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 alpha7 receptors (alpha7 nAChR) is useful for the treatment of cognitive disturbances in schizophrenia and Alzheimer's disease. Recently, selective alpha7 nAChR agonists have been discovered and are used to validate the alpha7 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 alpha7 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 alpha7 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 alpha7 nAChR antagonist methyllycaconitine. Also, SSR180711 displayed no c-Fos-inducing effect in alpha7 nAChR knock-out mice. In conclusion, these results show that selective pharmacologic stimulation of alpha7 nAChR function results in activation of forebrain regions similar to conventional antipsychotics.
Hansen
Henrik H
HH
Department of Translational Neurobiology, NeuroSearch A/S, Ballerup, Denmark. heh@neuroresearch.dk
Timmermann
Daniel B
DB
Peters
Dan
D
Walters
Carrie
C
Damaj
M Imad
MI
Mikkelsen
Jens D
JD
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D007150:Immunohistochemistry; D008032:Limbic System / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018722:Nicotinic Agonists / Q000494:pharmacology*; D016548:Prosencephalon / Q000187:drug effects* / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D064569:alpha7 Nicotinic Acetylcholine Receptor
D014150:Antipsychotic Agents; D001549:Benzamides; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; C579166:Chrna7 protein, mouse; C579165:Chrna7 protein, rat; D018722:Nicotinic Agonists; C498513:PNU-282987; D016760:Proto-Oncogene Proteins c-fos; D011978:Receptors, Nicotinic; C516833:SSR180711; D064569:alpha7 Nicotinic Acetylcholine Receptor