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The Journal of Neuroscience, October 15, 2003, 23(28):9374-9384

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Behavioral/Systems/Cognitive
Biphasic Effects of Cannabinoids on Acetylcholine Release in the Hippocampus: Site and Mechanism of Action

Eleni T. Tzavara, Mark Wade, and George G. Nomikos

Eli Lilly and Company, Lilly Corporate Center, Neuroscience Discovery Research, Indianapolis, Indianapolis 46285-0510

Cannabinoids have been shown to critically modulate cholinergic neurotransmission in the hippocampus, yet opposing effects of cannabinoid receptor 1 (CB₁R) agonists on hippocampal synaptic acetylcholine (ACh) efflux have been reported. This study shows that administration of a synthetic CB₁R agonist results in a biphasic, dose-dependent, effect on hippocampal ACh: a low (0.5 mg/kg, i.p.) and a high (5 mg/kg, i.p) dose of WIN55,212-2 induces a transient stimulation and a prolonged inhibition of hippocampal ACh efflux, respectively. Both effects of WIN55,212-2 are mediated through CB₁ receptors coupled to G_i but involve different neuroanatomical sites. Thus, intrahippocampal infusion of the CB₁R antagonist SR141716A or pertussis toxin blocked the inhibition of hippocampal ACh release induced by the high dose of WIN55,212-2, but was without effect on the stimulatory action of the low dose. In contrast, this latter effect was blocked by SR141716A or pertussis toxin infused, in dual microdialysis experiments, in the septum, in which the majority of cholinergic cell bodies projecting to the hippocampus reside. The stimulatory and inhibitory effects of WIN55,212-2 on hippocampal ACh involve dopamine D₁ and D₂ receptor activation, respectively, given that pretreatment with D₁ and D₂ receptor antagonists prevents the respective actions of WIN55,212-2. We propose that the in vivo observed biphasic effects of CB₁R agonists on hippocampal ACh release result from a differential, functional association of anatomicaly distinct subpopulations of CB₁-G_i coupled receptors to neurotransmitter systems that have opposing effects on ACh release. This concept could provide a theoretical framework to understand endocannabinoids as state-dependent modulators of neuronal activity.

Key words: cannabinoids; acetylcholine; hippocampus; biphasic; microdialysis; septum; D₁ dopamine receptors; D₂ dopamine receptors

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Received July 16, 2003; revised August 19, 2003; accepted August 20, 2003.

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