Expression of the cannabinoid receptor CB1 in distinct neuronal subpopulations in the adult mouse forebrain

Cannabinoids can modulate motor behaviour, learning and memory, cognition a nd pain perception. These effects correlate with the expression of the cann abinoid receptor 1 (CB1) and with the presence of endogenous cannabinoids i n the brain. In trying to obtain further insights into the mechanisms under lying the modulatory effects of cannabinoids, CB1-positive neurons were det ermined in the murine forebrain at a single cell resolution. We performed a double in situ hybridization study to detect mRNA of CB1 in combination wi th mRNA of glutamic acid decarboxylase 65k, neuropeptide cholecystokinin (C CK), parvalbumin, calretinin and calbindin D28k, respectively. Our results revealed that CB1-expressing cells can be divided into distinct neuronal su bpopulations. There is a clear distinction between neurons containing CB1 m RNA either at high levels or low levels. The majority of high CB1-expressin g cells are GABAergic (gamma-aminobutyric acid) neurons belonging mainly to the cholecystokinin-positive and parvalbumin-negative type of interneurons (basket cells) and, to a lower extent, to the calbindin D28k-positive mid- proximal dendritic inhibitory interneurons. Only a fraction of low CB1-expr essing cells is GABAergic. In the hippocampus, amygdala and entorhinal cort ex area, CB1 mRNA is present at low but significant levels in many non-GABA ergic cells that can be considered as projecting principal neurons. Thus, a complex mechanism appears to underlie the modulatory effects of cannabinoi ds. They might act on principal glutamatergic circuits as well as modulate local GABAergic inhibitory circuits. CB1 is very highly coexpressed with CC K. It is known that cannabinoids and CCK often have opposite effects on beh aviour and physiology. Therefore, we suggest that a putative cross-talk bet ween cannabinoids and CCK might exist and will be relevant to better unders tanding of physiology and pharmacology of the cannabinoid system.