Nicotine acts in the anterior cingulate, but not dorsal or ventral hippocampus, to reverse ethanol-induced learning impairments in the plus-maze discriminative avoidance task


Thomas J. Gould, Department of Psychology, Center for Substance Abuse Research, Weiss Hall, Temple University, Philadelphia, PA 19122, USA. E-mail:


The current study examines the role of the dorsal and ventral hippocampus, and anterior cingulate in the interactive effects of ethanol and nicotine on learning, anxiety and locomotion in the plus-maze discriminative avoidance task, which allows dissociation of drug effects on each behaviour. At training, time spent in each of the arms of the elevated plus-maze was recorded for 5 minutes. Each time that the mouse entered the aversive enclosed arm, a light and white noise were turned on. At testing, no cues were turned on and time spent in each arm was recorded for 3 minutes. The effects of systemic ethanol (1.0 or 1.4 g/kg) and nicotine (0.35 µg/0.50 µl/side) infused into the anterior cingulate, dorsal and ventral hippocampus were examined, as were the interactive effects of systemic ethanol (1.0 g/kg) and nicotine (0.09 mg/kg) with the high-affinity nicotinic receptor antagonist dihydro-beta-erythroidine (DHβE) (18.0 µg/0.50 µl/side) infused into the anterior cingulate. Ethanol dose dependently decreased anxiety, increased locomotion, and decreased learning. Anterior cingulate-infused nicotine decreased anxiety and reversed ethanol-associated learning deficits. Anterior cingulate-infused DHβE blocked reversal of ethanol-induced learning deficits by systemic nicotine. Dorsal hippocampus-infused nicotine reversed ethanol-induced anxiolysis and hyper-locomotion (1.4 g/kg) but produced no behavioural changes in ethanol-naïve mice. Ventral hippocampus-infused nicotine enhanced anxiolysis associated with 1.4 g/kg ethanol, but had no other effects. The anterior cingulate is necessary and sufficient for nicotine reversal of ethanol-induced learning deficits. In addition, the anterior cingulate, dorsal hippocampus and ventral hippocampus may mediate drug-induced changes in anxiety.