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Adolescent alcohol use can lead to numerous consequences, including altered stress reactivity and higher risk for later anxiety and alcohol use disorders. Many studies have examined the consequences of heavy ethanol exposure in adolescence, but far less is understood about lower levels of intoxication. The present study examined moderate adolescent ethanol exposure as a possible factor in increasing stress reactivity in adulthood, measured through general and social anxiety-like behaviors, as well voluntary ethanol intake. Male and female Sprague–Dawley rats underwent an adolescent chronic intermittent ethanol (aCIE) vapor exposure during early adolescence, reaching moderate blood ethanol concentrations. Animals then underwent two days of forced swim stress in adulthood. We found that ethanol-exposed males consumed more ethanol than their air counterparts and an interesting stress and ethanol exposure interaction in males. There were no significant effects on voluntary drinking in females. However, the social interaction test revealed increased play-fighting behavior in ethanol-exposed females and reduced social preference in females after two days of stress exposure. Overall, this work provides evidence for sex-specific, long-term effects of moderate aCIE and susceptibility to acute stress in adulthood.

Adolescent alcohol exposure is associated with many negative outcomes that persist into adulthood, including altered affective and reward-related behaviors. However, the long-term neurological disruptions underlying these behavioral states are not fully understood. The basolateral amygdala (BLA) plays a critical role in many of these behaviors, and shifts in the excitatory/inhibitory balance in this area are capable of directly modulating their expression.While changes to BLA physiology have been demonstrated during the acute withdrawal phase following adolescent ethanol exposure, no studies to date have examined whether these persist long-term. The kappa opioid receptor (KOR) system is a neuromodulatory system that acts as a prominent mediator of negative affective behaviors, and alterations of this system have been implicated in the behavioral profile caused by chronic alcohol exposure in adulthood. Notably, in the BLA, the KOR system undergoes functional changes between adolescence and adulthood, but whether BLA KORs are functionally disrupted by adolescent ethanol exposure has not been examined. In this study, we exposed male and female Sprague-Dawley rats to a vapor inhalation model of moderate adolescent chronic intermittent ethanol (aCIE) and examined the long-term effects on GABAergic and glutamatergic neurotransmission within the adult BLA using whole-cell patch-clamp electrophysiology. We also assessed how KOR activation modulated these neurotransmitter systems in aCIE versus control rats using the selective KOR agonist, U69593. This investigation revealed that aCIE exposure disrupted basal glutamate transmission in females by increasing spontaneous excitatory postsynaptic current (sEPSC) frequency, while having no effects on glutamate transmission in males or GABA transmission in either sex.Interestingly, we also found that aCIE exposure unmasked a KOR-mediated suppression of spontaneous inhibitory postsynaptic current (sIPSC) frequency and sEPSC amplitude only in males, with no effects of aCIE exposure on KOR function in females. Together, these data suggest that moderate-level adolescent ethanol exposure produces long-term changes to BLA physiology and BLA KOR function, and that these changes are sex-dependent. This is the first study to examine persistent adaptations to both BLA physiology and KOR function following adolescent alcohol exposure, and opens a broad avenue for future investigation into other neurobiological and behavioral consequences of adolescent ethanol exposure-induced disruptions of these systems.

Prenatal opioid exposures lead to extensive cognitive and emotion-regulation problems in children, persisting at least through school-age. Methadone, an opioid typically used for the treatment of opioid use disorder, has been approved for use in pregnant women for several decades. Importantly, however, the impacts of prenatal methadone exposure (PME), particularly on offspring as they progress into adulthood, has not been extensively examined. In recent years, children and young animal models have shown cognitive deficits related to PME, including evidence of hippocampal dysfunction. The present work aims to examine the persistent nature of these deficits, as well as determine how they may differ by sex. Pregnant Sprague Dawley rats either received subcutaneous methadone or water injections twice daily from gestational days 3-20 or were left undisturbed. Following postnatal day 70, male and female offspring were behaviorally tested for impairments in recognition memory using the Novel Object Recognition task and working spatial memory through Spontaneous Alternation. Additionally, using whole-cell patch-clamp electrophysiology, hippocampal dentate granule cell function was examined in adult offspring. Results indicate that methadone-exposed females showed decreased excitability and increased inhibition of these dentate granule cells, while males did not. These findings were accompanied by impairments in female working spatial memory and impaired recognition memory of both sexes. Overall, this work supports the continued investigation of the long-term effects of PME on adult male and female learning and memory, as well as promotes further exploration of adult hippocampal function as a neural mechanism impacted by this exposure.

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