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Background: Sensitivity to the motor-impairing and hypnotic effects of ethanol (EtOH) increases notably during development. Less is known, however, about the ontogeny of EtOH tolerance and the ontogenetic relationship among different types of tolerance. Consequently, we compared the ontogenetic development of acute, rapid, and chronic tolerance to EtOH-induced motor impairment and hypothermia in a swim task. Methods: Preweanling, adolescent, and adult female and male Sprague-Dawley rats were given chronic saline (control group), five daily EtOH exposures before EtOH on test day (chronic group), one EtOH exposure before test day (rapid group), or EtOH exposure only on test day (acute groups). Separate groups of animals in the acute groups were tested at 15, 60, or 105 min after injection to estimate acute tolerance development via calculating slopes of the linear regression of impairment relative to brain alcohol levels at each postinjection interval. Initial EtOH perturbation of swim performance was equated across age by varying EtOH dose. Results: Acute tolerance was evident to the motor-impairing effects of EtOH at all ages. When impairment was indexed relative to brain alcohol levels, rapid and chronic tolerance to the motor-impairing effects of EtOH on latency to reach the start was seen across age, although this tolerance tended to be more pronounced in adults. Somewhat different ontogenetic patterns of tolerance development were observed with EtOH-induced hypothermia, a dependent measure for which EtOH perturbation was not equated across age. Conclusions: The degree of initial perturbation by EtOH seems to be an important predictor of tolerance expression during ontogeny. That is, ontogenetic profiles of tolerance development differ significantly when EtOH-induced motor impairment is equated across age rather than dose of EtOH administered . The role of target response measures and context stress should also be considered when exploring ontogenetic expression of EtOH tolerance.

Background: Recent evidence suggests that human infants prefer alcohol-flavored milk when fed through a bottle. Animal models also indicate a surprising predisposition for neonatal and infant rats to voluntarily and willingly ingest ethanol. These findings suggest high susceptibility to the reinforcing properties of ethanol early in ontogeny. Methods: A surrogate nipple technique—a highly effective tool for investigation of the reinforcing properties of different fluids—was applied in the present study. Tests of ethanol reinforcement were accomplished in terms of two basic paradigms of Pavlovian conditioning. In one paradigm, the conditioned stimulus (CS) was the surrogate nipple, and in the other, the CS was a novel odor. Results: Newborn rats showed sustained attachment to the nipple providing 5% ethanol, and later reproduced this behavioral pattern toward the empty nipple (CS alone). Ingestion of ethanol yielding appetitive reinforcement was accompanied by detectable blood alcohol concentrations, with most in the range of 20–30 mg/dl. The reinforcing efficacy of ethanol was also confirmed in the classical olfactory conditioning paradigm: following pairing with intraoral ethanol infusions, the odor (CS) alone elicited sustained attachment to an empty nipple. Females showed better olfactory conditioning with low concentrations of ethanol, whereas males were effectively more conditioned to high concentrations. Although there were no reinforcing consequences of intraperitoneally injected ethanol [as an unconditioned stimulus (US)] when a neutral odor was the CS, when paired with ingestion of water from a nipple, the injection of ethanol had a reinforcing effect. Conclusions: The present series of experiments revealed ethanol reinforcement in the newborn rat. Two varieties of Pavlovian conditioning established that ethanol can serve as an effective US, and hence reinforcer, in such a way as to increase the approach and responsiveness toward stimuli paired with that US, indicating appetitive reinforcement.

Background: First experiences with alcohol in humans occur predominantly in adolescence, and to a large extent the attractiveness of alcohol at this age is based on its ability to facilitate certain forms of social behavior (social facilitation). Adolescence is strongly marked by a focus on peer relationships, and the social nature of the situation plays an important role in responsiveness to alcohol. Peer-directed social activity of adolescent rats may be a valuable experimental model for the study of ethanol-induced changes in social behavior and assessment of the role of the social context in responsiveness to ethanol. Method: In the present study we used a modified dyad social interaction test to characterize acute effects of ethanol on different forms of social behavior (social investigation, contact behavior, and play) and social motivation (preference/avoidance of a peer) in adolescent rats. Ethanol effects on behavior directed toward a peer were compared with those induced by exposure to an inanimate novel object. Results: In the social context, the effects of ethanol were dose-dependent and biphasic. Low doses of ethanol (0.25–0.75 g/kg) produced apparent social facilitation (increased social activity and enhanced social preference), whereas higher doses (3 and 4 g/kg) caused social inhibition (decreased social activity and avoidance of a peer). This pattern was not observed for a nonsocial stimulus: Although overall activity in the nonsocial context was suppressed by 2 and 3 g/kg of ethanol, 0.5 g/kg of ethanol did not activate overall activity directed to the inanimate object. Conclusions: These findings demonstrate that the social nature of the testing situation plays an important role in responsiveness to alcohol in adolescence, especially to its activating effects. The results suggest also that the study of ethanol effects on social behavior of adolescent rats may be an effective tool for the study of adolescent alcohol use and abuse.

Prenatal exposure to cocaine in rats has previously been shown to alter the behavioral and hormonal responses to acute stressors, although no work has yet examined stress adaptation in these animals in adulthood, a possibility examined in this experiment. Male and female offspring of Sprague-Dawley rat dams given 40 mg/kg/3 ml subcutaneously daily from gestational days 8-20 (C40), saline injected and pair-fed dams (PF), and non-treated dams (NT) were tested in adulthood (90-120 days). Offspring were given a 5-min open field test 24 h following the last of 1 (Acute), 9 (Chronic) or 0 (control) daily 15-min intermittent footshock sessions. Substantially more behavioral adaptation was evident in NT offspring than in C40 and PF animals. The attenuated stress adaptation seen in C40 offspring extends prior work showing altered stress responsiveness in these animals, although the PF data caution against the conclusion that this lack of stress adaptation necessarily reflects gestational exposure to cocaine per se.

Adolescents across a variety of species exhibit age-specific behavioral characteristics that may have evolved to help them attain the necessary skills for independence. These adolescent-related characteristics, such as an increase in risk taking, may be promoted less by the hormonal changes of puberty than by developmental events occurring in brain. Among the prominent brain transformations of adolescence are alterations in the prefrontal cortex, limbic brain areas, and their dopamine input, systems that are sensitive to stressors and form part of the neural circuitry modulating the motivational value of drugs and other reinforcing stimuli. Such developmental transformations of the adolescent brain may predispose adolescents to behave in particular ways and make them particularly likely to initiate use of alcohol and other drugs.

Background: In humans, early postnatal experience with alcohol is far from rare and includes exposure to alcohol through breast milk or through the bottle to attain sedative effects (Croce, 1987). Exposure to alcohol though mother's milk alters the infant's suckling behavior. However, acute effects of alcohol on suckling behavior using animal models remain to be investigated. Methods: The present study was designed to examine the effects of neonatal alcohol exposure on attachment to a surrogate nipple and ingestion of milk in rat pups, nafve both to suckling and to maternal care. Cesarean-delivered rat pups were pre-exposed to four dosages of ethanol (0, 1, 2, and 3 g/kg intragastrically) and tested 30 min after ethanol administration. Results: Suckling behavior was impaired only in pups exposed to a dosage of 3 g/kg of ethanol. Pups in this group demonstrated longer latency to attach followed by less efficient suckling–the pups maintained contact with the nipple but showed decreased ingestion of milk from it. Pups treated with 1 g/kg of ethanol showed the greatest suckling efficiency, ingesting far more milk per minute attached to the surrogate nipple than pups in all other groups. At the same time, nonevoked motor activity was significantly suppressed by all three dosages of ethanol. Blood alcohol levels showed a linear relationship with dose at 30 min postintubation. Conclusions: These findings suggest a dissociation between acute ethanol effects on suckling and overall motor activity, with suckling apparently less sensitive to suppressive and more sensitive to activating effects of ethanol.

To successfully negotiate the developmental transition between youth and adulthood, adolescents must maneuver this often stressful period while acquiring skills necessary for independence. Certain behavioral features, including age-related increases in social behavior and risk-taking/novelty-seeking, are common among adolescents of diverse mammalian species and may aid in this process. Reduced positive incentive values from stimuli may lead adolescents to pursue new appetitive reinforcers through drug use and other risk-taking behaviors, with their relative insensitivity to drugs supporting comparatively greater per occasion use. Pubertal increases in gonadal hormones are a hallmark of adolescence, although there is little evidence for a simple association of these hormones with behavioral change during adolescence. Prominent developmental transformations are seen in prefrontal cortex and limbic brain regions of adolescents across a variety of species, alterations that include an apparent shift in the balance between mesocortical and mesolimbic dopamine systems. Developmental changes in these stressor-sensitive regions, which are critical for attributing incentive salience to drugs and other stimuli, likely contribute to the unique characteristics of adolescence.

The periadolescent period in the rat is characterized by alterations in novelty seeking and exploratory behavior, as well as changes in the behavioral responsiveness to many drugs of abuse. These alterations may be predictive of alterations in the reward value of drugs of abuse. The present experiments examined whether adolescent rats (34-37 days old) differ from their adult counterparts in the expression of drug-induced place conditioning for morphine (0, 2.5, or 5 mg/kg; Experiment I) and cocaine (0, 5, or 10 mg/kg; Experiments II and III). Animals received multiple conditioning days, followed 24 h later by a drug-free CPP test. All drugs were given intraperitoneally immediately prior to confinement in the CS+ compartment, while vehicle injections were given prior to exposure to the CS- chamber. For both drugs, there were no significant differences between adolescents and adults in amount of place conditioning seen when drug exposure was paired with the nonpreferred chamber. When cocaine was paired with either the preferred or nonpreferred compartment (Experiment III), again, the magnitude of the place conditioning observed did not differ between adolescents and adults. The lack of age differences in expression of drug-induced place conditioning in the present experiments is not likely a result of ceiling effects, because the data suggest that the doses used included near-threshold doses. Although these findings need to be confirmed using other approaches for assessing drug reward before concluding that adolescent and adult rats exhibit similar sensitivity to the rewarding effects of morphine and cocaine, the current data revealed no differences between adolescents and adults in the magnitude of place conditioning expressed for morphine or cocaine.

The impact of gestational cocaine in conjunction with postnatal handling on schedule-induced polydipsia (SIP) was examined. Rat offspring were derived from Sprague–Dawley dams injected subcutaneously with 40 mg/kg/3 cc cocaine hydrochloride (C40) on gestational days 8–20, dams injected with vehicle and pair fed 4 (PF4) days to mimic the acute anorexic effects of cocaine administration, and nontreated (NT) control dams. In adulthood, offspring were food deprived and given 13 daily 30-min SIP sessions, with water intake recorded during the scheduled (fixed time 60 s—FT60) food delivery. For 4 days thereafter, animals received saline, 5 or 10 mg/kg of cocaine in counterbalanced order prior to SIP testing. Acquisition and maintenance of SIP, but not cocaine-induced suppression of SIP performance, were observed to be dependent upon prenatal treatment, handling, and gender. Females acquired SIP faster and exhibited notably higher levels of polydipsia than males. Early handling increased levels of established SIP in NT offspring, while enhancing SIP acquisition in both PF4 and C40 offspring. In nonhandled animals, NT offspring exhibited less SIP than PF4 and C40 offspring, differences that were attenuated by early handling. These effects are discussed in relation to previously reported neurohormonal characteristics of these gender and treatment variables.

The present study investigated 1) the effects of individual and grouped housing on social investigation, social contact behavior, and play behavior in adolescent rats tested with low socially active (grouped) and high socially active (isolated) play partners; and 2) the effects of long-term (8 days) and short-term (24 h) isolation on social behavioral manifestations and social motivation in terms of preference or avoidance of play partners. Social isolation of adolescent rats activated play behavior and social behaviors different from play, but play was predominantly affected under the conditions of this study. Long-term isolation was more effective than short-term, and resulted in greater manifestation of play and social preference. Adolescent rats were able to modify their social behaviors in response to social activity of the play partner: in isolated animals exposed to low socially active group-housed partners, play behavior was transformed into social activities unrelated to play; exposure of group-housed adolescents to high socially active previously isolated partners resulted in an increase of play behavior. Testing that allowed avoidance of social contacts revealed a dissociation between manifestations of play behavior and social motivation: group-housed play partners of isolated animals showed elevated levels of play behavior but a tendency to avoid their isolated pairmates.

Operant responding on a progressive ratio (PR) schedule for intravenous cocaine as well as sucrose reinforcement was examined in female rats throughout the reproductive process. Self-administration sessions began before mating, and continued throughout pregnancy and until lactational Day 8; following parturition, litters were present with dams during operant sessions. Physiological changes associated with the reproductive process dramatically altered PR responding for cocaine, while PR responding for sucrose was relatively stable throughout pregnancy and lactation. Female animals exhibited the highest number of responses/session for cocaine during estrus and the 1st trimester of pregnancy and the lowest responding near parturition, with levels only partially recovering during lactation. Dams self-administering cocaine exhibited notably different patterns of maternal behavior in the operant chambers than dams responding for sucrose. Thus, cocaine's reinforcing efficacy may be influenced by (a) the changing physiological profile associated with the reproductive process and (b) competition from the reinforcing properties of offspring during lactation. © 1999 John Wiley & Sons, Inc. Dev Psychobiol 35: 136–145, 1999

THE objective of the Symposium is to present new data concerning the developmental effects of cocaine in humans and in animal models. In so doing, the Symposium will identify new clinical and preclinical findings which, together with many decades of experience, will expand our understanding of the mechanisms by which cocaine produces neurobehavioral alterations. The ultimate objective being to understand the biological consequences of cocaine use during pregnancy and to draw attention to the problems associated with substance abuse in pregnancy.

Rationale: Altered hormonal stress responsiveness has been implicated in psychostimulant responsivity, and early handling represents a mild environmental manipulation which alters the hormonal profile following stress exposure. Objective: The present experiments examined whether early handling in rats would alter locomotor effects of amphetamine, as well as cross-sensitization of locomotor responsiveness after chronic stress. Conditioned place preference (CPP) for amphetamine was also measured. Methods: Handling consisted of daily 15-min isolation periods from days 1–12 postnatally. Novelty- and amphetamine (0, 1.5 mg/kg)-induced locomotion were examined using circular corridors in adult rats that were either restrained repeatedly over 8 days or not disturbed prior to testing. The effects of handling on amphetamine (0, 1, 2, 5 mg/kg) conditioned place preference (CPP) were also examined following 3 days of drug-compartment pairings. Results: Early handling produced a more rapid post-stress recovery in corticosterone levels. Handled animals also exhibited a significant attenuation in amphetamine-induced CPP compared to non-handled controls. Locomotor responsiveness to novelty and amphetamine was not altered by early handling. Although no cross-sensitization was observed, evidence for stress sensitization was seen, but was unaffected by early handling. Conclusions: Handled animals showed an attenuated CPP for amphetamine, data suggesting that sensitivity to the reward value of drugs of abuse in adulthood may be susceptible to relatively minor environmental manipulations early in life. This effect of handling on CPP does not seem to reflect differences in locomotor sensitivity to amphetamine.

The influence of the treatment-to-test interval on the expression of behavioral sensitization to cocaine was assessed following chronic cocaine exposure during the late preweanling period. From postnatal day 14 (P14) to P20, Sprague–Dawley rat pups received a daily intraperitoneal injection of either 30 mg/kg/2 cc cocaine or an equivalent volume of saline that was paired with placement in the treatment/test context for 30 min. Animals were challenged with 15 mg/kg cocaine in this context on the test day following drug-free intervals of 1, 3, 7, 14, or 21 days. Behavioral sensitization was evident following the preweanling cocaine regimen in terms of both matrix crossings and stereotypy. For matrix crossings, there was no evidence that this sensitization decreased across the time intervals examined, and sensitization was evident with stereotypy even at the 21-day injection–test interval. The expression of sensitization, however, was partially overshadowed by an overall reduced sensitivity to cocaine seen in testing during the periadolescent period (i.e., at P34 and P41). Thus, behavioral sensitization to cocaine can be expressed for weeks following chronic treatment during the late preweanling period, although the magnitude of behavioral expression may be influenced by age-related neurobehavioral alterations.

Sensitivity to the hypnotic effects of ethanol was examined in Sprague-Dawley male and female rats at 16, 26, 36, 46, 56, or 96 days postnatally. Following administration of 3.5, 4.0, 4.5, or 5.0 g/kg of a 17% v/v ethanol solution, sleep times were recorded and blood alcohol levels (BALs) and brain alcohol levels (BrALs) were measured upon awakening. In addition to examining ethanol sleep time during ontogeny, data were used to estimate acute tolerance (indexed by the slope of the linear regressions of waking BALs and BrALs as a function of dose) and initial brain sensitivity to ethanol (indexed by calculating the y-intercept from the linear regression of BrALs as a function of sleep time). The results showed a marked increase in sensitivity to ethanol hypnosis during ontogeny, with young animals exhibiting shorter ethanol-induced sleep times and high waking BALs and BrALs. This ontogenetic increase in ethanol sensitivity was associated with a developmental decline in acute tolerance, with acute tolerance being most pronounced at postnatal day (P) 16 and evident only up to P36. Initial sensitivity conversely increased with age, with P16 pups showing lower initial brain sensitivity to ethanol than at all other ages. Gender differences emerged in adulthood, with males sleeping significantly longer than females at P56 and P96. These findings suggest that the marked insensitivity of young animals to the hypnotic effects of ethanol is related to both pronounced acute tolerance, as well as reduced initial brain sensitivity to ethanol early in life.

In the research on readiness to change (RTC) one's drinking, there has been little assessment of the influence of positive drinking consequences or other potential moderating variables. To address these limitations, we examined how young adults' RTC their alcohol consumption shortly following a drinking episode was associated with self-reported drinking consequences, as well as any potential moderating effects of gender and Breath Alcohol Concentration (BrAC). In street interviews outside bars, 238 young adults were administered questionnaires about their drinking, including a measure examining participants' current readiness to reduce their alcohol consumption. Within 72 h of their drinking episode, 67 participants (36 males; entire sample M age = 20.90 years, Range = 18–26 years) completed an online survey, once again measuring RTC as well as positive and negative drinking consequences. Consistent with our hypothesis, positive drinking consequences were negatively associated with participants' changes in RTC. Additionally, a three-way interaction of gender × BrAC × positive drinking consequences on RTC showed that females with low BrACs reported higher RTC scores when they had endorsed fewer positive drinking consequences. Interestingly, negative drinking consequences alone did not impact individuals' RTC. Because positive drinking consequences were a significantly better predictor of RTC than were negative drinking consequences, researchers are advised to examine both types of consequences in future studies. Finally, effective alcohol education programs for those who have never consumed alcohol as well as social drinkers should include consideration of the experience of positive outcomes.

It has previously been shown that pre-pubertal or adult gonadectomy (GX) increases ethanol intake in male rats. This study examined whether this sex-selective increase reflects a GX-induced maintenance in males of more adolescent-typical responsiveness to ethanol characterized by enhanced sensitivity to positive (e.g., socially facilitating) and a decreased sensitivity to adverse (e.g., socially inhibitory) effects of ethanol. Male and female Sprague-Dawley rats were pre-pubertally GX, sham (SH)-operated, or non-manipulated (NM) at postnatal day (P) 25. During the late adolescent transition into adulthood (P48 — baseline day), rats were given a saline injection, placed alone into a familiar test apparatus for 30 min and then exposed for 10 min to an unfamiliar partner of the same age and sex. On the following day (P49), similar testing occurred after administration of 0.5, 0.75, 1.0 or 1.25 g/kg ethanol. At baseline, GX males and females displayed higher levels of social activity (especially adolescent-typical play and contact behavior) than SH and NM animals, with GX females displaying greater social activity than GX males. Neither males nor females demonstrated social facilitation at lower ethanol doses, regardless of hormonal status. Whereas the social inhibitory effects of higher doses of ethanol were similar across groups among females, SH males were less sensitive than both GX and NM males to ethanol-induced social inhibition. These results suggest that enhanced ethanol intake in GX males is not related to alterations in sensitivity to ethanol's social inhibitory effects. GX, however, results in retention of adolescent-typical social behaviors, with older GX adolescent rats resembling early adolescents in exhibiting elevated social activity—particularly play and contact behavior.

Francisco Aboitiz*, F. Xavier Castellanos and Ximena Carrasco Departamento de Psiquiatria, Facultad de Medicina, and Centro Interdisciplinario de Neurociencia, Pontificia Universidad Catolica de Chile, Santiago, Chile New York University Child Study Center, Nathan Kline Institute for Psychiatric Research, New York, NY, USA Servicio de Neurologia y Psiquiatria infantil, Hospital Luis Calvo Mackenna Facultad de Medicina, Universidad de Chile, Santiago, Chile

Altered behavioral responses to stressors have been observed in animals exposed to cocaine prenatally. In the present study, both behavioral and physiological responses to repeated and single stressor exposure were measured in animals prenatally exposed to cocaine. Offspring were derived from 3 prenatal treatment groups: dams that were administered 40 mg/kg cocaine from gestational day 8-20 (C40); dams that were pair-fed and -watered to weight-matched C40 dams (PF); and untreated dams (LCC). Starting on postnatal day 16-17 (P16-17), offspring from the 3 prenatal treatment groups were exposed to either footshock or isolation daily for 5 days. Two days after the last day of stressor exposure (P21-22), subjects were given 1 final exposure to the stressor to which they were previously exposed. In addition, at P21-22, littermates of animals given repeated exposure to stressors were exposed to either footshock or isolation for the first and only time. During all footshock sessions, the duration of freezing behavior was recorded. Plasma adrenocorticotrophin (ACTH) and corticosterone levels were determined from blood samples taken immediately following the final stressor session and brains were processed for C-FOS immunoreactivity (FOS-IR). Plasma corticosterone was increased following either single or repeated exposure to either stressor compared to homecage control animals. Plasma ACTH was increased by exposure to both repeated and single footshock exposure, but the increase was not as great following repeated footshock exposure, suggesting adaptation to repeated exposure to this stressor. Following both single and repeated footshock exposure, FOS-IR was increased relative to baseline levels in the paraventricular nucleus of the hypothalamus (PVN) and in the supraoptic nucleus (SON), but not the locus coeruleus (LC). Repeatedly footshocked animals exhibited more time freezing than animals given a single footshock session. Prenatal exposure to cocaine resulted in more time spent freezing in C40 than LCC animals during the chronic footshock exposure period; however, no differences were seen in any of the physiological measures taken from these 2 groups on the final test day. The implications of these findings are discussed in the context of other research examining the effects of prenatal cocaine exposure on stress responses.

Adolescence is an evolutionarily conserved developmental period characterized by notable maturational changes in the brain along with various age-related behavioral characteristics, including the propensity to initiate alcohol and other drug use and consume more alcohol per occasion than adults. After a brief review of adolescent neurobehavioral function from an evolutionary perspective, the paper will turn to assessment of adolescent alcohol sensitivity and consequences, with a focus on work from our laboratory. After summarizing evidence showing that adolescents differ considerably from adults in their sensitivity to various effects of alcohol, potential contributors to these age-typical sensitivities will be discussed, and the degree to which these findings are generalizable to other drugs and to human adolescents will be considered. Recent studies are then reviewed to illustrate that repeated alcohol exposure during adolescence induces behavioral, cognitive, and neural alterations that are highly specific, replicable, persistent and dependent on the timing of the exposure. Research in this area is in its early stages, however, and more work will be necessary to characterize the extent of these neurobehavioral alterations and further determine the degree to which observed effects are specific to alcohol exposure during adolescence.

BACKGROUND: Perception of alcohol intoxication presumably plays an important role in guiding behavior during a current drinking episode. Yet, there has been surprisingly little investigation of what aspects associated with intoxication are used by individuals to attribute their level of intoxication. METHODS: Building on recent laboratory-based findings, this study employed a complex field-based design to explore the relative contributions of motor performance versus cognitive performance-specifically executive control-on self-attributions of intoxication. Individuals recruited outside of bars (N = 280; mean age = 22; range: 18 to 32) completed a structured interview, self-report questionnaire, and neuropsychological testing battery, and provided a breath alcohol concentration (BrAC) sample. RESULTS: Results of a multiple linear regression analysis demonstrated that current level of subjective intoxication was associated with current alcohol-related stimulant effects, current sedative effects, and current BrAC. After controlling for the unique variance accounted for by these factors, subjective intoxication was better predicted by simple motor speed, as indexed by performance on the Finger Tapping Test, than by executive control, as indexed by performance on the Trail Making Test. CONCLUSIONS: These results-generated from data collected in a naturally occurring setting-support previous findings from a more traditional laboratory-based investigation, thus illustrating the iterative process of linking field methodology and controlled laboratory experimentation. Language: en

In rats, considerable differences in the social consequences of acute ethanol are seen across ontogeny, with adolescents being more sensitive to low dose ethanol-induced social facilitation and less sensitive to the social inhibition evident at higher ethanol doses relative to adults. Stressor exposure induces social anxiety-like behavior, indexed via decreases in social preference, and alters responsiveness to the social consequences of acute ethanol by enhancing ethanol-associated social facilitation and anxiolysis regardless of age. Given that substantial ontogenetic differences in the social consequences of ethanol are evident even within the adolescent period, the present study was designed to investigate whether similar stress-associated alterations in social behavior and ethanol responsiveness are evident in early and late adolescents. Juvenile–early adolescent [postnatal days (P) 24–28] and mid–late adolescent (P38–42) male and female Sprague–Dawley rats were repeatedly restrained (90 min/day) for 5 days, followed by examination of ethanol-induced (0, 0.25, 0.5, or 1.0 g/kg) alterations in social behaviors on the last day. Responsiveness to restraint stress in terms of both stress-induced behavioral alterations and stress-associated changes in sensitivity to the social consequences of acute ethanol challenge differed drastically at the two ages. Repeated restraint increased anxiety-like behavior in a social context in older adolescents, whereas previously stressed young adolescent males showed substantial increases in play fighting — an effect of stress not evident in P28 females or P42 adolescents of either sex. Unexpectedly, repeated restraint eliminated sensitivity to ethanol-induced social facilitation in P28 adolescent males and made their female counterparts less sensitive to this effect. In contrast, previously stressed late adolescents became sensitive to the socially facilitating and anxiolytic effects of acute ethanol.

We have shown that adults exposed to ethanol during adolescence exhibit a deficit in the retention of context fear, reminiscent of that normally seen in preweanling rats. However, preweanlings have been reported to exhibit a potentiation of context fear when they are conditioned in the presence of a tone. Therefore, this study examined context retention 24 hr after tone or context conditioning in male Sprague-Dawley rats exposed intragastrically to 4 g/kg ethanol or water every 48 hr (total of 11 exposures) during adolescence [Postnatal day (P) 28-48] or adulthood (P70-90). Approximately 3 weeks following exposure, retention of fear to the context in animals exposed to ethanol during adolescence was attenuated after context conditioning, but enhanced after tone conditioning. Comparable adult ethanol exposure groups showed typical overshadowing of context fear retention after tone conditioning. These data suggest that adolescent ethanol exposure may induce an immature pattern of cognitive processing.

To the extent that craving serves to compel excessive drinking, it would be of significant import to predict the intensity of an individual’s craving over the course of a drinking episode. Previous research indicates that regular alcohol use (measured by the AUDIT) and the number of drinks individuals have already consumed that evening independently predict craving to drink (Schoenmakers & Wiers, 2010). The current study aims to replicate those findings by testing whether these same variables predict craving to drink in a sample of 1,320 bar patrons in a naturalistic setting. In addition, we extend those findings by testing whether regular alcohol use and self-reported number of drinks consumed interact to predict craving, and whether gender independently predicts craving or interacts with other variables to predict craving. Results indicate that for men, AUDIT score alone predicted craving, whereas for women, AUDIT score and number of drinks consumed interacted to predict craving, with craving highest among women with either high AUDIT scores or relatively high consumption levels. Our findings have implications for targeted intervention and prevention efforts, as women who have a history of harmful alcohol use and consume several drinks in an evening might be at the greatest risk for continued alcohol consumption.

Pavlovian fear conditioning is an ideal model to investigate how learning and memory are influenced by alcohol use during adolescence because the neural mechanisms involved have been studied extensively. In Exp 1, adolescent and adult male Sprague-Dawley rats were non-injected or injected with saline, 1 or 1.5 g/kg ethanol intraperitoneally 10 min prior to tone or context conditioning. Twenty-four hours later, animals were tested for tone or context retention and extinction, with examination of extinction retention conducted 24 h thereafter. In Exp 2, a context extinction session was inserted between the tone conditioning and the tone fear retention/extinction days to reduce pre-CS baseline freezing levels at test. Basal levels of acquisition, fear retention, extinction, and extinction retention after tone conditioning were similar between adolescent and adult rats. In contrast adolescents showed faster context extinction than adults, while again not differing from adults during context acquisition, retention or extinction retention. In terms of ethanol effects, adolescents were less sensitive to ethanol-induced context retention deficits than adults. No age differences emerged in terms of tone fear retention, with ethanol disrupting tone fear retention at both ages in Exp 1, but at neither age in Exp 2, a difference seemingly due to group differences in pre-CS freezing during tone testing in Exp 1, but not Exp 2. These results suggest that age differences in the acute effects of ethanol on cognitive function are task-specific, and provide further evidence for age differences cognitive functioning in a task thought to be hippocampally related.

It is important to study age-related differences that may put adolescents at risk for alcohol-related problems. Adolescents seem less sensitive to the aversive effects of ethanol than adults. Less is known of appetitive effects of ethanol and stress modulation of these effects. This study aims to describe the effects of acute social or restraint stress on ethanol-precipitated locomotor activity (LMA), in adolescent and adult rats. Effects of activation of the kappa system on ethanol-induced LMA were also evaluated. Adolescent or adult rats were restrained for 90 min, exposed to social deprivation stress for 90 or 180 min or administered with the kappa agonist U62,066E before being given ethanol, and assessed for LMA. Adolescents were significantly more sensitive to the stimulating, and less sensitive to the sedative, effects of ethanol than adults. Basal locomotion was significantly increased by social deprivation stress in adult, but not in adolescent, rats. U62,066E significantly reduced basal and ethanol-induced locomotion in the adolescents. Corticosterone and progesterone levels were significantly higher in adolescents than in adults. Adolescents exhibit greater sensitivity to ethanol-induced LMA and reduced sensitivity to ethanol-induced motor sedation than adult rats. Ethanol’s effects on motor activity were not affected by acute stress. Unlike adults, adolescents were insensitive to acute restraint and social deprivation stress but exhibited motor depression after activation of the endogenous kappa opioid receptor system.

Contents: Preface. F.A. King, C.J. Yarbrough, Yerkes Primate Research Center: A Historical Perspective. Part I: Limbic System and Behavior. L.E. Jarrard, T.L. Davidson, The Hippocampus and Complex, Nonspatial Discrimination: Is Learning Still "Not Possible?" N.A. Schmajuk, H.T. Blair, Time, Space, and the Hippocampus. D.S. Olton, Repairing the Damaged Septohippocampal System. L.W. Means, Working Memory for Water-Escape Loci in Rodents. J.J. Chrobak, A.L. Vi, G. Buzsaki, Septal Regulation of the Hippocampal-Entorhinal Network: Memory Formation and Failure. A. Poplawsky, The Effects of Gangliosides or Nimodipine on Promoting Behavioral Recovery in Rats With Septal Damage. D.P. Kimble, J.P. Vicedomini, The Septohippocampal Connection: Some Behavioral and Anatomical Relationships. Part II: Plasticity in Behavior and Brain. M.G. Packard, C.L. Williams, L. Cahill, J.L. McGaugh, The Anatomy of a Memory Modulatory System: From Periphery to Brain. T.L. Petit, Structure and Plasticity of the Hebbian Synapse: The Cascading Events for Memory Storage. F.H. Gage, G.R. Chalmers, K.L. Eagle, M.H. Tuszynski, M.D. Kawaja, Functional Recovery Following Damage to the Adult Rat Septohippocampal System. M.L. Woodruff, R.H. Baisden, Variables Influencing Behavior After Transplants of Fetal Hippocampus. G.M.J. Ramakers, I.J.A. Urban, P.N.E. de Graan, W.H. Gispen, Hebbian Plasticity in the Hippocampus: Involvement of Protein Phosphorylation and Protein Kinase C. J.E. Springer, F.M. Sessler, B.J. Gwag, Neuronal Activity Regulates Nerve Growth Factor mRNA Expression in the Adult Rat Hippocampal Formation. B. Bohus, G.A. Cottrell, C. Nyakas, H.J.A. Beldhuis, P.G.M. Luiten, Stress, Stress Hormones, Kindling, and Neural Plasticity. Part III: Neural and Chemical Determinants of Normal and Abnormal Behavior. J.H. Hannigan, Behavioral Plasticity After Teratogenic Alcohol Exposure as Recovery of Function. S.A. McDougall, C.A. Crawford, A.J. Nonneman, Age-Related Differences in Dopamine-Mediated Behaviors: Effects of Irreversible Antagonism. C. Van Hartesveldt, Development of Dopamine Systems and Behavior. R.W. Doty, Brainstem Influences on Forebrain Processes, Including Memory. D. de Wied, ACTH Neuropeptides, Learning and Creativity. K.H. Pribram, The Enigma of Reinforcement. J.P. Ryan, Wandering in Alzheimer's Disease: Clinical and Neurobiological Perspectives. K.F. Jensen, Evaluating the Structural Integrity of the Nervous System for Risk Assessment.

Low doses of ethanol have been shown to facilitate social behavior in adolescent rats. The present study sought to investigate whether this ethanol effect is associated with increases in the incentive salience of social stimuli when assessed via approach behavior toward a peer (separated from the experimental animal by a mesh barrier) and 50 kHz ultrasonic vocalization (USV) production in that context. A 0.5 g/kg ethanol dose was found to increase social approach/investigation of adolescent male Sprague-Dawley rats during the first 5 min of the 10 min test whereas 50 kHz USV production was elevated by 0.25 g/kg during the last 5 min of testing. 50 kHz USV production and social approach were generally not correlated, indicating a clear dissociation between these measures. This is the first study to demonstrate that ethanol-induced social facilitation in adolescents is associated with an ethanol-induced increase in the incentive salience of social stimuli.

A hypothesized action of ethanol is that it reduces processing of contextual stimuli. Given previous reports of age-related differences in stimulus selection, in the present study we utilized a conditioned suppression paradigm within an enhanced sensory context to examine the effects of ethanol on context and tone learning in preweanling and adult Sprague-Dawley rats as a function of tone-footshock interval. Although ethanol had some impairing influence on both context and tone conditioning in adults, tone responding nevertheless remained evident, whereas context conditioning was abolished regardless of the tone-footshock interval. In preweanlings, both context and tone responding were abolished by ethanol unless training occurred with contiguous tone-footshock pairings. It is suggested that age-specific modes of encoding are differentially sensitive to the effects of alcohol.

Adolescent rats are more sensitive than adults to ethanol-induced social facilitation, but are less sensitive to the suppression of social interactions seen at higher ethanol doses. Given recent findings that point to age differences in ethanol responsiveness, even within the adolescent period, the present study assessed acute effects of low to moderate doses of ethanol on social behavior of early, mid- or late adolescent rats. Age-related changes in responsiveness to the effects of ethanol on social behavior were apparent even within the adolescent period, with early adolescents being more sensitive to ethanol-induced social facilitation and less sensitive to ethanol-induced social inhibition than mid- and late adolescents. Given that ethanol-induced social facilitation as well as a lower sensitivity to the adverse effects of ethanol may contribute to heavy drinking, this pattern of early adolescent responsiveness to ethanol's social consequences may put them at higher risk for extensive alcohol use.

Despite the high prevalence of adolescent smoking, few studies have examined nicotine sensitivity during this developmental period. In the present study we examined adolescent and adult rats' preference/aversion for a flavor previously paired with nicotine. Paired (nicotine + Kool-Aid) and unpaired (Kool-Aid) solutions were presented in the home cage on alternating nights, with water given during the light phase for six days. A choice test was conducted 24 hr after the last night of conditioning, with both flavors presented simultaneously during the dark cycle. On test day, although the flavor previously paired with nicotine was not preferred at either age, adolescent rats consumed significantly more of the paired flavor than adults. These results suggest that adolescent rats are less sensitive to the aversive properties of nicotine. This finding taken together with adolescents' increased sensitivity to the rewarding properties of nicotine, may result in an increased vulnerability to nicotine dependence.

Offspring of dams given 40 mg/kg cocaine SC on gestational days (GD) 8–20 (E8-20) (C40), dams given 0.9% saline SC on E8-20 that were pair fed and watered to C40 dams (PF), and untreated control dams given ad lib access to food and water (LC) were challenged with haloperidol (0.0, 0.05, 0.10, or 0.50 mg/kg) at either 21, 35, or 60 days postnatally (P21, 35, 60). One hour postinjection, animals were sacrificed, trunk blood collected for assay of prolactin, and the striatum (ST) and nucleus accumbens (NAc) removed. The ratio of the dopamine metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid to dopamine (DA) as well as the ratio of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) to serotonin (5-HT) were determined in these brain regions as an index of DA and 5-HT turnover, respectively. Assessment of 5-HIAA/5-HT ratios did not indicate any reliable dose or prenatal treatment effects. Reminiscent of previous findings obtained in C40 offspring at P11 (35), P21 C40 offspring exhibited a slightly reduced sensitivity to haloperidol relative to LC controls both in terms of DA ratios in the NAc as well as plasma prolactin levels. These findings were also evident in PF controls suggesting that they may be the result of prenatal undernutrition. Furthermore, this reduced sensitivity was not evident at the older test ages. At P60, planned comparisons revealed haloperidol-induced increases in prolactin levels in C40 males but not PF or LC males; these findings could potentially reflect feminization in males following prenatal cocaine exposure. Taken together, these data suggest that prenatal cocaine exposure does not produce long-term alterations in basal or haloperidol-induced increases in DA turnover rates in the nigrostriatal or mesolimbic dopamine pathways, although adult male C40 offspring may exhibit a potential alteration in tuberoinfundibular DA release as indexed by altered plasma prolactin levels.

The kappa opioid receptor (KOR) antagonist, nor-binaltorphimine (nor-BNI), was used to investigate the role of the KOR system in mediating ethanol intake. On P25 (adolescent) or P67 (adult) male and female rats were individually housed and given ad libitum access to food and water. The experimental procedure was initiated on P28 or P70: animals were given 30 min/day access to a 10% ethanol/supersaccharin solution every other day (3 baseline exposures). On the day after the final baseline test, rats were injected with nor-BNI (0, 2.5, 5, 10 mg/kg), with testing initiated 24 hr later (30-min access every other day, 3 test exposures). Nor-BNI (10 mg/kg) increased ethanol intake in adult males, whereas the same dose decreased intake in adult females, suggesting pronounced sex differences in KOR-associated mediation of ethanol intake in adulthood. There was no impact of nor-BNI in adolescent animals of either sex, suggesting that the KOR may play less of a role in modulating ethanol intake during adolescence.

Adolescents ages 10–15 experience dramatic changes in their biological, cognitive, emotional, and social development as well as in their physical and social environments. These include the physiological and psychological changes associated with puberty; further development of the brain; changes in family, peer, and romantic relationships; and exposure to new societal and cultural influences. During this period, many adolescents also begin to use alcohol. Alcohol use during adolescence has adverse effects on the body and increases the risk of alcohol dependence later in life. To better understand why some children drink whereas others do not, researchers are examining nonspecific and alcohol-specific factors that put adolescents at risk for, or which protect them from, early alcohol use and its associated problems. Nonspecific risk factors include certain temperamental and personality traits, family factors, and nonnormative development. Examples of nonspecific protective factors include certain temperamental characteristics, religiosity, and parenting factors (e.g., parental nurturance and monitoring). Among the most influential alcohol-specific risk and protective factors are a family history of alcoholism and the influences of siblings and peers, all of which shape an adolescent’s expectancies about the effects of alcohol, which in turn help determine alcohol use behaviors.

Underage alcohol use can be viewed as a developmental phenomenon because many kinds of developmental changes and expectations appear to influence this behavior and also because it has consequences for development. Data on alcohol use, abuse, and dependence show clear age-related patterns. Moreover, many of the effects that alcohol use has on the drinker, in both the short and long term, depend on the developmental timing of alcohol use or exposure. Finally, many developmental connections have been observed in the risk and protective factors that predict the likelihood of problem alcohol use in young people. Therefore, efforts to understand and address underage drinking would benefit from a developmental perspective, and the general principles of developmental psychopathology offer a useful conceptual framework for research and prevention concerned with underage drinking.

The study assessed possible age differences in brain activation patterns to low dose ethanol (.5 g/kg intraperitoneally) and the influence of social context on this activation. Early adolescent or young adult male Sprague-Dawley rats were placed either alone or with an unfamiliar partner of the same age and sex following saline or ethanol administration. c-Fos protein immunoreactivity was used to index neuronal activation in 15 regions of interest. Ethanol had little effect on c-Fos activation. In adolescents, social context activated an "autonomic" network including the basolateral and central amygdala, bed nucleus of the stria terminalis, lateral hypothalamus, and lateral septum. In contrast, when adult rats were alone, activation was evident in a "reward" network that included the substantia nigra, nucleus accumbens, anterior cingulate and orbitofrontal cortices, lateral parabrachial nucleus, and locus coeruleus.

The dynorphin (DYN)/kappa opioid receptor (KOR) system is involved in the dysphoric properties of drugs of abuse. Given that adolescents show reduced sensitivity to aversive effects of many drugs, alterations in the DYN/KOR system may contribute to the prevalence of drug use during adolescence.The present study was designed to assess dysphoric properties of a selective kappa agonist, U62,066, in adolescent and adult rats using both conditioned taste aversion (CTA) and conditioned place aversion (CPA) paradigms.For CTA, water-restricted rats were administered U62,066 following 30 min access to a saccharin solution, with subsequent saccharin consumption used to index aversion. For CPA, animals were allowed access to both compartments of a two-compartment chamber for a 15-min pre- and post-conditioning test. For conditioning, subjects were administered U62,066 prior to confinement to one side of the chamber and saline prior to confinement to the other side for a total of four pairings.Overall, adolescents displayed reduced sensitivity to the kappa agonist relative to adults. Adults demonstrated taste aversions to the 0.2 and 0.3 mg/kg doses of U62,066, whereas adolescents did not display aversions to any tested doses. Adults demonstrated a place aversion to the 0.1 and 0.2 mg/kg dose of U62,066 when paired with the preferred side of the conditioning chamber. Adolescents did not display aversions to any of the doses tested.Reduced sensitivity to DYN/KOR system activation during adolescence may be a contributing factor to the age-typical insensitivity to aversive properties of drugs commonly abused by adolescents.

This article is part of a Special Issue “Puberty and Adolescence”. Adolescence is characterized by a variety of behavioral alterations, including elevations in novelty-seeking and experimentation with alcohol and other drugs of abuse. Some adolescent-typical neurobehavioral alterations may depend upon pubertal rises in gonadal hormones, whereas others may be unrelated to puberty. Using a variety of approaches, studies in laboratory animals have not revealed clear relationships between pubertal-related changes and adolescent- or adult-typical behaviors that are not strongly sexually dimorphic. Data reviewed suggest surprisingly modest influences of gonadal hormones on alcohol intake, alcohol preference and novelty-directed behaviors. Gonadectomy in males (but not females) increased ethanol intake in adulthood following surgery either pre-pubertally or in adulthood, with these increases in intake largely reversed by testosterone replacement in adulthood, supporting an activational role of androgens in moderating ethanol intake in males. In contrast, neither pre-pubertal nor adult gonadectomy influenced sensitivity to the social inhibitory or aversive effects of ethanol when indexed via conditioned taste aversions, although gonadectomy at either age altered the microstructure of social behavior of both males and females. Unexpectedly, the pre-pubertal surgical manipulation process itself was found to increase later ethanol intake, decrease sensitivity to ethanol's social inhibitory effects, attenuate novelty-directed behavior and lower social motivation, with gonadal hormones being necessary for these long-lasting effects of early surgical perturbations.

The present series of experiments examined affective properties of a moderate dose of ethanol using the conditioned place preference (CPP) paradigm in ethanol-naive, adult male Sprague–Dawley rats. The apparatus and the procedure used were both unbiased. In Experiment 1, rats were given four 30 min conditioning sessions with 1.5 g/kg ethanol (i.p.) or an equivalent volume of saline on the paired side. Animals were found to demonstrate CPP to the ethanol-paired side, an unexpected finding at this relatively high dose in rats. To replicate this finding, and to examine the possibility of non-associative conditioning, an unpaired control group was included in Experiment 2. Once again, rats showed a CPP to the side paired with ethanol relative to either control group. Given that testing in an unfamiliar environment typically results in elevated levels of anxiety and that animals in Experiments 1 and 2 were not exposed to the apparatus prior to conditioning, Experiment 3 was conducted to examine the potential role of context unfamiliarity for induction of ethanol CPP in this test situation by varying whether animals were exposed to the apparatus prior to conditioning. In this study, pre-exposure to the CPP apparatus was found to eliminate the CPP to ethanol observed in rats who were not familiarized with the apparatus. Collectively, these studies demonstrate that ethanol-naive rats can find ethanol reinforcing as indexed by the CPP test, and provide some evidence for the conditions under which this uncommon finding is observed.

Adult male rats were exposed to a chronic variable stress treatment, an animal model of depression, with or without concurrent daily administration of desipramine. Animals given chronic and variable stress were submitted daily to a different stressor following an injection of either saline or desipramine (5 mg/kg, i.p.), whereas control animals were unmanipulated except for the injection process. One day after the last event of the chronic procedure, control and stressed animals were administered saline or morphine (0.75 or 1.5 mg/kg, i.p.) and their locomotion assessed for 90 min. In an additional experiment, 24 h after the last stressor, stressed and control rats were challenged with either saline or one of two higher doses (behaviorally suppressant) of morphine (5 and 10 mg/kg, i.p.). A significantly greater increase in locomotor activity following a low dose (1.5 mg/kg) of morphine was observed in chronically stressed rats as compared tocontrol rats. This potentiated locomotor response to morphine in stressed rats was prevented by desipramine pretreatment. The chronic and variable stress treatment did not modify the sedative response to the high doses of morphine. These data support the suggestion that a chronic and variables stress procedure results in sensitization to the stimulant effect of opioid stimulation, and that pretreatment with the antidepressant agent desipramine blocks the development of this sensitization.

The behaviors displayed in a forced swim test were investigated in rats previously exposed to a chronic variable stress treatment or chronic administration of morphine. In addition, to further explore the participation of an endogenous opiate mechanism in these behavioral effects, naloxone was either administered during the chronic treatment (prior to each stress or morphine exposure) or immediately prior to the forced swim test. Animals were submitted daily to a different stressor for 1 week or injected with morphine (10 mg/kg, IP) for 6 days, whereas controls were unmanipulated except for the injection process. On the day following the last stressor, control and stressed animals were administered saline or naloxone (2 mg/kg, IP) 15 min prior to the forced swim test. Morphine treated animals were similarly tested on the third day following the last morphine injection. In a separate group of rats, naloxone (2 mg/kg, IP) was administered daily 10 min prior to each stressor of the chronic stress regime or each daily morphine injection. A significant increase in the time spent in immobility was observed in stressed animals as well as in rats chronically treated with morphine. In both groups, this potentiated immobility was attenuated by naloxone pretreatment prior to the forced swim test or when given before each daily stressor or morphine injection. In addition, the concurrent exposure to stress or morphine along with naloxone administration enhanced struggling in the first 5 min of the forced swim test.(ABSTRACT TRUNCATED AT 250 WORDS)

Sex- and age-typical responses to ethanol and novel stimuli tend to emerge postpubertally, suggesting a potential organizational or activational role for pubertal hormones in these behaviors. To test this possibility, male and female rats were gonadectomized (GX) or received sham gonadectomy (SH) either prepubertally on postnatal day (P) 23 (early) or in adulthood on P70 (late). Animals were tested as adults for response to novelty and, on the following day, challenged with either saline or ethanol (1 g/kg) prior to social interaction testing with an unfamiliar partner in a familiar setting under low light conditions. Gonadectomy did not influence ethanol-induced social inhibition in either sex, but instead altered the microstructure of social behavior, with GX animals exhibiting proportionally less time in social investigation and proportionally more time in contact behavior than SH animals, regardless of age of gonadectomy. The early sham surgical manipulation process itself influenced social motivation, with early SH surgery eliminating ethanol-induced decreases in social preference in both sexes. Response to novelty was unaffected by gonadectomy, but was suppressed in early compared to late SH manipulated animals. These results suggest that adult-typical responses to ethanol and novelty-directed behaviors are little influenced by gonadal hormones during puberty or in adulthood. However, the experience of surgical manipulation itself during development exerts behavioral and pharmacological consequences that last into adulthood.