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CB₁ Receptor Antagonism Increases Hippocampal Acetylcholine Release: Site and Mechanism of Action

Eli Lilly and Company, Lilly Corporate Center, Neuroscience Discovery Research, Indianapolis, Indiana (A.D., M.R.W., R.J.D., G.G.N.); and Center for Neuroscience of Coimbra, Institute of Biochemistry, Faculty of Medicine, University of Coimbra, Coimbra, Portugal (A.K., R.J.R., N.R., R.A.C.)

Evidence indicates that blockade of cannabinoid receptors increases acetylcholine (ACh) release in brain cortical regions. Although it is assumed that this type of effect is mediated through CB₁ receptor (CB₁R) antagonism, several in vitro functional studies recently have suggested non-CB₁R involvement. In addition, neither the precise neuroanatomical site nor the exact mechanisms underlying this effect are known. We thoroughly examined these issues using a combination of systemic and local administration of CB₁R antagonists, different methods of in vivo microdialysis, CB₁R knockout (KO) mice, tissue measurements of ACh, and immunochemistry. First, we showed that systemic injections of the CB₁R antagonists N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR-141716A) and N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) dose-dependently increased hippocampal ACh efflux. Likewise, local hippocampal, but not septal, infusions of SR141716A or AM251 increased hippocampal ACh release. It is noteworthy that the stimulatory effects of systemically administered CB₁R antagonists on hippocampal ACh release were completely abolished in CB₁R KO mice. CB₁R KO mice had similar basal but higher stress-enhanced hippocampal ACh levels compared with wild-type controls. It is interesting that dopamine D₁ receptor antagonism counteracted the stimulatory effect of CB₁R blockade on hippocampal ACh levels. Finally, immunohistochemical methods revealed that a high proportion of CB₁R-positive nerve terminals were found in hippocampus and confirmed the colocalization of CB₁ receptors with cholinergic and dopaminergic nerve terminals. In conclusion, hippocampal ACh release may specifically be controlled through CB₁Rs located on both cholinergic and dopaminergic neuronal projections, and CB₁R antagonism increases hippocampal ACh release, probably through both a direct disinhibition of ACh release and an indirect increase in dopaminergic neurotransmission at the D₁ receptors.

Address correspondence to: Dr. George G. Nomikos, Amgen, Amgen Cambridge Research Center, Neuroscience, One Kendall Square, Building 1000, Cambridge, MA 02139. E-mail: gnomikos{at}amgen.com