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Regular version of the site

Article

Nicotine reverses hypofrontality in animal models of addiction and schizophrenia

Nature Medicine. 2017. Vol. 23. No. 3. P. 347.
Koukouli F., Rooy M. E., Tziotis D., Sailor K., O'Neill H., Levenga J., Witte M., Nilges M., Changeux J., Hoeffer C., Stitzel J., Gutkin B., DiGregorio D., Maskos U.

The prefrontal cortex (PFC) underlies higher cognitive processes1 that are modulated by nicotinic acetylcholine receptor (nAChR) activation by cholinergic inputs2 . PFC spontaneous default activity3 is altered in neuropsychiatric disorders4 , including schizophrenia5 —a disorder that can be accompanied by heavy smoking6 . Recently, genome-wide association studies (GWAS) identified single-nucleotide polymorphisms (SNPs) in the human CHRNA5 gene, encoding the α5 nAChR subunit, that increase the risks for both smoking and schizophrenia7,8. Mice with altered nAChR gene function exhibit PFC-dependent behavioral deficits9–11, but it is unknown how the corresponding human polymorphisms alter the cellular and circuit mechanisms underlying behavior. Here we show that mice expressing a human α5SNP exhibit neurocognitive behavioral deficits in social interaction and sensorimotor gating tasks. Two-photon calcium imaging in awake mouse models showed that nicotine can differentially influence PFC pyramidal cell activity by nAChR modulation of layer II/III hierarchical inhibitory circuits. In α5- SNP-expressing and α5-knockout mice, lower activity of vasoactive intestinal polypeptide (VIP) interneurons resulted in an increased somatostatin (SOM) interneuron inhibitory drive over layer II/III pyramidal neurons. The decreased activity observed in α5-SNP-expressing mice resembles the hypofrontality observed in patients with psychiatric disorders, including schizophrenia and addiction5,12. Chronic nicotine administration reversed this hypofrontality, suggesting that administration of nicotine may represent a therapeutic strategy for the treatment of schizophrenia, and a physiological basis for the tendency of patients with schizophrenia to self-medicate by smoking13.