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Intranasal pregnenolone increases acetylcholine in frontal cortex, hippocampus, and amygdala—Preferentially in the hemisphere ipsilateral to the injected nostril

Benedetta Fazari, Cvetana Ilieva Decheva, Victoria González García, Laila Abdel‐Hafiz, Susanne Nikolaus, Cornelis P. Hollenberg, Joseph P. Huston, Maria A. de Souza Silva, Claudia Mattern

Journal of Neurochemistry. Volume153, Issue2 Pages 189-202

This study determined the effects of intranasal pregnenolone (IN‐PREG) on acetylcholine (ACh) levels in selected areas of the rat brain, using in vivo microdialysis. Previous studies showed that PREG rapidly reaches the rodent brain after intranasal administration and that direct infusion of PREG and PREG‐S into the basal forebrain modulates ACh release in frontal cortex, amygdala, and hippocampus. In the present study, we investigated the effects of IN‐PREG on the cholinergic system in the rat brain. In the first experiment, IN‐PREG (5.6 and 11.2 mg/ml) or vehicle was applied bilaterally, and we hypothesized that IN‐PREG would increase ACh levels in amygdala, hippocampus, and frontal cortex, relative to baseline and vehicle. Dialysate was collected for 100 min, based on pilot data of duration of effect. Bilateral IN‐PREG (5.6 and 11.2 mg/ml) increased frontal cortex and hippocampal ACh relative to both baseline and vehicle. Moreover, 11.2 mg/ml PREG increased ACh in the amygdala relative to baseline, the lower dose, and vehicle. Therefore, in the second experiment, IN‐PREG (11.2 mg/ml) was applied only into one nostril, with vehicle applied into the other nostril, in order to determine whether ACh is predominantly increased in the ipsilateral relative to the contralateral amygdala. Unilateral application of IN‐PREG increased ACh in the ipsilateral amygdala, whereas no effect was observed on the contralateral side, suggesting that PREG was transported from the nostrils to the brain via the olfactory epithelial pathway, but not by circulation. The present data provide additional information on IN‐PREG action in the cholinergic system of frontal cortex, amygdala, and hippocampus. This may be relevant for therapeutic IN application of PREG in neurogenerative and neuropsychiatric disorders.

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