Interestingly, both CB1 and CB2Rs are also found in human placenta and have been shown to play a role in regulating serotonin transporter activity [Kenney et al. 1999]. Indeed further research has revealed that the endocannabinoid system also plays a trans-isomer significant role in
various aspects of human reproduction [Taylor et al. 2010]. In the brain, CB1Rs are found at the terminals of central and peripheral neurons, where they mostly mediate inhibitory action on ongoing Inhibitors,research,lifescience,medical release of a number of excitatory and inhibitory dopaminergic, gamma-aminobutyric acid (GABA), glutamatergic, serotoninergic, noradrenalin and acetylcholine neurotransmitter systems (Figure 1). Because of the involvement Inhibitors,research,lifescience,medical of these systems they affect functions such as cognition, memory, motor movements and pain perception [Howlett et al. 2002]. The release of endocannabinoids, such as AEA and 2-AG, from the postsynaptic sites to the synaptic cleft occur in response to elevation of intracellular calcium and they then act as retrograde neurotransmitters Inhibitors,research,lifescience,medical on presynaptically located CB1Rs to maintain homeostasis and prevent the excessive neuronal activity [Howlett et al. 2002; Terry et al. 2009]. They are then rapidly removed from the extracellular space by cannabinoid transporters, often referred to
as anandamide membrane transporters, which facilitate their breakdown by internalizing Inhibitors,research,lifescience,medical the molecule and allowing access to fatty acid amide hydrolase [Pertwee, 2010]. Despite its significance in the endocannabinoid system, little is known about the cannabinoid transporters. When cannabis is used, d-9-THC as a partial agonist binds to CB1R and acts in a less selective manner in inhibiting the release of neurotransmitters normally modulated by endocannabinoids such as AEA and 2-AG. It has been putatively suggested that it may also increase the release of dopamine, glutamate and acetylcholine in certain brain regions, possibly by inhibiting the release Inhibitors,research,lifescience,medical of an inhibitory neurotransmitter
like GABA onto dopamine, glutamate or acetylcholine-releasing neurons [Bhattacharyya et al. 2009a] (Figure 2). Figure 2. CB1 receptors – effects of endocannabinoids and d-9-THC Release nearly of Anandamide (AEA) and 2- arachidonoylglycerol (2-AG) to inhibit glutamate (Glu), Gamma-aminobutyric acid (GABA), acetylcholine (Ach), dopamine, noradrenaline (NA) and serotonin (5-HT). … However, the functionalities of the CB1Rs are not always straightforward due to complex interactions with the other neurotransmitter systems. These are related to CB1Rs and CB2Rs being members of the super family of G-protein-coupled receptors (GPCRs) [Pertwee et al. 2010]. GPCRs sense an external molecule outside the nerve cell and by contact with the molecule can signal transduction pathways, which ultimately lead to cellular responses.