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The Journal of Neuroscience, May 24, 2006, 26(21):5794-5799; doi:10.1523/JNEUROSCI.0372-06.2006

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Brief Communications
Cannabinoid Receptor Type 1 Located on Presynaptic Terminals of Principal Neurons in the Forebrain Controls Glutamatergic Synaptic Transmission

Maria R. Domenici,^1,6 * Shahnaz C. Azad,^1,4 * Giovanni Marsicano,³ Anja Schierloh,^1,7 Carsten T. Wotjak,² Hans-Ulrich Dodt,¹ Walter Zieglgänsberger,¹ Beat Lutz,³ and Gerhard Rammes^1,5

¹Department of Clinical Neuropharmacology and ²Neuronal Plasticity, Max Planck Institute of Psychiatry, 80804 Munich, Germany, ³Department of Physiological Chemistry, Johannes-Gutenberg University, 55099 Mainz, Germany, ⁴Department of Anaesthesiology, Ludwig-Maximilians University, 81377 Munich, Germany, ⁵Department of Anaesthesiology, Technical University, 81675 Munich, Germany, ⁶Department of Drug Research and Evaluation, Istituto Superiore di Sanità, 00161 Rome, Italy, and ⁷Friedrich-Schiedel Institute of Neuroscience, Technical University, 80802 Munich, Germany

Correspondence should be addressed to Dr. Gerhard Rammes, Department of Clinical Neuropharmacology, Max Planck Institute of Psychiatry, Kraepelinstrasse 2, 80804 München, Germany. Email: rammes{at}mpipsykl.mpg.de

It is widely accepted that cannabinoids regulate GABA release by activation of cannabinoid receptor type 1 (CB1). Results obtained from a variety of brain regions consistently indicate that cannabinoid agonists can also reduce glutamatergic synaptic transmission. However, there are still conflicting data concerning the role of CB1 in cannabinoid-induced inhibition of glutamatergic transmission in cortical areas. Here, we provide direct evidence that activation of CB1 on terminals of principal neurons controls excitatory synaptic responses in the forebrain. In slices of the basolateral amygdala, the CA1 region of the hippocampus, and the primary somatosensory cortex of wild-type mice, application of the CB1 agonist (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (WIN55,212-2; WIN) (5 µM) reduced evoked excitatory postsynaptic responses. In contrast, in slices obtained from conditional mouse mutants lacking CB1 in all principal forebrain neurons but not in GABAergic interneurons (CB1^{f/f;CaMKIICre}), WIN no longer affected glutamatergic synaptic transmission in any of the brain regions tested. Compatible with a presynaptic mechanism, WIN did not change the sensitivity to focally uncaged L-glutamate. WIN reduced glutamatergic responses in slices obtained from mice lacking CB1 exclusively in GABAergic neurons (CB1^{f/f;Dlx5/6-Cre}), thus excluding the involvement of CB1 expressed on GABAergic neurons in this effect of the drug. The present data strongly indicate that excitatory synaptic transmission in forebrain areas is directly modulated by CB1 expressed on presynaptic axon terminals originating from glutamatergic neurons.

Key words: CB1; cannabinoids; glutamatergic; amygdala; hippocampus; cortex; principal neurons; caged glutamate; AMPA-EPSC

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Received Jan. 26, 2006; revised March 31, 2006; accepted April 19, 2006.

Correspondence should be addressed to Dr. Gerhard Rammes, Department of Clinical Neuropharmacology, Max Planck Institute of Psychiatry, Kraepelinstrasse 2, 80804 München, Germany. Email: rammes{at}mpipsykl.mpg.de

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