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Research suggests that addictive traits are indeed heritable, but very few preclinical studies have explored transgenerational effects of paternal alcohol exposure. The present study addressed this gap in knowledge. We explored whether offspring of ethanol-exposed sires would be more likely to accept ethanol than descendants of water-exposed and control sires. We also investigated whether the second generation of ethanol-exposed descendants would accept ethanol more than controls and were more or less likely to experience anxiety-like behavior in behavioral assessments. We exposed male rats to repeated binge doses of alcohol (4 g/kg/day across 8 days), water, or left them untreated and mated them with untreated females. We then bred the offspring of these rats to test transgenerational effects of paternal alcohol exposure. We tested 14-day-old offspring from the first and second filial generation for their acceptance of ethanol and water, and measured anxiety-like behavior in 38-day-old, second-generation offspring using an elevated plus maze. The results indicate that offspring of ethanol-exposed sires increase ethanol acceptance in the first generation compared to untreated controls, whereas in the second-generation increased ethanol acceptance vs. these controls is seen in descendants of both ethanol- and vehicle-treated sires. At adolescence, the second generation of rats derived from alcohol-exposed sires exhibited significantly more time spent in the open arms and significantly more arm entries than any other group. The present study suggests that parental ethanol exposure is associated with lingering effects in the infant and adolescent offspring. The second filial generation was also found to be affected, albeit similarly by grandparental ethanol exposure or by the stress of the vehicle administration.

Alcohol use is associated with a variety of negative consequences, including heightened likelihood of cognitive impairment, proclivity to alcohol use disorders (AUD), and alterations in the drinker's offspring. Children and rodents exposed to alcohol during pregnancy, or those whose fathers consumed alcohol prior to mating, often exhibit neurodevelopmental, physiological, and behavioral deficits. The present study assessed cognitive function and alcohol intake in male and female rats that were offspring of alcohol-exposed fathers. Adult male rats were exposed to alcohol or vehicle (0.0 or 2.0 g/kg, respectively; twice daily for 2 days followed by a rest day, for a total of eight alcohol or vehicle exposure days), or were left untreated and then mated with non-manipulated females. The offspring were assessed for alcohol intake, via intraoral infusion, followed by cognitive assessment via an alternating T-maze task. The results indicated that paternal ethanol exposure, prior to breeding, resulted in offspring that consumed significantly more ethanol than vehicle or untreated controls. Furthermore, the offspring of alcohol-exposed fathers exhibited a significant failure to initiate and complete the T-maze performance tests. Although, when they did engage in the tests they performed at the level of controls (i.e., 80% correct). The present results add to a growing body of literature suggesting that paternal pre-conception alcohol exposure can have deleterious effects on the offspring. Fil: Hollander, Jessica. Southern Connecticut State University; Estados Unidos Fil: McNivens, Megan. Southern Connecticut State University; Estados Unidos Fil: Pautassi, Ricardo Marcos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina Fil: Nizhnikov, Michael. Southern Connecticut State University; Estados Unidos

Adolescents are sensitive to the anxiolytic effect of ethanol, and evidence suggests that they may be more sensitive to stress than adults. Relatively little is known, however, about age-related differences in stress modulation of ethanol drinking or stress modulation of ethanol-induced sedation and hypnosis. We observed that chronic restraint stress transiently exacerbated free-choice ethanol drinking in adolescent, but not in adult, rats. Restraint stress altered exploration patterns of a light-dark box apparatus in adolescents and adults. Stressed animals spent significantly more time in the white area of the maze and made significantly more transfers between compartments than their non-stressed peers. Behavioral response to acute stress, on the other hand, was modulated by prior restraint stress only in adults. Adolescents, unlike adults, exhibited ethanol-induced motor stimulation in an open field. Stress increased the duration of loss of the righting reflex after a high ethanol dose, yet this effect was similar at both ages. Ethanol-induced sleep time was much higher in adult than in adolescent rats, yet stress diminished ethanol-induced sleep time only in adults. The study indicates age-related differences that may increase the risk for initiation and escalation in alcohol drinking. Fil: Fernandez, Macarena Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina. University Of Binghamton; Estados Unidos Fil: Fabio, Maria Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina. University Of Binghamton; Estados Unidos Fil: Miranda Morales, Roberto Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina Fil: Virgolini, Miriam Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacología; Argentina Fil: de Giovanni, Laura Noemi. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacología; Argentina Fil: Hansen, Cristian. Laboratorio de Análisis Clínicos Especializados; Argentina Fil: Wille-bille, Aranza. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina Fil: Nizhnikov, Michael. Southern Connecticut State University; Estados Unidos Fil: Spear, Linda P.. University Of Binghamton; Estados Unidos Fil: Pautassi, Ricardo Marcos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina. Universidad Nacional de Córdoba. Facultad de Psicología; Argentina

Pairing a conditioned stimulus (CS) with ethanol generally produces aversion for that CS in adult rodents. However, infant rats (PD1-PD3) exposed to ethanol demonstrate appetitive reinforcement to ethanol ( Nizhnikov, Varlinskaya, Petrov, & Spear, 2006 ; Petrov, Varlinskaya, & Spear, 2003 ). This sensitivity to the appetitive properties of ethanol during infancy may be transient, as during the second postnatal week rat pups tend to exhibit conditioned aversions to flavors paired with ethanol. The present study examined changes in the motivation properties of ethanol through ontogeny and the neurobiology underlying these changes. Rat pups were exposed to a taste conditioning procedure on PD4 or PD12. Rat pups were intraorally infused with 2.5% of their body weight of saccharin solution (0.1%) and immediately after injected intraperitoneolly (i.p.) with one of six doses of ethanol (0.0–2.0 g/kg). A day later pups were given saccharine infusions and percent body weight gain was used as an index of ethanol's reinforcing effects. PD4 pups expressed appetitive reinforcement to ethanol, as indicated by greater saccharin intake, as compared to control counterparts and to the older PD12 pups. Subsequent experiments revealed that PD4 pups were less sensitive to the aversive properties of the drug than PD12 pups. The older pups found high doses of ethanol aversive while PD4 rat pups did not condition aversions to this dose of ethanol after a single trial. A similar pattern of results was observed between the low doses of ethanol and the highest doses of a kappa opioid agonist. The PD12 animals did not condition to the kappa opioid agonist, while the younger rats expressed an appetitive response. These results illustrate an ontogenetic change in the motivational properties of ethanol, with sensitivity to its appetitive properties declining and responsiveness to the aversive properties increasing with age during early infancy.

Alcohol abuse and dependence is considered a developmental disorder with etiological onset during late childhood and adolescence, and understanding age-related differences in ethanol sensitivity is important. Low to moderate ethanol doses (0.5 and 2.0 g/kg, i.g.) induce single-trial, appetitive second-order place conditioning (SOC) in adolescent, but not adult, rats. Recent studies have demonstrated that adolescents may be less sensitive than adults to the aversive properties of ethanol, reflected by conditioned taste aversion. The present study assessed the aversive motivational effects of high-dose ethanol (3.0 and 3.25 g/kg, i.g., for adolescent and adults, respectively) using SOC. These doses were derived from Experiment 1, which found similar blood and brain ethanol levels in adolescent and adult rats given 3.0 and 3.25 g/kg ethanol, respectively. In Experiment 2, animals received ethanol or vehicle paired with intraoral pulses of sucrose (conditioned stimulus 1 [CS1]). After one, two, or three conditioning trials, rats were presented with the CS1 while in a distinctive chamber (CS2). When tested for CS2 preference, ethanol-treated animals exhibited reduced preference for the CS2 compared with controls. This result, indicative of ethanol-mediated aversive place conditioning, was similar for adolescents and adults, for females and males, and after one, two, or three training trials. One finding, however, suggested that adolescents were less sensitive than adults to ethanol’s aversive effects at the intermediate level of training. In conjunction with previous results, the present study showed that in adolescent rats subjected to SOC, ethanol’s hedonic effects vary from appetitive to aversive as the ethanol dose increases. Adolescent and adult animals appear to perceive the post-ingestive effects of high-dose ethanol as similarly aversive when assessed by SOC.

Little is known about the acute motivational effects of inhaled ethanol during early postnatal development. We analyzed the motivational properties of ethanol inhalation in infant rats by using two distinct schedules of ethanol vapor delivery. Ethanol was presented in a continuous conditioning trial or in separate, distributed trials. Maximum blood ethanol concentrations (BECs) induced by these schedules were 55 and 15 mg%, respectively (Experiment 1). In Experiment 2, subjects were given daily pairings (postnatal days [PD] 14 and 15) between a tactile conditioned stimulus (CS, sandpaper) and the postabsorptive effects of ethanol inhalation. A tactile preference test (PD16) revealed a significant aversion for the CS in pups given continuous exposure to ethanol vapor. In Experiment 3, an ethanol pre-exposure phase (PD13) preceded tactile-ethanol pairings. During conditioning, pups were given distributed pairings between the tactile CS and ethanol or uncontaminated air. At test, ethanol-pre-exposed animals spent significantly more time on the ethanol-related CS than on an alternative texture. These results indicate that inhaled ethanol exerts differential hedonic effects in infant rats as a function of schedules of exposure that yield different levels of intoxication. Continuous experience with ethanol vapor induces aversive learning. Yet, pre-exposure to ethanol vapor allowed expression of ethanol-induced appetitive learning in pups given distributed vapor ethanol exposure.