News and Publications

Pharmacology of Brain Cannabinoids

P. Schweitzer, G.R. Siggins, S.G. Madamba, D. Piomelli*

* The Neurosciences Institute, San Diego, CA

Our research focuses on the mechanism of action of cannabinoids at the cellular level. Cannabinoid drugs have powerful psychoactive properties and alter many physiologic processes in the brain via activation of specific receptors. A primary challenge is to elucidate the role of the endogenous cannabinoid signaling system, in order to understand the effects of cannabinoid drugs. The hippocampus, a structure associated with learning and memory processes, has one of the highest densities of cannabinoid receptors in the brain. We use slices of hippocampus obtained from adult rats to study synaptic transmission and potassium conductances in this brain structure.

Cannabinoid agonists prevent the induction of long-term potentiation, the electrophysiologic model for learning and memory, by activating central cannabinoid receptors (CB1 receptors). We used moderate stimulation models in the presence or absence of a CB1 antagonist to determine if endogenously formed cannabinoids attenuate or prevent potentiation; that is, does the presence of a CB1 antagonist facilitate long-term potentiation? A train of 50 shocks induced limited potentiation of synaptic transmission in the absence of the antagonist and sustained potentiation in the presence of the antagonist. These results indicate that endogenously formed cannabinoids control the enhancement of synaptic activity in the hippocampus and suggest that the endogenous cannabinoid system may serve as a "brake" to limit the level of potentiation and modulate synaptic plasticity.

We also investigated whether cannabinoids modulate the M-current (I_M), a persistent conductance of potassium ions that clamps the neuronal membrane near rest. Superfusion of nondegradable cannabinoid agonists consistently reduced I_M amplitude by about 50--60%. The I_M inhibition was prevented by a CB1 antagonist, indicating a receptor-mediated mechanism. Thus, cannabinoids may increase neuronal excitability by inhibiting I_M.

Arachidonic acid and its metabolites, the eicosanoids, are lipidic messengers that modulate ion channels and synaptic transmission. The fatty acid is a degradation product of the endogenous cannabinoids, arachidonylethanolamine (anandamide) and 2-arachidonylglycerol. However, studies in our laboratory indicated that eicosanoids augment I_M. Interestingly, the eicosanoids reportedly increase long-term potentiation. The effects of eicosanoids are thus opposed to those of cannabinoids, a finding that indicates a tight compartmentalization of arachidonic acid pools.

Our results show that cannabinoids not only can postsynaptically increase hippocampal excitability by diminishing I_M but may also decrease neuronal activity by inhibiting synaptic plasticity. Surprisingly, the cannabinoids and the eicosanoids, 2 related families of lipid mediators, have opposite effects on various electrophysiologic measurements.

PUBLICATIONS

Schweitzer, P., Madamba, S.G., Siggins, G.R. Somatostatin increases a voltage-insensitive K⁺ conductance in rat CA1 hippocampal neurons. J. Neurophysiol. 79:1230, 1998.