoverished environment with no toys (II) or enriched with toys (IE). Social rats were housed three/cage with (SE3) or without (SI3) toys. Starting on PND 29, 5 mg/kg MDMA or saline was injected and activity was measured for 60 min once daily for five consecutive days. On PND 36–40, cocaine CPP was conducted.

Results

Saline vehicle-induced activity of II rats was higher than other groups, and all groups became sensitized to the locomotor-stimulant effects of MDMA. In II rats, maximal CPP was increased after MDMA pre-exposure compared to vehicle. Environmental enrichment blocked this; however, dose–effect curves for cocaine CPP shifted to the left in both IE and SE3 rats. In rats with just social enrichment, there were no effects of MDMA on cocaine CPP.

Conclusion

Drug prevention and treatment strategies should take into account different environments in which adolescents live. These findings show that MDMA increases cocaine reward in male adolescents, and social enrichment diminishes, while environmental enrichment enhances this.     

Genetic propensities to increase ethanol intake in response to stress: studies with selectively bred swim test susceptible (SUS), alcohol-preferring (P), and non-preferring (NP) lines of rats

Rationale

Swim test susceptible (SUS) rats selectively bred for reduced struggling in the forced swim test (FST) following stress show high voluntary ethanol intake like alcohol-preferring (P) rats selectively bred for ethanol preference. It is unknown whether stress enhances drinking in SUS rats or FST behavior in P and non-preferring (NP) rats.

Objectives

The aim of this study was to assess the response to stress in male SUS, Sprague-Dawley (SD), P, and NP rats on 10% ethanol drinking and FST behavior.

Methods

In experiment 1, SUS and SD rats had limited access to ethanol and water following white noise, rehousing, and forced swim stress. In experiment 2, P and NP rats received footshock, white noise, restraint, or no stress prior to the FST. Rats then had continuous access to ethanol and water, and the effects of weekly exposures to stress were measured.

Results

SUS rats drank more ethanol (M?=?2.98?g/kg) than SD rats (M?=?1.26?g/kg) at baseline. Stress produced sustained increases (~33% of baseline) in ethanol intake in SUS rats. NP rats spent twice as much time immobile as P rats in the FST. Stress did not alter FST behavior in P or NP rats. Only footshock produced an increase (~29%) in ethanol intake in P rats.

Conclusions

Selection for stress-induced depressive-like behavior in SUS rats is associated with enhanced stress-induced ethanol drinking. However, the selection for alcohol preference is not associated with stress-induced depressive-like behavior but is associated with footshock stress-induced ethanol drinking. In these experiments, relationships among stress, depressive-like behavior, and alcohol preference were not symmetrical.     

Histamine and H3 receptor-dependent mechanisms regulate ethanol stimulation and conditioned place preference in mice

Rationale

Neuronal histamine has a prominent role in sleep–wake control and body homeostasis, but a number of studies suggest that histamine has also a role in higher brain functions including drug reward.

Objective

The present experiments characterized the involvement of histamine and its H3 receptor in ethanol-related behaviors in mice.

Materials and methods

Male histidine decarboxylase knockout (HDC KO) and control mice were used to study the role of histamine in ethanol-induced stimulation of locomotor activity, impairment of motor coordination, and conditioned place preference (CPP). Male C57BL/6Sca mice were used to study the effects of H3 receptor antagonist in the effects of ethanol on locomotor activity.

Results

The HDC KO mice displayed a weaker stimulatory response to acute ethanol than the wild-type (WT) mice. No differences between genotypes were found after ethanol administration on accelerating rotarod. The HDC KO mice showed stronger ethanol-induced CPP than the WT mice. Binding of the GABA_A receptor ligand [³H]Ro15-4513 was not markedly changed in HDC KO mouse brain and thus could not explain altered responses in KO mice. Ethanol increased the activity of C57BL/6Sca mice, and H3 receptor antagonist ciproxifan inhibited this stimulation. In CPP paradigm ciproxifan, an H3 receptor inverse agonist potentiated ethanol reward.

Conclusions

Histaminergic neurotransmission seems to be necessary for the stimulatory effect of ethanol to occur, whereas lack of histamine leads to changes that enhance the conditioned reward by ethanol. Our findings also suggest a role for histamine H3 receptor in modulation of the ethanol stimulation and reward.     

Dysregulation of kappa-opioid receptor systems by chronic nicotine modulate the nicotine withdrawal syndrome in an age-dependent manner

Rationale

Mechanisms that mediate age differences during nicotine withdrawal are unclear.

Objective

This study compared kappa-opioid receptor (KOR) activation in na?ve and nicotine-treated adolescent and adult rats using behavioral and neurochemical approaches to study withdrawal.

Methods

The behavioral models used to assess withdrawal included conditioned place and elevated plus maze procedures. Deficits in dopamine transmission in the nucleus accumbens (NAcc) were examined using microdialysis procedures. Lastly, the effects of KOR stimulation and blockade on physical signs produced upon removal of nicotine were examined in adults.

Results

Nicotine-treated adults displayed a robust aversion to an environment paired with a KOR agonist versus na?ve adults. Neither of the adolescent groups displayed a place aversion. KOR activation produced an increase in anxiety-like behavior that was highest in nicotine-treated adults versus all other groups. KOR activation produced a decrease in NAcc dopamine that was largest in nicotine-treated adults versus all other groups. Lastly, KOR activation facilitated physical signs of withdrawal upon removal of nicotine and KOR blockade reduced this effect.

Conclusion

Chronic nicotine enhanced the affective, anxiogenic, and neurochemical effects produced by KOR activation in adult rats. Our data suggest that chronic nicotine elicits an increase in KOR function, and this may contribute to nicotine withdrawal since KOR activation facilitated and KOR blockade prevented withdrawal signs upon removal of nicotine. Given that chronic nicotine facilitated the neurochemical effects of KOR agonists in adults but not in adolescents, it is suggested that KOR regulation of mesolimbic dopamine may contribute to age differences in nicotine withdrawal.     

Viral over-expression of D1 dopamine receptors in the prefrontal cortex increase high-risk behaviors in adults: Comparison with adolescents

Rationale

Adolescents are often described as “lacking brakes” resulting in an increase in several behaviors associated with risk for addiction. Prefrontal cortex dopamine and cortico-limbic interaction play an important role in addiction, and we have previously shown that the dopamine D1 receptor is elevated on prelimbic prefrontal output neurons in adolescent rats. We hypothesized that a constellation of risk-related behaviors is mediated by prefrontal output neuron expression of D1.

Objectives

We aimed to determine the role of the dopamine D1 receptor in behavioral and neural correlates of risk for addiction that are often observed in adolescents. Therefore, high-risk behaviors as well as subcortical D2 receptor expression were investigated in adult animals with experimentally elevated D1 on prefrontal glutamatergic neurons.

Methods

A lentiviral vector that selectively expressed the D1 receptor within glutamate neurons was injected in the prelimbic prefrontal cortex of adult male rats. Place conditioning to cocaine, alcohol, and nicotine, as well as delay discounting, novelty preferences, anxiety, cocaine self-administration, and sucrose preferences were assessed.

Results

Virally mediated D1 over-expression in adults leads to stronger drug-cue associations and greater consumption of sweet solutions, elevates bias towards immediate satisfaction rather than delaying gratification, decreases anxiety, and causes rats to work harder for and take more cocaine. Furthermore, elevated cortical D1 reduces D2 receptors in the accumbens (a putative risk marker).

Conclusions

Together, these data suggest a common mechanism for increased motivational drive to seek and consume substances with hedonic value, consistent with adolescent addictive processes.     

Exercise to reduce the escalation of cocaine self-administration in adolescent and adult rats

Rationale

Concurrent access to an exercise wheel decreases cocaine self-administration under short access (5 h/day for 5 days) conditions and suppresses cocaine-primed reinstatement in adult rats.

Objective

The effect of exercise (wheel running) on the escalation of cocaine intake during long access (LgA, 6 h/day for 26 days) conditions was evaluated.

Methods

Adolescent and adult female rats acquired wheel running, and behavior was allowed to stabilize for 3?days. They were then implanted with an iv catheter and allowed to self-administer cocaine (0.4?mg/kg, iv) during 6-h daily sessions for 16?days with concurrent access to either an unlocked or a locked running wheel. Subsequently, for ten additional sessions, wheel access conditions during cocaine self-administration sessions were reversed (i.e., locked wheels became unlocked and vice versa).

Results

In the adolescents, concurrent access to the unlocked exercise wheel decreased responding for cocaine and attenuated escalation of cocaine intake irrespective of whether the locked or unlocked condition came first. However, cocaine intake increased when the wheel was subsequently locked for the adolescents that had initial access to an unlocked wheel. Concurrent wheel access either before or after the locked wheel access did not reduce cocaine intake in adults.

Conclusions

Wheel running reduced cocaine intake during LgA conditions in adolescent but not adult rats, and concurrent access to the running wheel was necessary. These results suggest that exercise prevents cocaine seeking and that this effect is more pronounced in adolescents than adults.     

Intellectual,neurocognitive, and academic achievement in abstinent adolescents with cannabis use disorder

Rationale

The active component of cannabis, delta-9 tetrahydrocannabinol (THC), has a long half-life and widespread neurocognitive effects. There are inconsistent reports of neurocognitive deficits in adults and adolescents with cannabis use disorders (CUD), particularly after a period of abstinence.

Objectives

This study aims to examine neurocognitive measures (IQ, academic achievement, attention, memory, executive functions) in abstinent adolescents with CUD, while controlling for demographic, psychopathology, and poly-substance confounders.

Methods

We investigated neurocognitive performance in three groups: adolescents with CUD after successful first treatment and in full remission (n?=?33); controls with psychiatric disorders without substance use disorder history (n?=?37); and healthy adolescents (n?=?43).

Results

Adolescents with psychiatric disorders, regardless of CUD status, performed significantly worse than the healthy adolescents in academic achievement. No group differences were seen in IQ, attention, memory, or executive functions. Lower academic achievement was positively associated with younger age of CUD onset, regular cannabis use, and maximum daily use. In the CUD group, lifetime nicotine use episodes were negatively associated with IQ. Lower overall neurocognitive function was associated with younger age of onset of regular cannabis use and relapse within the 1 year follow-up.

Conclusions

Verifiably, abstinent adolescents with CUD history did not differ from the two comparison groups, suggesting that previously reported neurocognitive deficits may be related to other factors, including residual drug effects, preexisting cognitive deficits, concurrent use of other substances (e.g., nicotine), or psychopathology. Adolescents with CUD may not be vulnerable to THC neuropsychological deficits once they achieve remission from all drugs for at least 30 days.     

Selective blockade of the orexin-2 receptor attenuates ethanol self-administration, place preference, and reinstatement

Rationale

Orexin-1 receptor antagonists have been shown to block the reinforcing effects of drugs of abuse and food. However, whether blockade of orexin-2 receptor has similar effects has not been determined. We have recently described the in vitro and in vivo effects of JNJ-10397049, a selective and brain penetrant orexin-2 receptor antagonist.

Objective

The goal of these studies was to evaluate whether systemic administration of JNJ-10397049 blocks the rewarding effects of ethanol and reverses ethanol withdrawal in rodents. As a comparison, SB-408124, a selective orexin-1 receptor antagonist, was also evaluated.

Methods

Rats were trained to orally self-administer ethanol (8% v/v) or saccharin (0.1% v/v) under a fixed-ratio 3 schedule of reinforcement. A separate group of rats received a liquid diet of ethanol (8% v/v) and withdrawal signs were evaluated 4?h after ethanol discontinuation. In addition, ethanol-induced increases in extracellular dopamine levels in the nucleus accumbens were tested. In separate experiments, the acquisition, expression, and reinstatement of conditioned place preference (CPP) were evaluated in mice.

Results

Our results indicate that JNJ-10397049 (1, 3, and 10?mg/kg, sc) dose-dependently reduced ethanol self-administration without changing saccharin self-administration, dopamine levels, or withdrawal signs in rats. Treatment with JNJ-10397049 (10?mg/kg, sc) attenuated the acquisition, expression, and reinstatement of ethanol CPP and ethanol-induced hyperactivity in mice. Surprisingly, SB-408124 (3, 10 and 30?mg/kg, sc) did not have any effect in these procedures.

Conclusions

Collectively, these results indicate, for the first time, that blockade of orexin-2 receptors is effective in reducing the reinforcing effects of ethanol.     

Chronic psychosocial stress causes delayed extinction and exacerbates reinstatement of ethanol-induced conditioned place preference in mice

Rationale

We have shown previously, using an animal model of voluntary ethanol intake and ethanol-conditioned place preference (EtOH-CPP), that exposure to chronic psychosocial stress induces increased ethanol intake and EtOH-CPP acquisition in mice.

Objective

Here, we examined the impact of chronic subordinate colony (CSC) exposure on EtOH-CPP extinction, as well as ethanol-induced reinstatement of CPP.

Methods

Mice were conditioned with saline or 1.5 g/kg ethanol and were tested in the EtOH-CPP model. In the first experiment, the mice were subjected to 19 days of chronic stress, and EtOH-CPP extinction was assessed during seven daily trials without ethanol injection. In the second experiment and after the EtOH-CPP test, the mice were subjected to 7 days of extinction trials before the 19 days of chronic stress. Drug-induced EtOH-CPP reinstatement was induced by a priming injection of 0.5 g/kg ethanol.

Results

Compared to the single-housed colony mice, CSC mice exhibited increased anxiety-like behavior in the elevated plus maze (EPM) and the open field tests. Interestingly, the CSC mice showed delayed EtOH-CPP extinction. More importantly, CSC mice showed increased alcohol-induced reinstatement of the EtOH-CPP behavior.

Conclusion

Taken together, this study indicates that chronic psychosocial stress can have long-term effects on EtOH-CPP extinction as well as drug-induced reinstatement behavior and may provide a suitable model to study the latent effects of chronic psychosocial stress on extinction and relapse to drug abuse.