Sex differences in sensitivity to the social consequences of acute ethanol and social drinking during adolescence.

In human adolescents, sociable males frequently drink to enhance positive emotional states, whereas anxious females often drink to avoid negative affective states. This study used a rat model of adolescence to provide information regarding possible sex differences in contributors to social drinking. The effects of ethanol (0, 0.5, and 0.75g/kg) on play fighting and social preference were assessed on P30, P32, and P34 using a within-subject design. Then animals were tested in a social drinking paradigm (P37-P40), with this testing revealing high drinkers and low drinkers. Sex differences in sensitivity to ethanol emerged among high and low drinkers. High socially drinking males, but not females, when tested prior to drinking sessions, showed significant increases in play fighting at both doses. In low drinking males, play fighting was increased by 0.5g/kg ethanol, whereas the higher dose of 0.75g/kg produced significant decreases in play fighting. High drinking females initially showed low levels of social preference than high drinking males and low drinking females and were extremely sensitive to ethanol-induced enhancement of this social measure. Low social drinkers, both males and females, were more sensitive to the suppressing effects of ethanol on social preference following 0.75g/kg ethanol. These findings indicate that during adolescence enhanced sensitivity to the facilitating effects of ethanol on play fighting is associated with heavy drinking among males, whereas low social preference together with high sensitivity to ethanol-induced enhancement of social preference is related to high social drinking in females.

Ethanol intake under social circumstances or alone in sprague-dawley rats: impact of age, sex, social activity, and social anxiety-like behavior.

BACKGROUND: In human adolescents, heavy drinking is often predicted by high sociability in males and high social anxiety in females. This study assessed the impact of baseline levels of social activity and social anxiety-like behavior in group-housed adolescent and adult male and female Sprague-Dawley rats on ethanol (EtOH) intake when drinking alone or in a social group. METHODS: Social activity and anxiety-like behavior initially were assessed in a modified social interaction test, followed by 6 drinking sessions that occurred every other day in animals given ad libitum food and water. Sessions consisted of 30-minute access to 10% EtOH in a "supersac" (3% sucrose + 0.1% saccharin) solution given alone as well as in groups of 5 same-sex littermates, with order of the alternating session types counterbalanced across animals. RESULTS: Adolescent males and adults of both sexes overall consumed more EtOH under social than alone circumstances, whereas adolescent females ingested more EtOH when alone. Highly socially active adolescent males demonstrated elevated levels of EtOH intake relative to their low and medium socially active counterparts when drinking in groups, but not when tested alone. Adolescent females with high levels of social anxiety-like behavior demonstrated the highest EtOH intake under social, but not alone circumstances. Among adults, baseline levels of social anxiety-like behavior did not contribute to individual differences in EtOH intake in either sex. CONCLUSIONS: The results clearly demonstrate that in adolescent rats, but not their adult counterparts, responsiveness to a social peer predicts EtOH intake in a social setting-circumstances under which drinking typically occurs in human adolescents. High levels of social activity in males and high levels of social anxiety-like behavior in females were associated with elevated social drinking, suggesting that males ingest EtOH for its socially enhancing properties, whereas females ingest EtOH for its socially anxiolytic effects.

Chronic intermittent ethanol exposure during adolescence: effects on social behavior and ethanol sensitivity in adulthood.

This study assessed long-lasting consequences of repeated ethanol exposure during two different periods of adolescence on 1) baseline levels of social investigation, play fighting, and social preference and 2) sensitivity to the social consequences of acute ethanol challenge. Adult male and female Sprague-Dawley rats were tested 25 days after repeated exposure to ethanol (3.5 g/kg intragastrically [i.g.], every other day for a total of 11 exposures) in a modified social interaction test. Early-mid adolescent intermittent exposure (e-AIE) occurred between postnatal days (P) 25 and 45, whereas late adolescent intermittent exposure (l-AIE) was conducted between P45 and P65. Significant decreases in social investigation and social preference were evident in adult male rats, but not their female counterparts following e-AIE, whereas neither males nor females demonstrated these alterations following l-AIE. In contrast, both e-AIE and l-AIE produced alterations in sensitivity to acute ethanol challenge in males tested 25 days after adolescent exposure. Ethanol-induced facilitation of social investigation and play fighting, reminiscent of that normally seen during adolescence, was evident in adult males after e-AIE, whereas control males showed an age-typical inhibition of social behavior. Males after l-AIE were found to be insensitive to the socially suppressing effects of acute ethanol challenge, suggesting the development of chronic tolerance in these animals. In contrast, females showed little evidence for alterations in sensitivity to acute ethanol challenge following either early or late AIE. The results of the present study demonstrate a particular vulnerability of young adolescent males to long-lasting detrimental effects of repeated ethanol. Retention of adolescent-typical sensitivity to the socially facilitating effects of ethanol could potentially make ethanol especially appealing to these males, therefore promoting relatively high levels of ethanol intake later in life.

Repeated restraint stress alters sensitivity to the social consequences of ethanol differentially in early and late adolescent rats.

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.

Ontogeny of ethanol intake in alcohol preferring (P) and alcohol nonpreferring (NP) rats.

There is a scarcity of research on ethanol affinity in alcohol-preferring (P) rats before weaning and it is unknown if neonate P rats exhibit ethanol intake preferences comparable to those observed in adult P rats. This study examined ethanol intake in P and alcohol-nonpreferring (NP) rats 3 hr after birth (Experiment 1, surrogate nipple test), at postnatal days (PD) 8, 12, and 18 (Experiment 2, consumption from the floor procedure) and at adolescence (Experiment 3, two-bottle choice test at PD32). The high-preference genotype was readily expressed 3 hr after birth. P neonates drank twice as much ethanol as their NP counterparts. This heightened ethanol preference transiently reversed at P8, reemerged as weaning approached (P18) and was fully expressed during adolescence. These results help to clarify the ontogeny of genetic predisposition for ethanol. Genetic predisposition for higher ethanol intake in P than in NP rats seems to be present immediately following birth.

Opioid antagonists block the acquisition of ethanol-mediated conditioned tactile preference in infant rats.

It has been difficult to find conditioned preference for tactile cues paired with ethanol intoxication in rats. Toward understanding the ontogeny of ethanol reinforcement, we aimed at establishing a simple and reliable procedure for (1) assessing primary appetitive conditioning to ethanol in infant rats and (2) discerning the role the opioid system plays in ethanol-mediated conditioning at this age. Experiment 1 determined the parameters (i.e., dose, interval of conditioning) for assessing ethanol-mediated conditioning. Pups were then trained with differential Pavlovian conditioning (Experiments 2 and 3) in which ethanol intoxication (1.0-2.0 g/kg, intragastrically or intraperitoneally delivered) was paired with a tactile stimulus (sandpaper) while an alternative texture signaled the absence of ethanol's effects. Unpaired control conditions were also used. Tactile preferences were assessed after two conditioning sessions. Paired rats spent significantly more time on sandpaper than unpaired controls, an effect that was greater after intragastric administration of 1.0 than 2.0 g/kg ethanol. This effect was replicated in Experiments 4a and 4c and found to be inhibited by pretreatment with general (naloxone [NAL]) or specific (d-Pen-Cys-Tyr-d-Trp-Orn-Thr-Pen-Thr-NH2 [CTOP] and naltrindole) opioid antagonists. Blood ethanol levels at conditioning were not altered by NAL (Experiment 4b). The study outlines a procedure that reveals appetitive conditioning to ethanol by infant rats. The results are discussed in terms of a potential ethanol-induced activation of the endogenous opioid system during the onset of the intoxication process.

Motivational effects of intraorally-infused ethanol in rat pups in an operant self-administration task.

Motivational effects of self-administered ethanol have rarely been studied in preweanling rats due primarily to the lack of age-appropriate operant tasks. The present experiments assessed the hedonic effects of intraoral ethanol in infant rats self-administered by activating a touch sensor. On postnatal day (PD) 13 pups were pre-exposed to the drug's pharmacological and/or sensory effects. Operant sessions were conducted during PDs 14-16 (Experiments 1 and 2). Paired animals were placed in chambers equipped with a touch-sensitive disk and received an intraoral infusion of ethanol (3 or 5% v/v, 5 microl) after each sensor contact. Yoked controls were equated for number and distribution of ethanol infusions but had no control over the contingency between operant behavior and intraoral infusion. In Experiment 2, training trials were preceded by a non-reinforced phase. Paired pups performed fewer operant responses than controls and decreased their operant responses across sessions. These results suggest that intraoral self-administered ethanol has an aversive hedonic value in two-week old rats. Operant behavior seems to have been associated with aversive orosensory effects derived from intraoral ethanol infusion.

Differential motivational properties of ethanol during early ontogeny as a function of dose and postadministration time.

While appetitive reinforcement effects of ethanol are easily detected in rat neonates, such phenomena rarely have been observed in older infants. Recently, Molina et al. [Molina, J. C., Ponce L. F., Truxell, E., & Spear N. E. (2006). Infantile sensitivity to ethanol's motivational effects: ethanol reinforcement during the third postnatal week. Alcohol Clin Exp Res 30, 1506-1519] reported such effects of ethanol in 14-day-olds using a second-order conditioning procedure. Infants also appear to be sensitive to biphasic reinforcement or general motivational effects of ethanol, with appetitive effects seeming to occur early in the state of intoxication and aversive effects predominant during late stages, but tests have been inconclusive. The present study examined the possibility of biphasic motivational effects of ethanol during infancy through the use of second-order conditioning procedures. Preweanling rats (14 days old) experienced intraoral water infusions (conditioned stimulus, CS) either 5-20 or 30-45 min after administration of 0.5 or 2.0 g/kg i.g. ethanol. Pups were then exposed to the CS while over a novel texture (second-order phase). Tests of tactile preference for that texture followed. Locomotive, thermal, hormonal (corticosterone release), and pharmacokinetic patterns likely to underlie the acquisition of ethanol-mediated conditioning were also examined in subsequent experiments. Intraoral CSs paired with either early or late effects of low-dose ethanol (0.5 g/kg, blood ethanol concentration: 40 mg%) became positive second-order reinforcers. Appetitive effects were also exhibited by pups exposed to the CS during commencement of the toxic episode induced by a 2.0 g/kg ethanol dose, 5-20 min after administration of ethanol, whereas aversions emerged when CS presentation occurred 30-45 min postadministration time (blood ethanol concentrations: 157 and 200 mg%, respectively). Overall, the results indicate that infants rapidly detect differential motivational properties of ethanol as a function of dose or drug postadministration time. Relatively neutral stimuli associated with these properties are later capable of acting as either positive or aversive reinforcers. Thermal and motor responses that accompany ethanol intoxication do not seem to be directly associated with differential hedonic properties of the drug at this stage of development.

Ethanol intake in the juvenile, adolescent, and adult rat: effects of age and prior exposure to ethanol.

BACKGROUND: Initial ingestion of ethanol by naïve rats has seemed to decrease dramatically with age. During the preweanling period, infant rats consume large quantities of high concentrations of ethanol without initiating procedures, in some instances exceeding doses required for severe motor incoordination. During adulthood, however, initial ingestion of ethanol without initiation procedures is low and infrequent. In the present study, the ontogeny of ethanol intake was measured in juvenile, adolescent and adult rats using a technique [consume off the floor (COF)] similar to that used to study intake during infancy. How this initial experience with ethanol affected subsequent affinity for ethanol intake was later assessed using 2-bottle choice preference tests. METHODS: Independent ingestion of ethanol was measured at 3 developmental periods, the juvenile period (P22-P28), adolescence (P30-P34) and adulthood (P60-P64), with systematic variation in ethanol concentration (15 or 30% v/v) and palatability (sweetness) of ethanol. Blood ethanol concentrations (BECs) were determined in all animals. This dependent variable served as an estimate of absolute ethanol ingestion. Three COF sessions were conducted for each age group. Following these sessions animals' ethanol consumption was also assessed using a 2-bottle choice test (water vs 15% v/v unsweetened ethanol). RESULTS: In all experiments, groups consuming 30% v/v ethanol exhibited significantly higher BECs than those exposed to 15% v/v ethanol. Adding saccharin to the ethanol increased absolute ethanol ingestion in only the oldest animals. During the pre-exposure phase (COF sessions) of each experiment, absolute ethanol intake was found to decline with repeated exposures. Sex effects were particularly evident during later stages of ontogeny (adolescents and adults). The overall pattern of results indicated that juveniles relative to adults show a marked predisposition to consume highly concentrated ethanol solutions and that BECs derived from the COF sessions influenced ethanol acceptance patterns in the subsequent 2-bottle test. CONCLUSIONS: Using the (COF) technique with BECs as an estimate of intake, absolute ethanol consumption seems to be quite high early in ontogeny and decline gradually into adulthood. Adding saccharin to ethanol solutions at the concentration used in the present study (0.1%) was generally not sufficient to increase absolute ethanol intake from the floor, except during adulthood. The experimental strategy employed in this study represents a novel approach for examining ethanol acceptance patterns across ontogeny and how experience with the process of intoxication affects subsequent ethanol preferences.

Infantile sensitivity to ethanol's motivational effects: Ethanol reinforcement during the third postnatal week.

BACKGROUND: Although tests specific to newborn rats have frequently verified their susceptibility to the reinforcing properties of ethanol, demonstration of comparable reinforcing effects in older infants has been elusive. Using a second-order conditioning procedure, the present study assessed in preweanling rats whether pairing with early postabsorptive effects of ethanol would render intraorally delivered gustatory stimuli capable of positive reinforcement for association with a salient texture. Direct reinforcing effects of ethanol were also evaluated through intake tests of gustatory stimuli previously paired with the drug. Blood ethanol levels (BELs) were determined for each of the ethanol doses used. METHODS: Pups (14 days old) were stimulated with intraoral infusion of sucrose (10% v/v), water, or quinine (0.0045% w/v) 5 minutes after being intragastrically (i.g.) administered 0.00, 0.25, 0.50, or 2.00 g/kg ethanol (Experiments 1 and 2). These stimuli were then briefly presented while pups experienced a rough texture (sandpaper). Rats were subsequently evaluated in a 2-way texture location test (sandpaper vs smooth surface). In Experiment 3, sucrose, water, or quinine was paired with early postabsorptive effects of ethanol (0.00, 0.50, or 2.0 g/kg). Consumption of these stimuli was later assessed. Motor activity patterns during the intake test were also evaluated. In Experiment 4, BELs corresponding to 0.25, 0.50, or 2.0 g/kg ethanol were determined 5 and 20 minutes after i.g. administration (time periods were in accord with the onset and offset of intraoral stimulation used in the previous experiments). RESULTS: Intraoral infusion of sucrose, water, or quinine, while under a state of sobriety and paired with sandpaper, resulted in roughly 50% preference for this texture. Sandpaper preferences were significantly elevated in pups that had experienced sucrose or water in a nonsober state-while under the effects of ethanol (Experiments 1 and 2). This indicated reinforcing effects of the ethanol intoxication. Pairing ethanol intoxication directly with consumption of sucrose, water, or quinine did not affect their later consumption. Yet, there were clear indications that this pairing resulted in conditioned behavioral activity patterns. Blood ethanol levels corresponding to the ethanol doses used here ranged between 10 and 150 mg%. CONCLUSIONS: Infants appear sensitive to pharmacological reinforcing properties of low and relatively high ethanol doses. This sensitivity was revealed indirectly, by pairing gustatory stimuli with ethanol intoxication and then allowing these stimuli to act as second-order reinforcement for a quite different (tactile) stimulus. Behavioral activation elicited by the gustatory stimuli previously paired with a state of intoxication seems to compete with the expression of ethanol's motivational properties as assessed through intake tests.

Immediate acceptance of ethanol in infant rats: ontogenetic differences with moderate but not high ethanol concentration.

BACKGROUND: During the preweanling period, infant rats consume large quantities of ethanol without initiating procedures. Ethanol intake during this period has seemed to be age related, with peak consumption occurring near the end of the second postnatal week, on postnatal day (P)12, but only a narrow range of conditions has been tested. METHODS: Independent ingestion of ethanol was measured at each of two ages, P12 and P18, with systematic variation in ethanol concentration, duration of exposure, and mode of fluid presentation. Ethanol ingestion was measured in terms of percentage body weight gain, grams of absolute ethanol ingested per unit body weight, and blood ethanol concentration. RESULTS: Ingestion of 30% ethanol during a 40-min period led to blood ethanol concentrations approaching 300 mg/100 ml at both P12 and P18. For ethanol concentrations of 10 or 20%, ingestion at P12 was greater than at P18. When ethanol was available from ethanol-soaked Kimwipe on the floor, ethanol intake transdermally or by inhalation was apparent but accounted for less than half of the overall ethanol intake. It was clear that for older infants, which are susceptible to ethanol's diuretic effects and are much more likely to self-void than those at P12, measurement of intake by percentage body weight gain can underestimate ethanol ingestion. CONCLUSIONS: The infant rat ingests extraordinarily high levels of ethanol, in concentrations as high as 30%, without initiation procedures. Acceptance of ethanol by infants on first exposure contrasts with the conventional rejection of these concentrations by adults. It is unclear why younger infants (P12) consume more 10 and 20% ethanol than older (P18) infants. These and other differences in ethanol intake between infants and older animals may be due initially to the relative ontogeny of receptors for bitter and sweet taste and subsequently to other factors.