Chronic Ethanol Exposure during Adolescence Increases Voluntary Ethanol Consumption in Adulthood in Female Sprague Dawley Rats.

Early alcohol use is a major concern due to the dramatic rise in alcohol use during adolescence. In humans, adolescent males and females consume alcohol at equivalent rates; however, in adulthood males are more likely to consume harmful levels of alcohol. In animal models, the long-term dose-dependent and sex-dependent effects of alcohol exposure during adolescence have not been readily assessed relative to exposure that is initiated in adulthood. The purpose of the present set of experiments was to determine if adolescent exposure to chronic ethanol would predispose male and female rats to greater ethanol intake in adulthood when compared to animals that were not exposed to chronic ethanol exposure until early adulthood. Male and female rats were chronically administered 0.75 g/kg or 1.5 g/kg ethanol or saline for 21 days during adolescence (postnatal day (PND) 30-50) or adulthood (PND 60-80). All rats subsequently underwent 14-days of abstinence (PND 51-64 or PND 81-94, respectively). Finally, all rats were given 30-min daily access to saccharin-sweetened ethanol or saccharin alone from PND 65-80 for adolescent-exposed rats and PND 95-110 for adult-exposed rats. Exposure to 0.75 g/kg ethanol did not alter ethanol or saccharin intake in adolescent-exposed or adult-exposed rats, regardless of sex. In contrast, chronic exposure to the higher 1.5 g/kg dose during adolescence increased ethanol intake in adulthood in female rats. However, there was no change in saccharin intake in animals exposed to 1.5 g/kg ethanol during adolescence or adulthood, regardless of sex. Additionally, there were no clear age- and ethanol-dependent changes in duration of loss of righting reflex and blood ethanol concentrations to a challenge administration of a higher dose of ethanol. The results of the present set of experiments indicate chronic exposure to a high dose of ethanol during adolescence in female rats did indeed predispose rats to consume more ethanol in adulthood. Given that these effects were only observed in adolescent-exposed female rats, these results support a unique vulnerability to the long-term consequences of adolescent ethanol exposure in female rats, an effect that is not merely mediated by the sweetener used in the ethanol solution.

Social Interaction With an Alcohol-Intoxicated or Cocaine-Injected Peer Selectively Alters Social Behaviors and Drinking in Adolescent Male and Female Rats.

BACKGROUND: Drinking alcohol is facilitated by social interactions with peers, especially during adolescence. The importance of peer social influences during adolescence on alcohol and substance use has recently received more attention. We have shown that social interaction with an alcohol-intoxicated peer influences adolescent alcohol drinking differently in male and female rats using the demonstrator-observer paradigm. The present set of experiments analyzed the social interaction session to determine changes in social behaviors and subsequent alcohol drinking in adolescent male and female rats. METHODS: Specifically, in Experiment 1, we determined whether specific social behaviors were altered during interaction with an alcohol-intoxicated demonstrator administered 1.5 g/kg ethanol (EtOH) and assessed changes in EtOH intake in adolescent observers. Experiment 2 examined changes in voluntary saccharin consumption to determine whether social interaction with an alcohol-intoxicated demonstrator administered 1.5 g/kg EtOH altered consumption of a palatable solution. In Experiment 3, we administered saline, and a low (5 mg/kg) or high (20 mg/kg) dose of cocaine to the demonstrator and assessed changes in the adolescent observers to determine whether social interaction with a "drugged" peer altered social behaviors and voluntary EtOH intake. RESULTS: We showed that social interaction with an alcohol-intoxicated demonstrator administered 1.5 g/kg EtOH (i) decreased social play and increased social investigation and social contact in adolescent male and female observers, (ii) did not alter nonsocial behaviors, (iii) did not alter saccharin consumption, and (iv) increased voluntary EtOH intake in adolescent female but not male observers. When the peer was injected with cocaine, (i) social play was dose-dependently decreased, (ii) there were no changes in other social or nonsocial behaviors, and (iii) voluntary EtOH intake in adolescent male and female observers was unaffected. CONCLUSIONS: The present results are consistent and extend our previous work, showing that social interaction with an alcohol-intoxicated peer selectively alters social behaviors and alcohol drinking in adolescent rats. Females appear to be more sensitive to the elevating effects of social interaction on voluntary EtOH consumption.

Reversal learning and experimenter-administered chronic intermittent ethanol exposure in male rats.

RATIONALE: Chronic alcohol exposure is associated with impaired decision making skills, cognitive deficits, and poor performance on tasks requiring behavioral flexibility. Although oral routes of alcohol administration are commonly used to examine effects of alcohol on various behaviors in rodents, only a few investigations have used intragastric exposures to evaluate ethanol's effects on behavioral flexibility in the adult rat. OBJECTIVES: The aim of the current series of experiments was to determine if behavioral flexibility impairments would be demonstrated across a variety of procedural factors, including route of administration [intraperitoneal injection (i.p.), intragastric gavage (i.g.)], ethanol dose (3-5 g/kg), number of daily exposures (once/day, twice/day), duration of exposure (2-6 weeks), or length of abstinence (5-7 days). METHODS: Adult male Sprague-Dawley rats were exposed to chronic intermittent ethanol (CIE) or vehicle and evaluated for behavioral intoxication, blood ethanol concentrations (BEC), and performance on a reversal learning odor discrimination task. RESULTS: While all rats displayed behavioral intoxication and elevated BECs, CIE i.p. rats had prolonged elevation in BECs and made the most errors during the reversal learning task. Unexpectedly, CIE i.g. exposures failed to produce deficits during reversal learning tasks regardless of ethanol dose, frequency/duration of exposure, or length of abstinence. CONCLUSIONS: Behavioral flexibility deficits resulting from CIE i.p. exposures may be due to the severity and chronicity of alcohol intoxication. Elucidating the impact of ethanol on behavioral flexibility is critical for developing a better understanding of the behavioral consequences of chronic alcohol exposure.

Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning.

Drugs that modulate serotonin (5-HT) synaptic concentrations impact neurogenesis and hippocampal (HPC)-dependent learning. The primary objective is to determine the extent to which psilocybin (PSOP) modulates neurogenesis and thereby affects acquisition and extinction of HPC-dependent trace fear conditioning. PSOP, the 5-HT2A agonist 25I-NBMeO and the 5-HT2A/C antagonist ketanserin were administered via an acute intraperitoneal injection to mice. Trace fear conditioning was measured as the amount of time spent immobile in the presence of the conditioned stimulus (CS, auditory tone), trace (silent interval) and post-trace interval over 10 trials. Extinction was determined by the number of trials required to resume mobility during CS, trace and post-trace when the shock was not delivered. Neurogenesis was determined by unbiased counts of cells in the dentate gyrus of the HPC birth-dated with BrdU co-expressing a neuronal marker. Mice treated with a range of doses of PSOP acquired a robust conditioned fear response. Mice injected with low doses of PSOP extinguished cued fear conditioning significantly more rapidly than high-dose PSOP or saline-treated mice. Injection of PSOP, 25I-NBMeO or ketanserin resulted in significant dose-dependent decreases in number of newborn neurons in hippocampus. At the low doses of PSOP that enhanced extinction, neurogenesis was not decreased, but rather tended toward an increase. Extinction of "fear conditioning" may be mediated by actions of the drugs at sites other than hippocampus such as the amygdala, which is known to mediate the perception of fear. Another caveat is that PSOP is not purely selective for 5-HT2A receptors. PSOP facilitates extinction of the classically conditioned fear response, and this, and similar agents, should be explored as potential treatments for post-traumatic stress disorder and related conditions.

Investigation of age-specific behavioral and proteomic changes in an animal model of chronic ethanol exposure.

Alcohol use during adolescence represents a major health concern given that this is a period in which the brain continues to undergo critical developmental changes. Much behavioral research has been conducted in animal models of alcohol exposure, and a vulnerable period in adolescence has been identified that suggests lasting effects of ethanol exposure during adolescence. However, identification of molecular changes underlying the behavioral outcomes observed as a result from exposure to ethanol during adolescence remains a major technical challenge. In this chapter, we describe a method that allows for assessment of the effects of chronic ethanol exposure during adolescence relative to adulthood through global-scale analysis of protein expression as well as evaluation of behavioral responsivity in adolescent and adult rats. Results from this type of analysis can facilitate identification of age-specific molecular markers associated with behavioral changes following treatment with ethanol or in other animal models of drug abuse.

Cocaine-induced reinstatement of a conditioned place preference in developing rats: involvement of the d2 receptor.

Reinstatement of conditioned place preferences have been used to investigate physiological mechanisms mediating drug-seeking behavior in adolescent and adult rodents; however, it is still unclear how psychostimulant exposure during adolescence affects neuron communication and whether these changes would elicit enhanced drug-seeking behavior later in adulthood. The present study determined whether the effects of intra-ventral tegmental area (VTA) or intra-nucleus accumbens septi (NAcc) dopamine (DA) D2 receptor antagonist infusions would block (or potentiate) cocaine-induced reinstatement of conditioned place preferences. Adolescent rats (postnatal day (PND 28-39)) were trained to express a cocaine place preference. The involvement of D2 receptors on cocaine-induced reinstatement was determined by intra-VTA or intra-NAcc infusion of the DA D2 receptor antagonist sulpiride (100 µM) during a cocaine-primed reinstatement test (10 mg/kg cocaine, i.p.). Infusion of sulpiride into the VTA but not the NAcc blocked reinstatement of conditioned place preference. These data suggest intrinsic compensatory mechanisms in the mesolimbic DA pathway mediate responsivity to cocaine-induced reinstatement of a conditioned place preference during development.

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.

Alcohol during adolescence selectively alters immediate and long-term behavior and neurochemistry.

Alcohol use increases across adolescence and is a concern in the United States. In humans, males and females consume different amounts of alcohol depending on the age of initiation, and the long-term consequences of early ethanol consumption are not readily understood. The purpose of our work was to better understand the immediate and long-term impact of ethanol exposure during adolescence and the effects it can have on behavior and dopaminergic responsivity. We have assessed sex differences in voluntary ethanol consumption during adolescence and adulthood and the influence of binge ethanol exposure during adolescence. We have observed that males are sensitive to passive social influences that mediate voluntary ethanol consumption, and early ethanol exposure induces long-term changes in responsivity to ethanol in adulthood. Exposure to moderate doses of ethanol during adolescence produced alterations in dopamine in the nucleus accumbens septi during adolescence and later in adulthood. Taken together, all of these data indicate that the adolescent brain is sensitive to the impact of early ethanol exposure during this critical developmental period.

Effects of MDMA ("ecstasy") during adolescence on place conditioning and hippocampal neurogenesis.

The use of 3,4,methylenedioxymethamphetamine (MDMA), the active agent in ecstasy, during adolescence is widespread yet the effects on adolescent behavior and brain development are unknown. The aim of the present study was 1) to evaluate effects of MDMA in adolescent rats using the conditioned place preference (CPP) paradigm to measure MDMA-induced reward and 2) assess effects of MDMA administration on cellular proliferation, survival and neurogenesis in the dentate gyrus of the hippocampus. During the adolescent period, MDMA CPP was measured in adolescents [postnatal day (PND) 28-39] by training rats to associate 1.25, 2.5, 5.0mg/kg MDMA or saline administration with environmental cues. After CPP ended, bromodeoxyuridine (BrdU) was injected and rats were euthanized either 24h (to evaluate cell proliferation) or 2 weeks (to assess neurogenesis) after the last MDMA injection. Adolescents expressed a CPP for 2.5mg/kg MDMA. Repeated exposure to 5.0mg/kg MDMA during adolescence increased cell proliferation, yet diminished neurogenesis, an effect that was replicated using flow cytometry. These findings suggest differential dose effects of adolescent MDMA exposure on reward related behaviors and hippocampal neurogenesis.

Repeated ethanol exposure during adolescence alters the developmental trajectory of dopaminergic output from the nucleus accumbens septi.

Individuals who begin using alcohol prior to 14 years of age are 4 times more likely to progress to addiction than those who do not initiate use until 21 years of age. The nucleus accumbens septi undergoes dramatic developmental transitions during the adolescent period, and dopaminergic activity within this region has been identified as a central neurochemical mediator of drug reward, addiction and dependence. Thus, alcohol-induced neurochemical alterations in dopaminergic activity within this brain region likely mediate the heightened vulnerability to addiction observed in adolescent alcohol users. To investigate this idea, Sprague-Dawley rats were exposed to intraperitoneal injections of either saline or ethanol (0.5, 1.0 or 2.0 g/kg) twice daily over four days beginning on postnatal day 21, 31, 41 or 56. Cannulas were implanted toward the nucleus accumbens septi, subsequent in vivo microdialysis was used to collect samples, and both basal and ethanol-stimulated dopamine overflow was measured using high performance liquid chromatography with electrochemical detection. A developmental transition in basal levels of dopamine in the nucleus accumbens septi was apparent with peak levels at postnatal day 45. An ethanol challenge produced unique responses across ages, with greater peak effects relative to baseline in younger animals (postnatal day 25 and 35). Following repeated exposure to ethanol, a significant increase in basal dopamine was apparent for all ages, and when these animals were challenged with ethanol, peak effects relative to baseline were decreased in younger animals, but unchanged in older animals (postnatal day 45 and 60). Results indicate that there is a key developmental transition in the ability of rats to adapt to the effects of repeated ethanol exposure, which occurs between postnatal day 35 and 45. This alteration may explain the increased addiction vulnerability observed in individuals who initiate alcohol use during early adolescence.

Social interaction and partner familiarity differentially alter voluntary ethanol intake in adolescent male and female rats.

Alcohol readily facilitates social interactions and this effect plays an important role in adolescent drinking behaviors. The ability of social interaction to alter behaviors in response to alcohol in adolescent animals has been assessed using the demonstrator-observer paradigm. The demonstrator is exposed to ethanol and the observer is tested for changes in behaviors in response to ethanol after social interaction between the dyad. The present experiment expanded on previous work to investigate the effects of different types of social interaction on subsequent voluntary ethanol consumption in adolescent male and female rats. Specifically, voluntary ethanol intake was assessed in adolescent observers after social interaction with an alcohol-free or -intoxicated same-sex familiar cage-mate or an age-matched unfamiliar conspecific. Demonstrators were intragastrically administered water or 1.5 g/kg ethanol and allowed to socially interact with observers for 30 min after a 1-h social isolation period. Subsequently, observers were allowed voluntary access to ethanol using a two-bottle choice paradigm overnight for 13 h. Male and female observers that interacted with an alcohol-intoxicated familiar cagemate consumed significantly more ethanol relative to their alcohol-free counterparts. However, adolescent male observers that socially interacted with an alcohol-intoxicated, age-matched unfamiliar conspecific consumed significantly less ethanol than controls. The opposite effect was observed in adolescent female observers. The present results are consistent and extend previous work in support of the idea that exposure to the demonstrator-observer paradigm alters voluntary ethanol intake in a sex- and familiarity-dependent manner. Partner familiarity can induce elevated or reduced ethanol consumption in males. However, females appear to be more sensitive to the elevating effects of social interaction on voluntary ethanol consumption, regardless of familiarity of the partner.

Voluntary ethanol consumption differs in adolescent and adult male rats using a modified sucrose-fading paradigm.

BACKGROUND: Initiation of alcohol consumption during adolescence is high, which usually begins with consumption of highly concentrated sweetened alcoholic beverages in adolescent humans. Enhanced voluntary ethanol (EtOH) intake has been observed previously in adolescent relative to adult rats under continuous access conditions using sweetened EtOH solutions. The present set of experiments investigated patterns of voluntary EtOH intake in adolescent and adult rats using sweetened EtOH solutions in a limited access paradigm. METHODS: Rats were trained with modified sucrose-substitution protocols that ended at either 5% sucrose-20% EtOH (5S/20E) (Exp. 1) or 5% sucrose-10% EtOH (5S/10E) (Exp. 2). RESULTS: Voluntary EtOH consumption differences between the 2 age groups were apparent at higher (i.e., 10 and 20%), but not lower (i.e., 2 and 5%) EtOH concentrations. Adolescent rats consumed more EtOH on a g/kg basis only at 20% EtOH (Exp. 1). Adolescent rats voluntarily consumed more EtOH than adults when maintained at 5S/10E (Exp. 2). To assess whether these age-related differences in voluntary EtOH intake were concentration dependent, rats were trained with 5S/20E and subsequently trained with decreasing EtOH concentrations (i.e., 5S/10E and 5S/5E). Adolescents consumed more EtOH when initially presented with the 5S/10E and 5S/20E EtOH concentrations, and subsequently at the lower 5S/5E EtOH concentration (Exp. 3). There were no differences in preference for the sucrose-only solution, however adolescents tended to consume more sucrose at the 5S sucrose concentration (Exp. 4). Given that adolescents consumed more EtOH at the 5S/10E and 5S/20E, but not at the 5S/5E EtOH concentrations, preference for sucrose does not solely explain the age differences in voluntary EtOH intake observed. CONCLUSIONS: Overall, results replicate previous work, demonstrating adolescent rats consume more EtOH relative to adults. However, the present results were observed using sweetened EtOH solutions in a limited access paradigm. The present modified sucrose-substitution paradigm may serve as a valid model of human adolescent drinking behavior.

Localization of stereotaxic coordinates for the ventral tegmental area in early adolescent, mid-adolescent and adult rats.

The ventral tegmental area (VTA) is a brain region implicated in drug addiction and related behaviors; however, little research has been conducted examining the role of the VTA in these processes in adolescent rats. Understanding the development of the VTA is imperative for elucidating mechanisms mediating adolescent vulnerability to drug addiction. The purpose of the present study was to define stereotaxic coordinates for the VTA in developing rats. Early adolescent [postnatal day (PND) 28], mid-adolescent (PND 35), or adult male rats (PND 70) were surgically implanted with a guide cannula aimed at the VTA. Adult coordinates, (P: -3.5, L: +1.0, V: -8.5 mm from Bregma) were used as a baseline and guided localization of VTA coordinates for early and mid-adolescent rats. After recovery, dye was injected via a microdialysis probe and brains were removed, sliced, and stained for histological verification of cannula placement in the VTA. Data suggest VTA coordinates in adolescents differ significantly from adult rats. These findings imply that it is imperative to consider anatomical differences in the development of the VTA when comparing the neurochemical effects of abused drugs in adolescent and adult rats.

Early adolescents show enhanced acute cocaine-induced locomotor activity in comparison to late adolescent and adult rats.

Initiation of drug use during adolescence is associated with an increased probability to develop a drug addiction. The present study examined dose-response effects of cocaine (0, 5, 10, or 20 mg/kg, i.p.) on locomotor activity in early adolescent (postnatal day (PND) 35), late adolescent (PND 45), and young adults (PND 60) by measuring total distance moved (TDM) and frequency of start-stops. In response to 20 mg/kg cocaine, early adolescents showed the greatest cocaine-induced increase in TDM in comparison to late adolescent and adult rats. At this same dose, early adolescents showed the greatest cocaine-induced attenuation of start-stops relative to older rats. Results suggest that early adolescents engage in more cocaine-induced locomotor activity and less stationary behavior indicating that early adolescents are more sensitive to locomotor activating effects of high dose cocaine than older rats.

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 ethanol exposure during adolescence increases basal dopamine in the nucleus accumbens septi during adulthood.

BACKGROUND: In humans, adolescent exposure to alcohol is associated with the onset of adult alcohol dependency and suggests that early use potentiates vulnerability to addiction. The aim of the present study was to address whether chronic ethanol exposure during adolescence would alter nucleus accumbens septi (NAcc) dopamine (DA) levels in the adult brain. METHODS: Rats were injected daily from postnatal day (PND) 30 to 50 with either 0.75 g/kg/i.p. ethanol or saline followed by an ethanol-abstinent period from PND 51 to 65. Changes in extracellular DA levels in the anterior NAcc shell were measured via the no net flux (NNF) paradigm. RESULTS: Extracellular DA levels were greater in rats chronically treated with ethanol during adolescence (6.5 nM DA) in comparison with saline-exposed controls (3.6 nM DA). There were no differences in extraction fraction (E(d)), an indirect measure of DA reuptake, between ethanol-treated (87%) and nontreated (68%) rats. CONCLUSIONS: Together these findings suggest that changes in extracellular DA may be an underlying physiological mechanism in adolescent vulnerability to the rewarding properties of ethanol.

Cocaine during adolescence enhances dopamine in response to a natural reinforcer.

The use of cocaine during adolescent development could alter the normal growth of brain regions affected by cocaine, specifically the reward system, and impact the adult mesolimbic system. However, there is scant literature aimed at determining whether animals are more vulnerable to the adverse effects of drugs during adolescence. The present study investigated whether cocaine pretreatment in either adolescence or adulthood altered the dopaminergic response to a naturally reinforcing substance in adulthood. To evaluate the responsivity of the mesolimbic system after repeated cocaine, sucrose was offered during the dialysis procedure and dialysates were collected. Regardless of age all saline pretreated rats had significant increases in sucrose-induced extracellular dopamine (DA) levels in the nucleus accumbens septi (NAcc) as compared to baseline levels. Rats pretreated with cocaine as adults also had significant increases in DA levels after sucrose. Interestingly, sucrose intake significantly enhanced DA levels in cocaine pretreated adolescent rats as compared to all other conditions. The results from the present study show that in rats pretreated with cocaine during adolescence there is an enhanced response of the dopaminergic system in animals exposed to a naturally reinforcing substance. Therefore, cocaine exposure during adolescence results in long-term functional changes in the mesolimbic pathway. Future studies need to ascertain the underlying mechanisms and their potential role in cocaine addiction.

Adolescents differ from adults in cocaine conditioned place preference and cocaine-induced dopamine in the nucleus accumbens septi.

In humans, adolescent exposure to illicit drugs predicts the onset of adult drug abuse and suggests that early drug use potentiates vulnerability to drug addiction. Cocaine conditioned place preferences were measured in early adolescent [postnatal day (PND) 35], late adolescent (PND 45) and young adult (PND 60) rats by injecting either 0, 5 or 20 mg/kg cocaine and conditioning them to environmental cues. Cocaine preferences were found for all ages at the high dose. PND 35s were the only age group to have a preference at the low dose. To address whether age-related differences in cocaine place preferences were related to differences in the mesolimbic dopaminergic system, we measured extracellular dopamine levels in the nucleus accumbens septi of PND 35, PND 45 and PND 60 rats via quantitative microdialysis under transient conditions. Rats were injected daily with either 5 mg/kg/ip or saline for 4 days and surgically implanted with a microdialysis probe aimed at the nucleus accumbens. Rats were perfused with either 0, 1, 10 or 40 nM dopamine and the extracellular dopamine concentration was measured. Our results show that adolescents differ from adults in basal dopamine. All cocaine treated rats, regardless of age, showed a significant increase in dopamine over baseline in response to a cocaine challenge. Additionally, there were age-related differences in the extraction fraction (E(d)), an indirect measure of dopamine reuptake. Together these findings suggest ontogenetic differences in extracellular dopamine and dopamine reuptake and that these differences may provide an explanation for adolescent vulnerability to addiction.

Effects of novelty on behavior in the adolescent and adult rat.

Adolescence is a time of high-risk behavior and increased exploration. This developmental period is marked by a greater probability of initiating drug use and is associated with an increased risk to develop addiction and dependency in adulthood. Human adolescents are predisposed towards an increased likelihood of risk taking behaviors (Zuckerman, 1986), including drug use or initiation. The purpose of the study was to examine differences in developmental risk taking behaviors. Adolescent and adult animals were exposed to a novel stimulus in a familiar environment to assess impulsive behaviors, novelty preference, and exploratory behaviors. Adolescent animals had greater novelty-induced locomotor activity, greater novelty preference, and showed higher approach and exploratory behaviors compared to adult animals. These data support the notion that adolescents may be predisposed toward sensation seeking and consequently, are more likely to engage in risk-taking behaviors, such as drug use initiation.

Cocaine-induced locomotor activity is increased by prior handling in adolescent but not adult female rats.

Adolescence is a period of transition that is associated with increased levels of stress and a heightened propensity to initiate drug use. Neuronal development is still occurring during this transitional period, which includes the continued development of the dopamine system during the adolescent period. In the present study, the effects of pre-test handling on cocaine-induced locomotor activity were investigated among female adolescent and young adult rats upon presentation to a novel environment. On postnatal days (PND) 41-44 and 56-59 animals were handled (b.i.d.) in the colony room for 3 min. On PND 45 or PND 60, animals were removed from the colony room, weighed, and administered an acute injection of either cocaine or saline and presented to a novel environment where behavior was recorded for 30 min. Adolescent females (PND 45) that were handled prior to cocaine administration demonstrated elevated levels of cocaine-induced activity relative to their age-matched non-handled counterparts and also to their handled-adult counterparts. In contrast, among non-handled animals, young adults (PND 60) exhibited elevated drug-induced locomotion at several time points during the trial. Non-handled adolescent animals demonstrated the previously described "hyporesponsive" behavioral profile relative to their non-handled adult counterparts. The results from the present experiment indicate that adolescent animals may be more sensitive to basic laboratory manipulations such as pre-test handling, and care must be taken when utilizing adolescent animals in behavioral testing. Handling appears to be a sensitive manipulation in elucidating differences in cocaine-induced behavioral activation between ages.