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.     

Acquisition and maintenance of cocaine self-administration in adolescent rats: effects of sex and gonadal hormones

Rationale Previous work has shown that adult female rats are more sensitive than adult male rats to the reinforcing effects of cocaine, an effect that appears to be due, at least in part, to ovarian hormones. Objective In this study, we examine sex differences in cocaine self-administration during adolescence, a period of marked hormonal change. Materials and methods Adolescent male and female Sprague–Dawley rats were trained to self-administer cocaine (0.75 mg/kg per infusion) under a fixed ratio 1 schedule (i.e., each response was reinforced by an infusion of cocaine) beginning on postnatal day 30. After acquisition, responding was assessed under a progressive-ratio schedule until postnatal day 50 with blood sampling occurring before the first five sessions to determine the relationship between gonadal hormones (i.e., estradiol, progesterone, and testosterone) and motivation for cocaine. Estrous cycle phase was monitored throughout the study. Separate groups of adolescent male and female rats were compared on the acquisition of and progressive-ratio responding for sucrose reinforcement. Results Females acquired cocaine self-administration more readily than did males, and a greater percentage of females acquired self-administration. Under progressive-ratio testing conditions, adolescent females responded at higher levels than adolescent males to obtain cocaine infusions, and in females, responding was positively associated with levels of estradiol and greatest during estrus. No sex differences were observed for sucrose reinforcement. Conclusion These findings suggest that sex differences are relevant during adolescence with evidence implicating circulating estradiol level as a factor that contributes to the enhanced sensitivity in females to the reinforcing effects of cocaine.     

Adolescent and adult responsiveness to the incentive value of cocaine reward in mice: role of neuronal nitric oxide synthase (nNOS) gene

A major concern in adolescent psychostimulant abuse is the long-term consequence of this practice, because early drug exposure may cause long-term adaptations, which render the organism more susceptible to drug abuse later in life. The incentive value of drug and natural reward in rodents is commonly assessed by the conditioned place preference (CPP) paradigm, which involves Pavlovian learning. The aims of the present study were to investigate: a) the acquisition, expression, maintenance and reinstatement of cocaine CPP from periadolescence (PD24-45) through adulthood (PD70); b) potential sexual dimorphism in adolescence and adulthood in response to cocaine-induced CPP; and c) the role of the neuronal nitric oxide synthase (nNOS) gene in long-term neural plasticity underlying responsiveness to cocaine and cocaine-associated cues. Adolescent wild type (WT) mice acquired significant cocaine (20 mg/kg) CPP that was maintained from PD24 through PD43. Upon extinction, CPP was reinstated in adulthood (PD70) following a priming injection of cocaine (5 mg/kg). In contrast, cocaine CPP acquired between PD26 and PD31 in adolescent nNOS knockout (KO) mice, was neither maintained nor reinstated by cocaine. There was no sexual dimorphism in adolescent WT and KO mice. Genotype differences and sexual dimorphism were observed in adult mice. Cocaine CPP in adult WT males (PD89-94) was maintained for 4 weeks post training, and subsequently reinstated by cocaine priming; the magnitude of CPP in adult WT males was lower than in female counterparts. CPP in adult KO males (PD88-93) was neither maintained nor reinstated by cocaine priming; in contrast, CPP in adult KO females was not significantly different from adult WT females. Results suggest that the nNOS gene is essential during adolescence of both sexes for the development of long-term neural plasticity underlying responsiveness to the incentive value of cocaine reward. Sexual dimorphism in response to cocaine CPP emerges in adulthood; nNOS contribution to long-term plasticity is therefore sexually dimorphic and age-dependent in female but not in male subjects.     

Influence of sex, estrous cycle, and drug-onset age on cocaine self-administration in rats (Rattus norvegicus)

The influence of sex, phase of the estrous cycle, and age of drug onset on cocaine self-administration was examined. Adult male, adult female, and adolescent male rats (Rattus norvegicus) were evaluated using low fixed-ratio (FR) schedules of drug delivery with a single fixed cocaine unit dose or a range of cocaine unit doses with a single FR schedule. Sex differences in adults were observed for mg/kg consumption of the 3.0-mg/kg unit dose, with consumption being significantly less in estrus females than in males. Over the estrous cycle, mg/kg consumption of this unit dose was significantly less during estrus than during metestrus-diestrus. Differences due to age of drug onset were also observed, with mg/kg consumption of the 3.0-mg/kg unit dose being significantly less in adolescent males than adult males or adult females during metestrus-diestrus. In contrast, these various groups did not have significantly different mg/kg intakes of cocaine unit doses <3.0 mg/kg, nor did they significantly differ in the rates and patterns of responding and number of infusions earned as a function of FR schedule or unit dose of cocaine available. The role of sex, estrus cycle, and drug-onset age on cocaine self-administration appears to be minimal under these experimental conditions. Experimental conditions that favor no sex or age differences in cocaine intake (1.0-mg/kg unit dose and low FR) may be useful for evaluating potential sex or age differences in the consequences of cocaine self-administration more reliably, as cocaine intake would not be an uncontrolled factor.     

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.     

Enhanced behavioral response to repeated-dose cocaine in adolescent rats

Rationale Most lifelong drug addiction in humans originates during adolescence. Important structural and functional changes in the brain occur during adolescence, but there has been little direct study of how this impacts on drug abuse vulnerability. An emerging literature suggests that adolescents exhibit different behavioral responses to single doses of several addictive drugs, including ethanol, amphetamine, and cocaine. However, few studies have explored behavioral responses to the repeated dosing that is characteristic of human abuse of these substances.Objectives We have investigated age-related behavioral responses to acute “binge” cocaine treatment between adults and adolescents.Results Adolescent rats displayed an exaggerated behavioral response to cocaine administered in two different binge patterns. Total locomotion after cocaine administration was the same in adolescents and adults. However, adolescent rats engaged in more intense stereotypic behaviors, including paw treading, head weaving, and focused sniffing than adult rats. These differences were observable following a modest dose of cocaine and became more robust following subsequent doses within a binge. Cocaine blood and brain levels were not significantly different between age groups during any of the exposure sessions.Conclusions These findings suggest that equivalent tissue concentrations of cocaine produce a greater behavioral response in young rats, and that adolescent animals display an apparent form of intrabinge sensitization.An erratum to this article can be found at     

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.     

Development and persistence of long-lasting behavioral sensitization to cocaine in female mice: Role of the nNOS gene

Our recent studies have shown that the neuronal nitric oxide synthase (nNOS) gene is required for the development and persistence of psychomotor sensitization to cocaine in adult but not adolescent male mice (Balda, M.A., Anderson, K.L., Itzhak, Y., 2008. Differential role of the nNOS gene in the development of behavioral sensitization to cocaine in adolescent and adult B6;129S mice. Psychopharmacology (Berlin) 200, 509-519.). The aim of the present study was to investigate the contribution of the nNOS gene to cocaine-induced behavioral sensitization in adolescent and adult female mice. Adolescent and adult wild type (WT) and nNOS knockout (KO) mice received saline or cocaine (20 mg/kg) for 5 days and then were challenged with cocaine (20 mg/kg) after a drug-free period of either 10, 30, or 90 days. Context-dependent sensitization was determined by measuring saline-induced locomotor activity in the previously cocaine-paired environment. Results show that adolescent females of both genotypes, like their adult counterparts, developed long-lasting behavioral sensitization to cocaine (a three-month period), suggesting high vulnerability of females to cocaine regardless of age. An effect of genotype was observed in the initiation of sensitization, e.g., delayed onset in the absence of the nNOS gene. The only age-dependent difference observed was that adult, but not adolescent mice developed context-dependent sensitization. The present study suggests that long-term expression of cocaine-induced behavioral sensitization in females (adolescent and adult) is nNOS-independent, unlike our previous findings in adult males.     

Female and male rats in late adolescence differ from adults in amphetamine-induced locomotor activity, but not in conditioned place preference for amphetamine

Rodent models display differences in drug-induced behaviour between prepubertal/young adolescents and adults that parallel developmental differences in people; however, little is known as to when the transition to 'adultlike' behaviour occurs. We investigated the differences in locomotor and reward responses to amphetamines in male and female rats in late adolescence and compared them with corresponding adult responses. Long-Evans rats were tested for locomotor activity and conditioned place preference (CPP) for amphetamine (0.25, 0.5 or 1.0 mg/kg), beginning at 45 or 69 days of age. Adolescent female rats moved less to the first injection of amphetamine compared with adult female rats irrespective of dose, whereas adolescent male rats did not differ from adults. Adolescent female rats significantly increased locomotor activity in response to subsequent injections of amphetamine at all three doses, whereas such sensitization was only found at the highest dose for adult female and male rats. No effect of repeated injections at any dose was observed in adolescent male rats. No age differences were observed in CPP, but female rats showed greater CPP during the dioestrous than during the oestrous phase of the cycle. These data suggest that differences in neural systems underlying some behavioural responses to amphetamine continue to mature postpubertally into late adolescence in a sex-specific manner.     

Repeated cocaine decreases the avoidance response to a novel aversive stimulus in rats

RATIONALE: Stress interacts with cocaine to produce enhanced neurochemical and behavioral responding to cocaine; however, few studies have examined unconditioned behavioral responses to aversive stimuli after repeated cocaine. OBJECTIVES. Studies were conducted to measure the approach/avoidance response to an aversive stimulus after repeated cocaine treatment in male and female rats. METHODS: An unconditioned approach/avoidance task was used in which rats were placed into a box with a novel, aversive stimulus (formaldehyde; Form), and place aversion was assessed. RESULTS: Initial studies established a dose-response curve using different concentrations of Form, and also determined that avoidance of Form was abolished by pretreatment with an anxiolytic dose of chlordiazepoxide. To examine the effects of prior cocaine treatment, intact or gonadectomized male and female rats were pretreated with daily saline or cocaine (15 mg/kg, IPx5 days), and their approach/avoidance response to Form was tested 4-7 days later. In intact males, cocaine decreased the avoidance of Form, and previous gonadectomy completely abolished this response. Decreased avoidance behavior did not appear to be linked to behavioral sensitization to cocaine, since gonadectomized males demonstrated locomotor sensitization when given subsequent cocaine challenge. In females, avoidance of Form was not altered by either cocaine or gonadectomy. Three experiments further characterized the approach/avoidance response to Form in males. In the first experiment, daily footshock stress did not significantly alter the avoidance of Form. In a second study, rats that displayed high and low locomotor responses to a novel cage showed no differences between groups in their avoidance of Form. In the third experiment, intra-nucleus accumbens microinjection of fluphenazine (5 micro g/side) attenuated the daily cocaine-induced decrease in avoidance of Form. CONCLUSIONS: These studies demonstrate that gonadal hormones may mediate cocaine-induced alterations in approach/avoidance to an aversive stimulus in males, and suggest that testosterone may act centrally to modulate dopamine responsiveness in the nucleus accumbens.     

Age- and sex-dependent amphetamine self-administration in rats

Rationale Recreational drug use peaks in the developmental stage of adolescence, and exposure to drugs during adolescence may predict drug dependence in adulthood. Nevertheless, adolescent drug vulnerability is not widely studied in animal models of drug intake, and very few studies have investigated sex differences in drug-related behavior during adolescence. Objectives We compared patterns of intravenous (i.v.) amphetamine self-administration among adolescent vs adult, male vs female Sprague–Dawley rats on a fixed ratio (FR) followed by a progressive ratio (PR) schedule of reinforcement. Materials and methods After surgical implantation of i.v. catheters, adolescent [postnatal day (P) 35–52] and adult (P90–106) male and female rats were allowed to acquire lever-pressing behavior reinforced by either 0.025 or 0.05 mg/kg/0.1-ml amphetamine infusions over 14 daily 2-h sessions on an FR1 schedule (n = 9–12 per age-, sex-, and dose-group). Subsequently, responding maintained by 0.0125 or 0.05 mg/kg per infusion amphetamine in 4-h sessions on a PR schedule was tested. Results Adolescent rats acquired amphetamine self-administration faster than adults, reached a higher number of infusions, and took more amphetamine than their adult counterparts during the acquisition phase, although age differences varied by dose. In PR testing, young adult males earned fewer infusions than older adult males, whereas young adult females earned more infusions than their older adult counterparts, and more than age-matched males. Conclusion These results suggest that i.v. amphetamine self-administration in rats is a useful model to investigate the potential neurochemical and endocrine bases for age and sex differences in vulnerability to behavioral reinforcement by amphetamine.     

The impact of early environmental rearing condition on the discriminative stimulus effects and Fos expression induced by cocaine in adult male and female rats

Rationale  A number of environmental manipulations, including maternal separation (MS), have been shown to alter behavioral responses to drugs of abuse. Objectives  This study assessed if MS affected the stimulus and Fos-inducing effects of cocaine. Materials and methods  In experiment 1, male and female Sprague–Dawley rats were exposed to brief maternal separations (BMS), long maternal separations (LMS), or animal facility rearing (AFR) and then trained as adults to discriminate cocaine (10 mg/kg, intraperitoneally) from saline. Following training, generalization tests to novel doses of cocaine and other dopaminergic compounds were performed. Assessments of variations in training dose pretreatment times were also made. In experiment 2, male and female rats exposed to MS conditions were administered cocaine or saline for 14 days, and Fos expression in the mesolimbic system was measured. Results  In males, BMS retarded the acquisition of the cocaine discrimination. Generalization to novel doses of cocaine did not differ among rearing conditions, but the training dose cue lasted longer in LMS. Distinct generalization and ED₅₀ profiles were found between male rearing conditions for all dopamine compounds. While BMS females had higher cocaine ED₅₀ estimates, no other differences were found in females. LMS males and females, as well as AFR females, had significant increases in Fos expression after cocaine in a region-specific manner. No differences were found with other rearing groups. Conclusion  Early environmental variables altered the stimulus effects (in a sex-dependent manner) as well as the neuronal responsiveness to cocaine, which may be mediated by the dopamine system.     

Effect of gonadectomy and gonadal hormone replacement on cocaine self-administration in female and male rats.

Both sex and gonadal steroid hormones may influence the abuse-related behavioral effects of cocaine under some conditions, but there is considerable inconsistency in the literature. In the present study, rats were trained under a fixed ratio (FR) 5 schedule of food presentation and were then allowed to self-administer cocaine (1.0 mg/kg/injection) until behavior stabilized. Subsequently, complete dose-effect functions for cocaine self-administration (0.032-3.2 mg/kg/injection) were determined in female and male rats before and after gonadectomy, and in gonadectomized female and male rats before and during chronic treatment with estradiol or testosterone, respectively. Sex, gonadectomy, and gonadal hormones did not alter the shape or position of dose-effect functions for cocaine self-administration. These results suggest that sex, estrogen, and testosterone levels are not critical determinants of cocaine's reinforcing effects in rats under these conditions. This study differed from earlier studies in that complete dose-effect functions for cocaine were determined. These findings suggest that the behavioral training history, the unit dose of cocaine, and the schedule of reinforcement are important variables in studies of sex and gonadal hormone effects on cocaine self-administration.     

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.     

Gonadal hormone modulation of the behavioral effects of Delta9-tetrahydrocannabinol in male and female rats

Female rats are more sensitive than males to many behavioral effects of cannabinoids. The purpose of the present study was to determine if sex differences in the antinociceptive and motoric effects of Delta(9)-tetrahydrocannabinol (THC) are due to activational effects of gonadal steroid hormones. THC-induced antinociception (tail withdrawal, paw pressure tests) and motoric effects (horizontal locomotion, catalepsy) were compared in male and female gonadectomized rats that were chronically treated with hormone (testosterone in males, estradiol in females) vs. those that were gonadectomized and had no hormone replacement. THC's effects were also compared between gonadally intact females tested during vaginal estrus vs. diestrus. THC (5 and 10 mg/kg i.p.) produced very similar antinociceptive effects in no-hormone vs. testosterone-treated males, but significantly less locomotor suppression in testosterone-treated males than those with no hormone replacement. In gonadectomized females, estradiol enhanced THC's antinociceptive but not motoric effects. In gonadally intact, cycling females, 5 mg/kg THC produced slightly to significantly greater behavioral effects in estrous than in diestrous females. These results suggest that sex differences in THC-induced behavioral effects in the adult rat can be attributed to activational effects of testosterone in males and/or estradiol in females.     

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.     

Adolescent vs. adult-onset nicotine self-administration in male rats: duration of effect and differential nicotinic receptor correlates

Adolescence is the life stage when tobacco addiction typically begins. Adolescent neurobehavioral development may be altered by nicotine self-administration in a way that persistently potentiates addiction. Previously, we showed that female adolescent rats self-administer more nicotine than do adults and that the increased nicotine intake then persists through the transition to adulthood [E.D. Levin, A. Rezvani, D. Montoya, J. Rose, H. Swartzwelder, Adolescent-onset nicotine self-administration modeled in female rats, Psychopharmacology 169 (2003) 141-149.]. In the current study, male Sprague-Dawley rats were given access to nicotine via the standard operant IV self-administration procedure (nicotine bitartrate dose of 0.03 mg/kg/infusion). One group of male rats started during adolescence the other group started in young adulthood. After the end of the four-week period of self-administration brain regions of the rats were assessed for alpha4beta2 nicotinic receptor binding. We found that male rats, like females, show higher nicotine self-administration when starting during adolescence as compared to starting in adulthood (p<0.001). Indeed, the effect in adolescent males was even greater than that in females, with more than triple the rate of nicotine self-administration vs. the adult-onset group during the first 2 weeks. The adolescent onset nicotine-self-administering rats also had significantly greater high affinity nicotinic receptor binding in the midbrain and the striatum, whereas hippocampal binding did not differ between the age groups. Striatal values significantly correlated with nicotine self-administration during the first 2 weeks in the adult-onset group but not the adolescent-onset rats, suggesting that the differences in self-administration may depend in part on underlying disparities in synaptic responses to nicotine. After the initial 2 weeks, nicotine self-administration in male rats declined toward adult-like levels, as the adolescent rats approached adulthood. This study showed that adolescent male rats self-administer significantly more nicotine than do male adult rats, but that adolescent-onset nicotine self-administration in male rats declines over weeks of continued use to approach adult-onset levels. In a previous study, we found that female rats also show greater nicotine self-administration with adolescent onset vs. adult onset, but that the females continued higher rates of self-administration into adulthood. Our results thus reinforce the concept that the adolescent brain is unusually receptive to the effects of nicotine in a manner that reinforces the potential for addiction.     

Progesterone and allopregnanolone are induced by cocaine in serum and brain tissues of male and female rats

Acute and chronic-cocaine administration increase serum levels of progesterone in both male and female rats. This study aimed to determine whether progesterone and its bioactive metabolite allopregnanolone (ALLOP) are altered in the hippocampus and striatum (areas known to modulate cocaine-induced behavioral response) after acute cocaine administration. To this end, male and female rats were administered 20 mg/kg and 5 mg/kg of cocaine, respectively (doses that produce equivalent behavioral responses between the sexes). Thirty minutes after drug treatment, serum and brain were collected and later analyzed for progesterone and ALLOP levels using HPLC measurements. At these cocaine doses, no sex differences in the overall behavioral responses after drug treatment were observed. In saline-treated controls, female rats had overall higher levels of progesterone in the serum than did male rats. After cocaine administration, progesterone and ALLOP levels in serum, hippocampus, and striatum were increased at similar levels in both sexes. In the hippocampus, progesterone levels were increased in both males and females, but ALLOP levels were increased only in females.     

Adult vs. adolescent rats differ in biobehavioral responses to chronic nicotine administration

More than 90% of smokers begin smoking during adolescence, suggesting that nicotine's actions may differ in adults vs. adolescents in ways that render adolescents vulnerable to smoking initiation. This experiment tested the hypothesis that nicotine's biobehavioral actions differ in adult and adolescent rats. Forty-two male (21 adolescents, 21 adults) and 41 female (21 adolescents, 20 adults) Sprague–Dawley rats were administered saline or 12 mg/kg/day nicotine via osmotic minipump for 21 days. Body weight, feeding, and locomotion (horizontal activity, vertical activity, center time) were measured before, during, and after saline or nicotine administration. Nicotine's effects depended on age and sex. Nicotine reduced body weight and feeding of adult males and females, and of adolescent males, but not of adolescent females. In addition, adolescent males were more sensitive than adults or adolescent females to nicotine's activity-enhancing effects. In cessation, nicotine-exposed adolescent males continued to exhibit greater activity than saline-exposed animals. Results indicate that nicotine's biobehavioral actions differ depending on age and sex.     

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.