Alpha-7 nicotinic acetylcholine receptor agonists selectively activate limbic regions of the rat forebrain: An effect similar to antipsychotics

It is considered that activation of nicotinic α₇ receptors (α₇ nAChR) is useful for the treatment of cognitive disturbances in schizophrenia and Alzheimer's disease. Recently, selective α₇ nAChR agonists have been discovered and are used to validate the α₇ nAChR as a drug target for the treatment of cognitive disturbances in schizophrenia. One important feature shared by all known antipsychotics is their capacity to induce expression of the neuronal immediate-early gene c-fos in the limbic forebrain. Using two novel and selective α₇ nAChR agonists, PNU-282987 and SSR180711, we investigated their ability to induce c-Fos expression in the limbic forebrain with particular emphasis on the same regions reported to be activated by antipsychotics. Both α₇ nAChR agonists increased c-Fos dose-dependently in the prefrontal cortex and the shell of nucleus accumbens, while leaving the core of nucleus accumbens and the dorsolateral striatum unaffected. The accumbal and cortical effect of SSR180711 was blocked completely by pre-administration of the α₇ nAChR antagonist methyllycaconitine. Also, SSR180711 displayed no c-Fos-inducing effect in α₇ nAChR knockout mice. In conclusion, these results show that selective pharmacologic stimulation of α₇ nAChR function results in activation of forebrain regions similar to conventional antipsychotics.