Testosterone differentially alters cocaine-induced ambulatory and rearing behavioral responses in adult and adolescent rats

Little is known about the physiological and behavioral effects of testosterone when co-administered with cocaine during adolescence. The present study aimed to determine whether exogenous testosterone administration differentially alters psychomotor responses to cocaine in adolescent and adult male rats. To this end, intact adolescent (30-days-old) and adult (60-day-old) male Fisher rats were pretreated with vehicle (sesame oil) or testosterone (5 or 10 mg/kg) 45 min prior to saline or cocaine (20 mg/kg) administration. Behavioral responses were monitored 1 h after drug treatment, and serum testosterone levels were determined. Serum testosterone levels were affected by age: saline- and cocaine-treated adults in the vehicle groups had higher serum testosterone levels than adolescent rats, but after co-administration of testosterone the adolescent rats had higher serum testosterone levels than the adults. Pretreatment with testosterone affected baseline activity in adolescent rats: 5 mg/kg of testosterone increased both rearing and ambulatory behaviors in saline-treated adolescent rats. After normalizing data to % saline, an interaction between hormone administration and cocaine-induced behavioral responses was observed; 5 mg/kg of testosterone decreased both ambulatory and rearing behaviors among adolescents whereas 10 mg/kg of testosterone decreased only rearing behaviors. Testosterone pretreatment did not alter cocaine-induced behavioral responses in adult rats. These findings suggest that adolescents are more sensitive than adults to an interaction between testosterone and cocaine, and, indirectly, suggest that androgen abuse may lessen cocaine-induced behavioral responses in younger cocaine users.     

Sensitivity to cocaine conditioned reward depends on sex and age

Human and animal laboratory studies show that females and males respond differently to drugs and that drug administration during adolescence leads to different behavioral effects than during adulthood. Adult female rats are more sensitive to the behavioral effects of cocaine than adult males, but it is not known if the same effect of sex exists during adolescence. In the present study, sensitivity to the conditioned reward of cocaine was evaluated using a conditioned place preference (CPP) paradigm where adolescent (PND 34) and adult (PND 66) male and female rats were trained and tested for the development of CPP to multiple doses of cocaine. Female rats developed CPP at lower doses than males, regardless of age. In addition, adolescent male and female rats established a CPP at lower doses of cocaine than adult male and female rats, respectively. Thus, both age and sex altered cocaine conditioned reward with the order of sensitivity being adolescent females > adult females > adolescent males > adult males. These data show that adolescents are more sensitive to the conditioned rewarding properties of cocaine than adults and that females respond to lower doses of cocaine compared to males regardless of age.     

Gonadal steroids mediate the opposite changes in cocaine-induced locomotion across adolescence in male and female rats

Evidence from both human studies and animal models indicates that cocaine elicits more behavioral stimulation in females than males. The present study sought to determine whether sex-specific responses to cocaine emerge during adolescence and to determine if gonadal steroid action during puberty affects adult responsiveness to cocaine. We administered cocaine using an escalating dose model in male and female rats at ages postnatal (PN) 28, 42, and 65 days. To assess the effects of pubertal gonadal steroid action, we compared the effects of binge cocaine administration on intact and prepubertally gonadectomized male and female rats in adulthood. Cocaine responses changed in opposite directions in males and females as they progressed through adolescence. At most doses, adolescent males were more responsive than adult males whereas adult females were more responsive than adolescent females. Ambulatory activity was age-dependent in males whereas non-ambulatory activity was age-dependent in females. Prepubertal gonadectomy increased behavioral responsiveness to the highest dose of cocaine in males whereas it decreased behavioral responsiveness to lower doses of cocaine in females. We conclude that sex differences in behavioral responses to cocaine arise during adolescence from a concurrent decrease in male responsiveness and increase in female responsiveness. Our results suggest that gonadal steroids exert lasting and opposing effects on the sensitivity of males and females to psychostimulants during development.     

Differential effects of self-administered cocaine in adolescent and adult rats on stimulus–reward learning

Rationale Adult cocaine addicts, abstinent at the time of testing, show a variety of neurocognitive impairments. Less clear is whether there are differences in the degree of impairment if cocaine use is initiated during adolescence rather than adulthood. Objectives Using a preclinical model, we evaluated if stimulus–reward learning was impacted differently in rats exposed to cocaine during adolescence (beginning on postnatal day 37) vs adulthood (beginning on postnatal days 74–79) and then tested after a drug-free period. Materials and methods A yoked-triad design of intravenous cocaine self-administration in adult (n = 8 triads) and adolescent (n = 8 triads) rats was used. Sets of three animals either contingently self-administered cocaine or received cocaine or saline in a noncontingent manner. Rats self-administering 1-mg/kg doses of cocaine responded under a fixed-ratio 5, timeout 20-s schedule of reinforcement. After 18 2-h drug or saline sessions, all rats (now adults) began the drug-free period in their home environments. Testing in a stimulus–reward learning task (conditioned cue preference) began 19 days later. Results Self-administration behavior was similar in adolescent and adult rats. Lever responses were not significantly different, and both age groups averaged approximately 20 infusions per session. Rats contingently self-administering cocaine or passively exposed to cocaine during adulthood showed stimulus–reward learning deficits in the conditioned cue preference task. Rats exposed to contingent or noncontingent cocaine during adolescence had normal learning, showing strong preferences for a Froot Loops-paired cue. Conclusions These findings suggest that adolescents are insensitive to cocaine-induced impairment of learning related to amygdala memory system functioning.     

Pretreatment with Δ9-tetrahydrocannabinol (THC) increases cocaine-stimulated activity in adolescent but not adult male rats

Marijuana (Cannabis sativa) remains one of the most widely used illegal drugs, with adolescents being particularly vulnerable to its use and abuse. In spite of this, most studies are conducted in adult animals even though the effects might be quite different in adolescents. Additionally, the use of marijuana often precedes the use of other psychoactive drugs including cocaine, especially when marijuana exposure begins during early adolescence. The purpose of this study was to examine the effects of repeated Δ9-tetrahydrocannabinol (THC), the major active ingredient in marijuana, in adolescents compared to adults and to determine its subsequent effects on cocaine-stimulated activity. To this end, adolescent (postnatal day PND 34) and adult (PND 66) rats were administered 3 mg/kg/day THC for 8 days and locomotor activity was measured on days 1, 2, 7 and 8 after dosing. On day 12 (4 days after the last dose of THC), rats were injected with escalating doses of cocaine and behavior was recorded. Results show that THC depressed locomotor activity in adult rats but not in adolescents. However, following a cocaine challenge, adolescents exposed to THC showed increased locomotor responses to cocaine compared to chronic vehicle-injected controls. This was not seen in adults. These results show that the effects of cocaine are enhanced after THC in adolescents, but not adults, and that this might account for the greater transition to cocaine after early, as opposed to later, marijuana use.     

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.     

Adolescent rats are protected from the conditioned aversive properties of cocaine and lithium chloride

In humans, most drug use is initiated during adolescence and adolescent users are more likely to become drug-dependent than adult users. Repeated, high levels of use are required for the transition from use to addiction. Individual levels of drug use are thought to result from a balance between the pleasant or rewarding and the unpleasant or aversive properties of the drug. Repeated high levels of drug use are required for the transition from drug use to dependence. We hypothesized that diminished aversive effects of drugs of abuse during adolescence might be one reason for higher rates of use and addiction during this phase. We therefore tested adolescent and adult CD rats in single-dose cocaine conditioned taste aversion (CTA) at a range of doses (10-40 mg/kg), and examined whether various behavioral markers of addiction vulnerability were correlated to outcome in cocaine CTA. We found that adolescents are indeed less susceptible to cocaine CTA. In fact, age was the predominant predictor of CTA outcome, predominating over measures of novelty-seeking, anxiety, and stress hormone levels, which are all known to be related to drug intake in other models. Furthermore, we found that adolescent rats are also less susceptible to conditioned taste aversion to a low dose of a non-addictive substance, lithium chloride. These results suggest that one explanation for elevated drug use and addiction among adolescents is reduced aversive or use-limiting effects of the drugs. This contributes to our understanding of why adolescence is a particularly vulnerable period for development of drug abuse.     

A single high dose of cocaine induces differential sensitization to specific behaviors across adolescence

Rationale Adolescence is a critical period for drug addiction. Acute stimulant exposure elicits different behavioral responses in adolescent and adult rodents. The same biological differences that mediate age-specific behavioral responsiveness to stimulants in rodents could contribute to increased addiction vulnerability in adolescent humans. Objectives This study compared the ability of a single high dose of cocaine (40 mg/kg) to induce behavioral sensitization to a challenge dose of cocaine (10 mg/kg) 24 h later in young adolescent postnatal day 28 (PN 28), mid-adolescent (PN 42), and young adult (PN 65) male rats. Horizontal activity was resolved into ambulatory and non-ambulatory movements. An observational behavioral rating was obtained by recording specific behaviors. We examined if individual behavioral responses to novelty and cocaine correlate with sensitization in each age group. Results Single dose cocaine pretreatment induced behavioral sensitization to non-ambulatory horizontal activity, sniffing behaviors, and stereotypies in animals of all ages. Ambulatory sensitization was observed only in the youngest adolescents. Cocaine pretreatment caused greater increases in stereotypies in the young adolescents than in adults. The magnitude of the behavioral response to the initial cocaine treatment was positively correlated with the magnitude of sensitization in individual young adolescents. High levels of novelty-induced ambulatory activity only correlated with the magnitude of ambulatory sensitization in the youngest adolescents. Conclusions We conclude that a single high dose of cocaine produces age-specific patterns of behavioral sensitization. Young adolescent rats appear to be more sensitive than adults to some of the behavioral alterations induced by a single high dose of cocaine.     

Behavioral responses during the initial exposures to a low dose of cocaine in late preweanling and adult rats

Human drug experimentation begins during late childhood and early adolescence, a critical time in physical and CNS development, when the immature CNS is vulnerable to the long-term effects of psychoactive drugs. Few preclinical animal studies have investigated responses to such drugs in a developmental stage equivalent to late childhood of humans. We used a rodent model to examine behavioral responses of female Sprague-Dawley late preweanling and adult rats during acute and repeated exposures to a low dose of cocaine. Results show that after cocaine injection, preweanling rats (18-21 days old) have locomotor responses that differ from adults, but after postnatal day 22, the responses are indistinguishable from adults even though rats are still not weaned. Before day 22, locomotor effects of cocaine differ from those in adults in three ways: preweanlings are active for a longer time after cocaine injection at day 18; preweanling activity peaks more rapidly after subcutaneous administration; and after only three injections of cocaine, a tolerance-like pattern is seen in preweanlings whereas an emerging pattern of sensitization to cocaine is seen in adults. The behavioral patterns of this age group offer a preclinical model of the early effects of drugs of abuse.     

Age-dependent effects of nicotine on locomotor activity and conditioned place preference in rats

Rationale Most adult smokers start smoking during their adolescence. This adolescent initiation may be due to multiple factors, but little evidence is available regarding whether their brains are differentially sensitive to the addictive effects of nicotine during adolescence.Objective To test the hypothesis that adolescents are more sensitive than adults to nicotines rewarding actions.Methods An unbiased, counterbalanced, place-conditioning procedure was used to examine drug-induced reward and locomotor activity. Early adolescent (postnatal day 28), late adolescent (P38) and adult (P90) rats received either saline or nicotine (0.125, 0.25 or 0.5 mg/kg, s.c.) and were tested for place conditioning.Results During early adolescence, a single nicotine injection (0.5 mg/kg) induced significant conditioned place preference (CPP). In contrast, during late adolescence or adulthood, nicotine did not induce CPP after either one or four conditioning trials. Initial locomotor responses to acute nicotine administration during the first conditioning trial also differed with age, with no effect at P28, but substantial inhibitory responses at all doses studied (0.125–0.5 mg/kg) at later ages. Although not differing in their initial locomotor response to nicotine, there was a significantly greater tolerance/sensitization during the second and subsequent drug exposures in late adolescents than in adults.Conclusions These findings provide evidence that adolescent brain is differentially sensitive to both the acute and repeated effects of nicotine relative to adult brain. Furthermore, there are significant differences in nicotine sensitivity between early and late phases of adolescence.     

Impact of alcohol and substance abuse on adolescent brain: a preclinical perspective

Use of alcohol and addictive substances by human juveniles and adolescents is common. Animal models offer researchers unique insight into the effects of alcohol and drugs on adolescents. Recent work in rat indicates that periadolescent substance use may disrupt normal pubertal development and may induce stronger effects on system subserving plasticity and cognition than in adults. Several processes may influence the adolescent risk of neurocognitive damage. The brain goes through various dynamic changes during adolescence and can seriously affect the short term growth process. The features of the adolescent brain may in fact predispose a youngster to behave in ways that place him or her at particular risk of experimenting with alcohol or other drugs. In addition to behavioral and neurochemical changes, a number of important physiological alterations occur during adolescence, including changes in brain regions implicated in the reinforcing properties of alcohol and other drugs of abuse. Damage during early stages can cause long term damage which is irreversible. The present review discusses the neurobehavioral, neurochemical and neuroendocrinal effects of alcohol and other drugs of abuse on the adolescent brain in rats.     

Cocaine-induced behavioral sensitization in adolescent rats endures until adulthood: lack of association with GluR1 and NR1 glutamate receptor subunits and tyrosine hydroxylase

Exposure to repeated cocaine induces enduring behavioral sensitization, which has been implicated in the psychostimulant-induced craving and psychosis. Adaptations in dopamine and glutamate neurotransmission in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) seem to mediate psychostimulant-induced behavioral sensitization. The abuse of drugs often begins during adolescence; however few studies have been devoted to study the effects of drugs of abuse at this age. The aim of our study was to examine whether repeated cocaine during adolescence could induce behavioral sensitization that endures into adulthood. Moreover, the protein levels of Tyrosine Hydroxylase (TH) and the glutamate receptor subunits GluR1 and NR1 in the NAc and mPFC were measured following the behavioral tests. Adolescent rats were treated with cocaine from postnatal day (PND) 30 to PND34 and behavioral sensitization was verified recording locomotor activity after cocaine challenge injection to adolescent (PND37) or adult (PND64 or 94) rats in separate groups at each time point. TH, GluR1, and NR1 protein levels were measured by Western blotting. Rats exposed to cocaine during adolescence expressed behavioral sensitization when tested on PND37 and PND64. In cocaine sensitized rats GluR1 protein was increased in the mPFC on PND37 but not in other ages. Thus, cocaine-induced behavioral sensitization during adolescence endures into early adulthood. However, cocaine pretreatment during adolescence induced a transient increase of GluR1 in the mPFC only when animals were challenged in the same age.     

Influence of handling or aversive stimulation during rats' neonatal or adolescence periods on oral cocaine self-administration and cocaine withdrawal

Adverse early life events may influence vulnerability for drug intake. The influence of handling or aversive stimulation during neonatal or adolescent periods on adult cocaine oral self-administration and withdrawal were investigated. Neonatal or adolescent rats were exposed to a modified unpredictable stress paradigm or handling for 10 days. When adults, oral cocaine was offered through the two-bottle choice paradigm for 30 days. Rats were submitted to the forced swimming test after cocaine withdrawal. Overall, there was a significant increase of cocaine choice throughout the days of cocaine consumption and an interaction between interventions and cocaine daily choice. Control rats started cocaine intake at a lower level and increased cocaine choice over time, while animals submitted to neonatal interventions started cocaine intake at higher levels of choice, with less increase in cocaine intake during the period of cocaine exposure. Rats receiving aversive stimulation during adolescence also started taking cocaine solution at higher levels. Significantly higher immobility duration and shorter latency to immobility during the forced swimming were detected in these same adolescents that received unpredictable stress, when compared to the control or handled rats, while there was no difference for rats stimulated neonatally. Therefore, early life events increase initial preference for cocaine and promote changes in its abuse pattern, according to the intensity of the event and the age of the individual at the time of the event. Moreover, adverse experiences during adolescence, but not in neonatal phases, increase the vulnerability to depressive-like behaviors during cocaine withdrawal of adult rats.     

Repeated binge ethanol administration during adolescence enhances voluntary sweetened ethanol intake in young adulthood in male and female rats

Binge alcohol consumption is a rising concern in the United States, especially among adolescents. During this developmental period alcohol use is usually initiated and has been shown to cause detrimental effects on brain structure and function as well as cognitive/behavioral impairments in rats. Binge models, where animals are repeatedly administered high doses of ethanol typically over a period of three or four days cause these effects. There has been little work conducted aimed at investigating the long-term behavioral consequences of repeated binge administration during adolescence on later ethanol-induced behavior in young adulthood and adulthood. The repeated four-day binge model may serve as a good approximate for patterns of human adolescent alcohol consumption as this is similar to a “bender” in human alcoholics. The present set of experiments examined the dose-response and sex-related differences induced by repeated binge ethanol administration during adolescence on sweetened ethanol (Experiment 1) or saccharin (Experiment 2) intake in young adulthood. In both experiments, on postnatal days (PND) 28-31, PND 35-38 and PND 42-45, ethanol (1.5, 3.0 or 5.0 g/kg) or water was administered intragastrically to adolescent rats. Rats underwent abstinence from PND 46-59. Subsequently, in young adulthood, ethanol and saccharin intake were assessed. Exposure to any dose of ethanol during adolescence significantly enhanced ethanol intake in adulthood. However, while female rats had higher overall g/kg intake, males appear to be more vulnerable to the impact of adolescent ethanol exposure on subsequently increased ethanol intake in young adulthood. Exposure to ethanol during adolescence did not alter saccharin consumption in young adulthood in male or female rats. Considering that adolescence is the developmental period in which ethanol experimentation and consumption is usually initiated, the present set of experiments demonstrate the importance of elucidating the impact of early binge-pattern ethanol exposure on the subsequent predisposition to drink later in life.     

Chronic cocaine or ethanol exposure during adolescence alters novelty-related behaviors in adulthood

Adolescence is a time of high-risk behavior and increased exploration. This developmental period is marked by a greater probability to initiate drug use and is associated with an increased risk to develop addiction and adulthood dependency and drug use at this time is associated with an increased risk. Human adolescents are predisposed toward an increased likelihood of risk-taking behaviors [Zuckerman M. Sensation seeking and the endogenous deficit theory of drug abuse. NIDA Res Monogr 1986;74:59-70.], including drug use or initiation. In the present study, adolescent animals were exposed to twenty days of either saline (0.9% sodium chloride), cocaine (20 mg/kg) or ethanol (1 g/kg) i.p. followed by a fifteen-day washout period. All animals were tested as adults on several behavioral measures including locomotor activity induced by a novel environment, time spent in the center of an open field, novelty preference and novel object exploration. Animals exposed to cocaine during adolescence and tested as adults exhibited a greater locomotor response in a novel environment, spent less time in the center of the novel open field and spent less time with a novel object, results that are indicative of a stress or anxiogenic response to novelty or a novel situation. Adolescent animals chronically administered ethanol and tested as adults, unlike cocaine-exposed were not different from controls in a novel environment, indicated by locomotor activity or time spent with a novel object. However, ethanol-exposed animals approached the novel object more, suggesting that exposure to ethanol during development may result in less-inhibited behaviors during adulthood. The differences in adult behavioral responses after drug exposure during adolescence are likely due to differences in the mechanisms of action of the drugs and subsequent reward and/or stress responsivity. Future studies are needed to determine the neural substrates of these long lasting drug-induced changes.     

Chronic nicotine differentially alters cocaine-induced locomotor activity in adolescent vs. adult male and female rats

Tobacco use is prevalent in the adolescent population. It is a major concern because tobacco is highly addictive and has also been linked to illicit drug use. There is not much research, however, on the interaction between nicotine and other stimulant drugs in animal models of early adolescence. This study examined the effects of chronic nicotine alone and on cocaine-stimulated activity in male and female periadolescent rats compared to male and female adult rats. During the seven-day nicotine pretreatment period, nicotine increased locomotor activity in all groups compared to vehicle controls. Male and female adult rats and female periadolescent rats developed sensitization to the locomotor-activating effects of nicotine over the 7-day treatment period, while male periadolescent rats did not. All groups treated with nicotine, however, exhibited sensitization to nicotine-induced repetitive motion over the 7-day nicotine treatment period. On day 8, male periadolescent rats pretreated with nicotine were more markedly sensitized to the locomotor-activating effects of cocaine than male adult rats, while female rats pretreated with nicotine were not sensitized to cocaine. In contrast, male and female periadolescent rats, but not adult rats, had increased amounts of repetitive beam breaks induced by cocaine after nicotine pretreatment. Overall, it appears that cross-sensitization to cocaine is greater in periadolescent than in adult rats, and that males are more sensitized than females. Thus, it may be that nicotine use during adolescence carries a greater risk than during adulthood and that male adolescents may be particularly vulnerable to the risk of cocaine abuse after nicotine use. This information should be taken into account so as to help us better understand the development of drug addiction in adolescents compared to adults.     

Effect of MDMA (ecstasy) on activity and cocaine conditioned place preference in adult and adolescent rats

MDMA (ecstasy) is a drug commonly used in adolescence, and many users of MDMA also use other illicit drugs. It is not known whether MDMA during adolescence alters subsequent responses to cocaine differently than in adults. This study examined the effects of MDMA in adolescent and adult rats on cocaine conditioned reward. At the start of these experiments, adolescent rats were at postnatal day (PND) 33 and adult rats at PND 60. Each rat was treated for 7 days with MDMA (2 or 5 mg/kg/day or vehicle) and locomotor activity was measured. Five days later cocaine conditioned place preference (CPP) was begun. Rats were trained for 3 days, in the morning with saline and in the afternoon with 10 mg/kg cocaine in 30 min sessions, and tested on the fourth day. MDMA stimulated activity in both age groups, but with a greater effect in the adult rats. Sensitization to the locomotor-stimulant effects of the lower dose of MDMA occurred in adult rats and in both groups to the higher dose. Cocaine did not produce a CPP in vehicle-treated adolescent rats, but a significant CPP was observed subsequent to treatment with MDMA. In contrast, cocaine-induced CPP was diminished after MDMA in adult rats. These effects were still evident 2 weeks later upon retest. Thus, under the present conditions, MDMA increased cocaine conditioned reward in adolescent and decreased it in adult rats. These findings suggest that exposure to MDMA during this critical developmental period may carry a greater risk than during adulthood and that male adolescents may be particularly vulnerable to the risk of stimulant abuse after use of MDMA.     

Attenuated incubation of cocaine seeking in male rats trained to self-administer cocaine during periadolescence

Rationale and objectives  Although onset of drug use during adolescence appears to increase long-term vulnerability to drug dependence in humans, relatively little is known about extinction and reinstatement of drug seeking after periadolescent onset of drug self-administration in laboratory animals. Furthermore, although cue-induced reinstatement of cocaine seeking increases progressively during abstinence from cocaine self-administration in adult subjects, this “incubation of cocaine craving” remains unexplored after adolescent drug intake in animal models. Materials and methods  We allowed periadolescent (postnatal day (PND) 35 at start) and adult (PND 83–95 at start) male Wistar rats to self-administer cocaine (0.36 mg/kg/infusion) in 2-h daily sessions on a fixed ratio 1 schedule of reinforcement over 14 days. Then, we compared extinction and cue-induced or cocaine priming-induced reinstatement (10 mg/kg cocaine, intraperitoneal) of cocaine seeking in both age groups after 30 days of abstinence in home cages. In separate cohorts, we tested for time-dependent increases in cue-induced reinstatement over approximately 1, 14, 30, or 60 days of abstinence in both age groups. Results  Adolescent and adult rats self-administered similar amounts of cocaine. Subsequent cue-induced reinstatement was lower in the adolescent-onset group after a 30-day abstinence period, but cocaine priming-induced reinstatement did not differ across ages. Also, extinction responding and time-dependent increases in cue-induced reinstatement (incubation) were less pronounced in rats that took cocaine as adolescents compared with adults. Conclusions  Surprisingly, these results may reflect resistance among adolescent subjects to some enduring effects of drug self-administration, such as reward learning.     

Binge toluene exposure alters glutamate, glutamine and GABA in the adolescent rat brain as measured by proton magnetic resonance spectroscopy

Despite the high incidence of toluene abuse in adolescents, little is known regarding the effect of binge exposure on neurochemical profiles during this developmental stage. In the current study, the effects of binge toluene exposure during adolescence on neurotransmitter levels were determined using high-resolution proton magnetic resonance spectroscopy ex vivo at 11.7T. Adolescent male Sprague-Dawley rats were exposed to toluene (0, 8000, or 12,000 ppm) for 15 min twice daily from postnatal day 28 (P28) through P34 and then euthanized either 1 or 7 days later (on P35 or P42) to assess glutamate (GLU), glutamine, and GABA levels in intact tissue punches from the medial prefrontal cortex (mPFC), anterior striatum and hippocampus. In the mPFC, toluene reduced GLU 1 day after exposure, with no effect on GABA, while after 7 days, GLU was no longer affected but there was an increase in GABA levels. In the hippocampus, neither GABA nor GLU was altered 1 day after exposure, whereas 7 days after exposure, increases were observed in GABA and GLU. Striatal GLU and GABA levels measured after either 1 or 7 days were not altered after toluene exposure. These findings show that 1 week of binge toluene inhalation selectively alters these neurotransmitters in the mPFC and hippocampus in adolescent rats, and that some of these effects endure at least 1 week after the exposure. The results suggest that age-dependent, differential neurochemical responses to toluene may contribute to the unique behavioral patterns associated with drug abuse among older children and young teens.     

Differential effects of inhaled toluene on locomotor activity in adolescent and adult rats

Inhalant abuse is a world-wide public health concern among adolescents. Most preclinical studies have assessed inhalant effects in adult animals leaving unclear how behavioral effects differ in younger animals. We exposed adolescent (postnatal day [PN] 28) and adult (PN90) male rats to toluene using 1 of 3 exposure patterns. These patterns modeled those reported in toluene abuse in teens and varied concentration, number and length of exposures, as well as the inter-exposure interval. Animals were exposed repeatedly over 12 days to toluene concentrations of 0, 8000 or 16,000 parts per million (ppm). Locomotor activity was quantified during toluene exposures and for 30 min following completion of the final daily toluene exposure. For each exposure pattern, there were significant toluene concentration-related increases and decreases in locomotor activity compared to the 0-ppm “air” controls at both ages. These changes depended upon when activity was measured — during or following exposure. Compared to adults, adolescents displayed greater locomotor activity on the first day and generally greater increases in activity over days than adults during toluene exposure. Adults displayed greater locomotor activity than adolescents in the “recovery” period following exposure on the first and subsequent days. Age group differences were clearest following the pattern of paced, brief (5-min) repeated binge exposures. The results suggest that locomotor behavior in rats during and following inhalation of high concentrations of toluene depends on age and the pattern of exposure. The results are consistent with dose-dependent shifts in sensitivity and sensitization or tolerance to repeated toluene in the adolescent animals compared to the adult animals. Alternate interpretations are possible and our interpretation is limited by the range of very high concentrations of toluene used. The results imply that both pharmacological and psychosocial factors contribute to the teen prevalence of inhalant abuse.