Zeitschrift für Alkoholismus und Drogenabhängigkeit
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Menthol-Activated Cells in the Reward-Addiction Neurocircuitry

Ozra Dehkordi, Richard M Millis, Maryam M Dalivand, Melanie Swang, Martha I Dávila-García

Background: Menthol, a commonly used flavoring additive in cigarettes has been found to facilitate smoking initiation and nicotine addiction. However, the neuroanatomical and neurochemical targets of menthol within the reward-addiction neurocircuitry remain unknown. In the present study in mice, we hypothesized that dopaminergic and GABAergic neurons of the reward-addiction circuitry are among the initial targets of menthol in the CNS. Methods: We tested this hypothesis by utilizing c-Fos immunohistochemical techniques and double labeling to identify the anatomical location of menthol activated cells with respect to tyrosine hydroxylase (TH) immunoreactive (IR) dopaminergic and GAD67-GFP positive GABAergic cells. Results: Menthol (100 mg/kg, IP) produced c-Fos activation at multiple sites of the mesocorticolimbic reward-addiction pathways including several structures previously shown to be activated by nicotine such as the periaqueductal gray (PAG), dorsal raphe (DR), ventral tegmental area (VTA), several thalamic and hypothalamic nuclei, amygdala, nucleus accumbens (NAcc) insular cortex, piriform cortex, anterior olfactory nucleus and cingulate-orbitofrontal cortex. Double-labeling studies showed that neither dopaminergic nor GABAergic neurons in VTA showed menthol-induced c-Fos immunoreactivity. Dopaminergic cells in PAG/DR region and hypothalamus were also devoid of menthol-induced c-Fos immunoreactivity. In addition to VTA, the GABAergic cells of NAcc and cingulate- orbitofrontal cortex were not targeted by menthol. Conclusion: The present study identifies several sites, including those of the mesocorticolimbic reward-addiction pathways that contain neurons activated by IP administration of menthol. However, neither dopaminergic nor GABAergic neurons appear to be the initial targets of menthol in reward-addiction neurocircuitry.