alpha 7 Nicotinic receptor agonism mitigates phencyclidine-induced changes in synaptophysin and Arc gene expression in the mouse prefrontal cortex

作者：Thomsen Morten S^*; Hansen Henrik H; Mikkelsen Jens D

来源：Neurochemistry International, 2010, 57(7): 756-761.

DOI：10.1016/j.neuint.2010.08.013

• Prefrontal cortex
• Nicotinic acetylcholine receptor
• Arc
• Parvalbumin
• Synaptophysin
• Glutamate decarboxylase 67

Repeated phencyclidine (PCP) administration in mice reproduces several histopathological features of schizophrenia, such as reduced synaptophysin and parvalbumin mRNA expression in the frontal cortex. These changes can be prevented by co-administering the alpha 7 nicotinic acetylcholine receptor (nAChR) agonist SSR180711 with PCP, but it is not known to what extent PCP-induced changes can be normalized once they have already occurred. Here we use semi-quantitative in situ hybridization to show that repeated administration of SSR180711 (3 mg/kg b.i.d. for 5 days) subsequent to repeated PCP administration (10 mg/kg/day for 10 days) is able to mitigate the reduction of synaptophysin mRNA expression induced by PCP in two prefrontal cortical regions, the medial prefrontal cortex (mPFC) and the ventrolateral orbitofrontal cortex (VLO). This effect is accompanied by a normalization of the PCP-induced increase in Arc mRNA expression in the same regions. In contrast, subsequent administration of SSR180711 does not affect PCP-induced decreases in parvalbumin mRNA in the mPFC, and glutamate decarboxylase 67 mRNA in the mPFC or VLO. These data demonstrate that it is possible to restore some, but not all, of the molecular dysregulations induced by repeated PCP administration with an alpha 7 nAChR agonist. They also suggest that the previously demonstrated cognitive improvement with SSR180711 subsequent to PCP treatment does not require normalization of parvalbumin expression, but may instead be related to a restoration of synaptophysin and/or Arc levels in the frontal cortex. These data lend support to the potential for development of alpha 7 nAChR agonists for the treatment of cognitive deficits in schizophrenia.

• 出版日期2010-12