The muscarinic agonist xanomeline increases monoamine release and immediate early gene expression in the rat prefrontal cortex.
BACKGROUND
The muscarinic agonist xanomeline has been shown to reduce antipsychotic-like behaviors in patients with Alzheimer's disease. Because atypical antipsychotic agents increase dopamine release in prefrontal cortex and induce immediate early gene expression in prefrontal cortex and nucleus accumbens, the effect of xanomeline was determined on these indices.


METHODS
The effect of xanomeline on extracellular levels of monoamines in brain regions was determined using a microdialysis technique, and changes in expression of the immediate early genes c-fos and zif/268 in brain regions were evaluated using in situ hybridization histochemistry.


RESULTS
Xanomeline increased extracellular levels of dopamine in prefrontal cortex and nucleus accumbens but not in striatum. Xanomeline increased expression of c-fos and zif/268 in prefrontal cortex and nucleus accumbens. There was no change in immediate early gene expression in striatum.


CONCLUSIONS
Xanomeline increased extracellular levels of dopamine, which is similar to the effects of the atypical antipsychotics clozapine and olanzapine. The regional pattern of immediate early gene expression induced by xanomeline resembled that of atypical antipsychotic agents. Based on the antipsychotic-like activity of xanomeline in Alzheimer's patients and the similarity to atypical antipsychotic agents, we suggest that xanomeline may be a novel antipsychotic agent.
Perry
K W
KW
Eli Lilly and Company Research Laboratories, Neuroscience Research Division, Lilly Corporate Center, Indianapolis, IN 46285-0510, USA.
Nisenbaum
L K
LK
George
C A
CA
Shannon
H E
HE
Felder
C C
CC
Bymaster
F P
FP
D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism*; D018678:Cholinergic Agents / Q000378:metabolism* / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000187:drug effects; D051766:Early Growth Response Protein 1; D017781:Genes, Immediate-Early / Q000187:drug effects*; D016762:Genes, fos / Q000187:drug effects; D017874:Immediate-Early Proteins / Q000187:drug effects; D008297:Male; D017551:Microdialysis; D017397:Prefrontal Cortex / Q000000981:diagnostic imaging / Q000187:drug effects*; D011725:Pyridines / Q000378:metabolism* / Q000494:pharmacology*; D011859:Radiography; D051381:Rats; D013830:Thiadiazoles / Q000378:metabolism* / Q000494:pharmacology*; D014157:Transcription Factors / Q000187:drug effects
D015306:Biogenic Monoamines; D018678:Cholinergic Agents; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D017874:Immediate-Early Proteins; D011725:Pyridines; D013830:Thiadiazoles; D014157:Transcription Factors; C075257:xanomeline