Expression and Function of CB1 Receptor in the Rat Striatum: Localization and Effects on D1 and D2 Dopamine Receptor-Mediated Motor Behaviors

Abstract

Cannabinoid CB 1 receptors are densely expressed on striatal projection neurons expressing dopamine D 1 or D 2 receptors. However, the specific neuronal distribution of CB 1 receptors within the striatum is not known. Previous research has established that the endocannabinoid system controls facilitation of behavior by dopamine D 2 receptors, but it is not clear if endocannabinoids also modulate D 1 receptor-mediated motor behavior. In the present study, we show that cannabinoid CB 1 receptor mRNA is present in striatonigral neurons expressing substance P and dopamine D 1 receptors, as well as in striatopallidal neurons expressing enkephalin and dopamine D 2 receptors. We explored the functional relevance of the interaction between dopamine D 1 and D 2 receptors and cannabinoid CB 1 receptors with behavioral pharmacology experiments. Potentiation of endogenous cannabinoid signaling by the uptake blocker AM404 blocked dopamine D 1 receptor-mediated grooming and D 2 receptor-mediated oral stereotypies. In addition, contralateral turning induced by unilateral intrastriatal infusion of D 1 receptor agonists is counteracted by AM404 and potentiated by the cannabinoid antagonist SR141716A. These results indicate that the endocannabinoid system negatively modulates D 1 receptor-mediated behaviors in addition to its previously described effect on dopamine D 2 receptor-mediated behaviors. The effect of AM404 on grooming behavior was absent in dopamine D 1 receptor knockout mice, demonstrating its dependence on D 1 receptors. This study indicates that the endocannabinoid system is a relevant negative modulator of both dopamine D 1 and D 2 receptor-mediated behaviors, a finding that may contribute to our understanding of basal ganglia motor disorders.

Revealing the role of the endocannabinoid system modulators, SR141716A, URB597 and VDM-11, in sleep homeostasis

“…This statement is based in the subsequent evidence: First, it has been described the presence of the CB 1 cannabinoid receptor in wake-related brain areas including hypothalamus and pons (Miederer et al, 2013;Soni et al, 2014). Second, there is an interactive relationship between the CB 1 cannabinoid receptor and DA system (Degroot et al, 2006;Davis and Nomikos, 2008;Martin et al, 2008;Kleijn et al, 2012;Dazzi et al, 2014). Third, previous reports have shown that SR141716A enhances NE contents (Tzavara et al, 2001(Tzavara et al, , 2003Bedse et al, 2015).…”

The bright side of psychoactive substances: cannabinoid-based drugs in motor diseases

“…CB 1 receptors are also densely located on presynaptic terminals of GABAergic MSNs projecting to SNpr [13]. CB 1 receptors have been detected both in direct striatonigral and D1-expressing neurons and in striatopallidal and D2-expressing neurons [12]. Also other efferent striatal outputs such as GP in humans, the entopeduncular nucleus in rodents, and the GABAergic projections from the GP to the STN contain high level of CB 1 receptors [13].…”

“…mRNA expression of CB 1 receptors are maximally present at BG level [12]. The localization of CB 1 receptors on presynaptic axon terminals of glutamatergic corticostriatal projecting neurons represents a key factor in the fundamental contribution of the eCB system to different forms of striatal plasticity.…”

Imaging in Parkinson's Disease

“…Cannabinoid type 1 receptors (CB1Rs) are expressed in the basal ganglia where they regulate intracellular levels of cAMP by interacting with Gi/o and Gs proteins in the direct and indirect pathways, respectively (Glass, Dragunow, & Faull, 1997;Herkenham et al, 1991;Mailleux & Vanderhaeghen, 1992;Martín et al, 2008). A PET study using [ 18 F]MK-9470 has shown significant decreases in CB1R levels in the substantia nigra of early de novo and advanced PD patients with and without LIDs (van Laere et al, 2012).…”