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Summary: Adolescent smoking is associated with pathological drinking later in life, but the biological basis for this vulnerability is unknown. To examine how adolescent nicotine exposure influences subsequent ethanol intake, nicotine was administered during adolescence or adulthood, and responses to alcohol were measured 1 month later. We found that adolescent, but not adult, nicotine exposure altered GABA signaling within the ventral tegmental area (VTA) and led to a long-lasting enhancement of alcohol self-administration. We detected depolarizing shifts in GABAA reversal potentials arising from impaired chloride extrusion in VTA GABA neurons. Alterations in GABA signaling were dependent on glucocorticoid receptor activation and were associated with attenuated dopaminergic neuron responses to alcohol in the lateral VTA. Importantly, enhancing chloride extrusion in adolescent nicotine-treated animals restored VTA GABA signaling and alcohol self-administration to control levels. Taken together, this work suggests that adolescent nicotine exposure increases the risk profile for increased alcohol drinking in adulthood. : Thomas et al. show that nicotine treatments during adolescence, but not adulthood, cause a long-term increase in alcohol self-administration in adult rodents. Adolescent nicotine exposure shifts GABAA receptor signaling within the ventral tegmental area circuitry, thereby altering subsequent responses to alcohol. Keywords: alcohol use disorder, reward, mesolimbic, nucleus accumbens, self-administration, chloride gradient, KCC2, glucocorticoid, gateway, dopamine

Dopamine release during reward-driven behaviors influences synaptic plasticity. However, dopamine innervation and release in the hippocampus and its role during aversive behaviors are controversial. Here, we show that in vivo hippocampal synaptic plasticity in the CA3-CA1 circuit underlies contextual learning during inhibitory avoidance (IA) training. Immunohistochemistry and molecular techniques verified sparse dopaminergic innervation of the hippocampus from the midbrain. The long-term synaptic potentiation (LTP) underlying the learning of IA was assessed with a D1-like dopamine receptor agonist or antagonist in ex vivo hippocampal slices and in vivo in freely moving mice. Inhibition of D1-like dopamine receptors impaired memory of the IA task and prevented the training-induced enhancement of both ex vivo and in vivo LTP induction. The results indicate that dopamine-receptor signaling during an aversive contextual task regulates aversive memory retention and regulates associated synaptic mechanisms in the hippocampus that likely underlie learning.

Following opioid cessation, patients with opioid use disorder experience physical and psychological withdrawal symptoms. Prolonged negative affect, including anxiety and heightened stress reactivity, continues after physical withdrawal symptoms subside, contributing to the high relapse rates. The nitric oxide system plays a role in synaptic plasticity downstream of the mu opioid receptor pathway, and nitric oxide synthase inhibitors attenuate physical opioid withdrawal signs. We hypothesized that N(gamma)-nitro-l-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, would reduce negative affect after protracted opioid withdrawal. Therefore, we first modeled withdrawal in male and female mice using 5 days of morphine injections followed by behavioral tests after one week of forced abstinence from morphine. One week of morphine withdrawal caused altered responses to tests of affective behavior in both male and female mice. There were, however, both subtle and significant sex differences among many of the behavioral measures of negative affect. Males and females had differences in immobility during the tail suspension test during morphine withdrawal, while only females had altered grooming in the sucrose splash test. Forced l-NAME in the animals’ drinking water during withdrawal attenuated all physical and affective measures of withdrawal in males and females but there were subtle differences. Together, these results suggest that the nitric oxide system may be a target to ameliorate the different behavioral manifestations of negative affect in males and females.