Paradoxical effects of menthol on passive avoidance and spatial memory in the rat

Menthol is well-known for its peripheral effects, e.g. cold receptor stimulation, pain modulation, and anti-inflammatory properties. However, its impacts on the CNS remain less understood. Here, we studied the acute and chronic effects of menthol, on passive avoidance learning-retention, and spatial memory, respectively.

An appropriate dose of menthol that did not acutely affect motor activity was determined. Rats were then administered either a single dose of menthol or the solvent via intraperitoneal injection before the training or test session. In one group, bicuculline (1 mg/kg) was coadministered with menthol to rats prior to the training session. To determine the chronic effect of menthol on spatial memory, rats received daily doses of menthol or the solvent for 12 days before each session of the spatial memory test.

A dose of 40 mg/kg of menthol did not significantly alter motor activity in the open field test, but higher doses caused significant decrease of locomotion. Administration of menthol (40 mg/kg) before the training session led to reduced learning and memory retention. This effect was found to be inhibited by bicuculline. However, menthol administration before the test session had no effect on fear memory retention. Chronic administration of menthol during the spatial memory test period improved reference and working spatial memory.

These findings suggest that menthol impairs fear memory learning and retention by activating GABA receptors. Menthol may also improve spatial memory through its reported anxiolytic action. Further studies are necessary to confirm this potential mechanism.