Effects of a two-hit model of early life adversity on oral ethanol self-administration and adrenergic receptor expression in adolescent rats

Abstract

<b>Abstract ID 24021</b> <b>Poster Board 215</b> Alcohol (EtOH) use significantly contributes to the three leading causes of death among adolescents: unintentional injuries, suicide, and homicide. Adolescents consume more EtOH per drinking occurrence than adults. Early life adversities (ELA), including prenatal opioid exposure (POE) and postnatal adverse experiences, increase the risk of problematic EtOH use among adolescents. POE is any exposure to opioids during gestation and postnatal adverse experiences include abuse, neglect, or household dysfunction, such as parental substance use disorder. Because they often co-occur and are risk factors for early EtOH use, we investigated the relationship between POE, postnatal adversity, and adolescent EtOH. We also aimed to determine how α-adrenoceptor activity is affected by these ELAs to in turn affect adolescent EtOH intake. To model POE, pregnant rats received 15 mg/kg/day morphine or vehicle via subcutaneous minipumps from gestational day 9 to birth. To model postnatal adversity, we used limited bedding and nesting (LBN) procedures in which dams and litters were restricted to 20% of normal bedding and nesting materials from postnatal day (PD) 3 to 11. LBN increases maternal stress and decreases maternal care quality. Starting on PD 31 or 33, rats were given access to bottles containing either a 20% EtOH (v/v) solution or water under an intermittent-access, two-bottle choice procedures for 24-hour sessions, three days per week for four weeks (12 sessions). Rats received either yohimbine (1 mg/kg; ip) or vehicle 30-min prior to each EtOH access session to determine if pharmacologically-induced sympathomimetic activity enhances the acquisition of EtOH in adolescent rats and to assess for altered α₂-adrenoceptor activity in rats that experienced POE and/or LBN. Cortices and brainstems from littermates without EtOH exposure were harvested on either PD 30 or PD 70 and used in radioligand receptor binding assays to quantify α₁- and α₂-adrenoceptor density. We hypothesized that adolescents with a history of combined POE and LBN (“two-hit” group) will consume more EtOH, have higher brain densities of α₁-adrenoceptor, and have lower brain densities of α₂-adrenoceptor than adolescents with either condition alone. In general, female rats drank more EtOH than male rats, and EtOH consumption was more affected by treatment condition in females than males. For example, female rats, more so than male rats, in the two-hit treatment group drank more EtOH after administration of yohimbine. Also, in the two-hit group, there was a decrease in EtOH consumption compared to the LBN and control groups within each sex. In our adrenoceptor density study, there was no difference in α₁-adrenoceptor expression between males and females and across treatment groups. However, in the female cortex, there was high variability and a main effect of sex in α₂-adrenoceptor expression with male expression being greater. Together, these results indicate a complex interaction between ELA, sex, and α-adrenoceptor activity that may support a stress inoculation hypothesis. Support/Funding Information: NIDA 5T32DA022981 ABI/ACRI Grant Award