PT  - JOURNAL ARTICLE
AU  - Maria R. Domenici
AU  - Shahnaz C. Azad
AU  - Giovanni Marsicano
AU  - Anja Schierloh
AU  - Carsten T. Wotjak
AU  - Hans-Ulrich Dodt
AU  - Walter Zieglgänsberger
AU  - Beat Lutz
AU  - Gerhard Rammes
TI  - Cannabinoid Receptor Type 1 Located on Presynaptic Terminals of Principal Neurons in the Forebrain Controls Glutamatergic Synaptic Transmission
AID  - 10.1523/JNEUROSCI.0372-06.2006
DP  - 2006 May 24
TA  - The Journal of Neuroscience
PG  - 5794--5799
VI  - 26
IP  - 21
4099  - http://www.jneurosci.org/content/26/21/5794.short
4100  - http://www.jneurosci.org/content/26/21/5794.full
SO  - J. Neurosci.2006 May 24; 26
AB  - 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 (CB1f/f;CaMKIIαCre), 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 (CB1f/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.