Rationale: Previous research indicates that nicotine administration enhances hippocampus-dependent forms of learning, including contextual fear conditioning. This effect is blocked by mecamylamine, a noncompetitive, broad-spectrum nicotinic receptor antagonist. Objectives: The present study extends previous research by further characterizing the nicotinic acetylcholinergic receptor (nAChR) subtypes through which nicotine acts to enhance contextual fear conditioning. Methods: C57BL/6J mice were trained with two conditioned stimulus (CS; 30 s, 85-dB white noise) - unconditioned stimulus (US; 2 s, 0.57-mA foot shock) pairings and tested 24 h later for contextual and cued fear conditioning. The effects of the α7 nAChR antagonist methyllycaconitine (MLA; 1.00, 10.00, and 20.00 mg/kg) and the effects of the α4β2 nAChR antagonist dihydro-beta-erythroidine (DHBE; 1.00, 3.00, and 6.00 mg/kg) on cued and contextual fear conditioning and on the enhancement of contextual fear conditioning by nicotine (0.25 mg/kg) were examined. Results: We demonstrate that DHBE (all doses) administration attenuates the enhancing effect of nicotine on contextual fear conditioning, and MLA administration has no significant effect on the enhancement of contextual fear conditioning by nicotine. Conclusions: The data suggest that non-α7 nAChRs (most likely α4β2 nAChRs) underlie the enhancement of contextual fear conditioning by nicotine.
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