The cannabinoid-1 receptor is abundantly expressed in striatal striosomes and striosome-dendron bouquets of the substantia nigra

Presynaptic cannabinoid-1 receptors (CB(1)-R) bind endogenous and exogenous cannabinoids to modulate neurotransmitter release. CB(1)-Rs are expressed throughout the basal ganglia, including striatum and substantia nigra, where they play a role in learning and control of motivated actions. However, the pattern of CB(1)-R expression across different striatal compartments, microcircuits and efferent targets, and the contribution of different CB(1)-R-expressing neurons to this pattern, are unclear. We use a combination of conventional techniques and novel genetic models to evaluate CB(1)-R expression in striosome (patch) and matrix compartments of the striatum, and in nigral targets of striatal medium spiny projection neurons (MSNs). CB(1)-R protein and mRNA follow a descending dorsolateral-to-ventromedial intensity gradient in the caudal striatum, with elevated expression in striosomes relative to the surrounding matrix. The lateral predominance of striosome CB(1)-Rs contrasts with that of the classical striosomal marker, the mu opioid receptor (MOR), which is expressed most prominently in rostromedial striosomes. The dorsolateral-to-ventromedial CB(1)-R gradient is similar to Drd2 dopamine receptor immunoreactivity and opposite to Substance P. This topology of CB(1)-R expression is maintained downstream in the globus pallidus and substantia nigra. Dense CB(1)-R-expressing striatonigral fibers extend dorsally within the substantia nigra pars reticulata, and colocalize with bundles of ventrally extending, striosome-targeted, dendrites of dopamine-containing neurons in the substantia nigra pars compacta (striosome-dendron bouquets). Within striatum, CB(1)-Rs colocalize with fluorescently labeled MSN collaterals within the striosomes. Cre recombinase-mediated deletion of CB(1)-Rs from cortical projection neurons or MSNs, and MSN-selective reintroduction of CB(1)-Rs in knockout mice, demonstrate that the principal source of CB(1)-Rs in dorsolateral striosomes is local MSN collaterals. These data suggest a role for CB(1)-Rs in caudal dorsolateral striosome collaterals and striosome-dendron bouquet projections to lateral substantia nigra, where they are anatomically poised to mediate presynaptic disinhibition of both striosomal MSNs and midbrain dopamine neurons in response to endocannabinoids and cannabinomimetics.