2010]. Interestingly some alkylamides from the Echinacea plant can also bind to the CB2Rs even more strongly than the endogenous cannabinoids [Raduner et al. 2006]. The mechanism

of action for CBD is not yet clear, as this compound does not bind to CB1Rs or CB2Rs [Tsou et al. 1998; Hayakawa et al. 2008]. Normally GPCRs are linked together to form a receptor complex. Inhibitors,research,lifescience,medical However, the signalling effects can be complex due to CB1Rs forming heteromers, which can be defined as having different parts such as subunits, with two or more other GPCRs, particularly if they are densely expressed in the same neuron. For instance, a CB1R can form a heteromer with dopamine D2 receptor, or in another instance it can also form a heteromer with two other receptors such as dopamine D2 and adenosine A2A [Navarro et al. 2008]. Interestingly, as a result, ligand bindings can produce unexpected pharmacological effects. For instance, in a heteromer complex, not only the Inhibitors,research,lifescience,medical antagonist of CB1R but also the other receptor antagonist can block the inhibitory effect of CB1R agonist. This has been demonstrated by Marcellino and colleagues when the CB1R antagonist rimonabant and the specific Inhibitors,research,lifescience,medical A2AR antagonist MSX-3 blocked the inhibitory effect of CB1 agonist on D2-like receptor agonist induced hyperlocomotion in rats [Marcellino

et al. 2008]. Receptor Inhibitors,research,lifescience,medical heteromers provide better understanding of how these different neurotransmitter systems interact with each other. Compelling evidence for the existence of CB1R heteromers in striatal dendritic spines of striatal GABAergic efferent neurons, particularly at a postsynaptic location, has also been reported [Ferré et al. 2009]. The authors propose that it is likely that functional CB1–A2A–D2 receptor heteromers can be found in the dendritic spines of GABAergic AZD6244 enkephalinergic neurons, where they are highly coexpressed, and their analysis provides new Inhibitors,research,lifescience,medical information on the role of endocannabinoids in striatal function, which can be considered as retrograde signals that inhibit neurotransmitter release. Further MYO10 evidence

for the existence of D2 and CB1Rs in ventral striatum is provided by electron microscopy analysis, which confirms the relevance to the rewarding and euphoric, as well as motor effects produced by cannabis, by enhancing dopamine levels particularly in the nucleus accumbens [Pickel et al. 2006]. CB1R expression in the striatum and their role in differential signalling between different developmental stages and sensorimotor and associative/limbic circuits have also been demonstrated in a recent study [van Waes et al. 2012]. Most recently it has been shown that CB2Rs form heteromers with CB1Rs in the brain and the agonist coactivation of CB1Rs and CB2Rs results in negative crosstalk in AKT1 phosphorylation and neurite outgrowth [Callén et al. 2012].