The interactive effects of nicotinic and muscarinic cholinergic receptor inhibition on fear conditioning in young and aged C57BL/6 mice

Abstract

Both normal aging and age-related disease, such as Alzheimer's disease, have diverse effects on forebrain-dependent cognitive tasks as well as the underlying neurobiological substrates. The purpose of the current study was to investigate if age-related alterations in the function of the cholinergic system are associated with memory impairments in auditory-cued and contextual fear conditioning. Young (2–3 months) and aged (19–20 months) C57BL/6 mice were administered scopolamine (0.1, 0.3, 0.5, or 1.0 mg/kg), a muscarinic cholinergic receptor antagonist, mecamylamine (1.0 and 2.0 mg/kg), a nicotinic cholinergic receptor antagonist, both scopolamine and mecamylamine (0.1 and 1.0 mg/kg, respectively), or saline prior to training. Training consisted of two white-noise CS (85 dB, 30 s)-footshock US (0.57 mA, 2 s) presentations. Testing occurred 48 h post-training. Scopolamine administration impaired contextual and cued fear conditioning in young and aged mice, although the aged mice were less sensitive to disruption by scopolamine. Mecamylamine did not disrupt conditioned fear in the young or aged mice. Scopolamine and mecamylamine co-administration, at doses sub-threshold for disrupting fear conditioning with separate administration, disrupted contextual and auditory-cued fear conditioning in the young mice, indicating that in the young mice the muscarinic and nicotinic cholinergic processes interact in the formation and maintenance of long-term memories for conditioned fear. Co-administration of both antagonists did not disrupt fear conditioning in the aged mice, indicating that age-related alterations in the cholinergic receptor subtypes may occur.