Role of metabotropic glutamate receptor 5 in the procholinergic effects of neuropsychotherapeutic compounds.
We investigated the participation of the metabotropic glutamate receptor type 5 (mGluR5) in mediating increases in cortical acetylcholine (ACh) efflux elicited by established or putative neuropsychotherapeutic compounds, using in vivo microdialysis in rats. The norepinephrine transporter inhibitor atomoxetine, the cannabinoid CB1 receptor antagonist SR141716A, the dopamine D1 receptor agonist dihydrexidine, and the atypical antipsychotic clozapine increased cortical ACh (by about 2-3 fold), whereas the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) by itself had no effect. The stimulatory effects of atomoxetine, SR141716A and dihydrexidine on cortical ACh were abolished by pretreatment with MPEP. MPEP also attenuated the stimulatory effect of clozapine on ACh efflux. Thus, mGluR5 activation appears to be involved in the procholinergic effects of compounds that exhibit therapeutic properties or potential in neuropsychiatry.
Tzavara
Eleni T
ET
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
Wade
Mark R
MR
Davis
Richard J
RJ
El Khoury
Marie-Anne
MA
Nomikos
George G
GG
D000109:Acetylcholine / Q000502:physiology*; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology; D018678:Cholinergic Agents / Q000494:pharmacology*; D011619:Psychotropic Drugs / Q000494:pharmacology*; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*
D018678:Cholinergic Agents; C578937:Grm5 protein, rat; D011619:Psychotropic Drugs; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D000109:Acetylcholine