Alcohol and nicotine, either from tobacco or increasingly from electronic cigarettes, are the two most commonly co-used drugs of abuse. Dual use has increased over time among teenagers and young adults, and represents a major public health concern among adolescents. During adolescence, the brain undergoes a profound reorganization in areas critical for executive function, reward processing, and motivated behavior that are necessary for adult autonomy, but do leave the adolescent brain vulnerable to the deleterious effects of drugs of abuse, including nicotine and alcohol. Neurobiological mechanisms mediating high rates of co-use are not well understood. However, as shown in this dissertation, developmental and sex-dependent changes in the dynorphin/kappa opioid receptor (KOR) system likely contribute.

In this dissertation, I emphasize the profound complexity of the KOR system in modulating acute drug- and mood-associated behaviors across development and between sexes. The present studies use behavioral pharmacological approaches to demonstrate that KOR activity differentially modulates the reinforcing properties of nicotine and/or alcohol. Anatomical studies suggest that distinct, drug-specific anatomical pathways containing KORs modulate the reinforcing properties of these drugs. I have also shown that drug-induced versus direct KOR activation differentially influences mood-associated behaviors. Concurrent nicotine and alcohol (Nic+EtOH) produced a KOR-dependent decrease in anxiety-like behavior in adult females that was paralleled by increased KOR function in the basolateral amygdala. In contrast, two selective KOR agonists exerted a robust anxiogenic effect in this group, that may suggest distinct circuitry mediating direct versus indirect KOR activation on anxiety. Both adolescent and adult males displayed increased anxiety following KOR agonist treatment, while only adolescent males were sensitive to the pro-depressant effects of direct KOR activation, and Nic+EtOH had a subtle anxiolytic effect in this group. I also demonstrate a unique and previously unknown immaturity of KORs in adolescent females, as they were largely impervious to the effects of KOR manipulation on drug- or mood-associated behaviors. As a whole, my work emphasizes the profound complexity of KOR signaling and highlights important maturational and sex-dependent changes in KOR function. These changes may act as a critical, but underrecognized, influence of nicotine and alcohol co-use among teenagers and women.