An Examination of the Neural Substrates Underlying the Dissociable and Interactive Effects of Acute Ethanol and Nicotine on Learning, Anxiety, and Locomotion in Fear Conditioning and the Plus Maze Discriminative Avoidance Task

Abstract

Studies have demonstrated dissociable effects of nicotine alone versus in combination with ethanol on learning, and these effects may depend on different neural substrates. Furthermore, the effects of nicotine in different brain areas may produce other behavioral changes - such as changes in anxiety - that alter learning. This research examines the interactive effects of ethanol and nicotine on learning, anxiety, and locomotion, and the dissociation of these effects by brain area. Specifically, we examine the interactive effects of systemic ethanol with nicotine infusion into the dorsal hippocampus, ventral hippocampus, or anterior cingulate on contextual and cued fear conditioning and the plus-maze discriminative avoidance task (PMDAT). In addition, we use dihydro-beta-erythroidine (DHbetaE), a nicotinic receptor antagonist, to examine the involvement of acetylcholingeric nicotinic receptors (nAChRs) in the effects of ethanol alone and in the mediation of ethanol-induced changes by nicotine. In the PMDAT, we examine whether caffeine produces the same effects as nicotine in the PMDAT. In fear conditioning, nicotine acts in the dorsal hippocampus to enhance contextual fear conditioning and in the anterior cingulate to reverse ethanol-induced contextual and cued fear conditioning deficits through inactivation of high-affinity beta2 subunit-containing nAChRs. In the PMDAT, ethanol produces learning deficits, anxiolysis, and increased locomotion, and nicotine reverses the effects of ethanol. Although caffeine and ethanol interact to modulate behavior in the PMDAT, caffeine fails to reverse ethanol-induced learning deficits. Finally, the effects of nicotine and ethanol, both alone and in combination, on learning, anxiety, and locomotion depend on distinct neural substrates. Nicotine acts in the anterior cingulate to reverse ethanol-induced learning deficits but produces diverse effects on anxiety that vary across all three brain areas.