coupled receptors (GPCRs) in the central nervous system, where it is concentrated at the axonal plasma membrane of specific neurons. Whilst the , therapeutic and psychotropic effects of cannabinoid receptor stimulation have been recognised for over 4000 years, through recreational and medicinal Cannabis use, ,it is only in the last few decades that our scientific understanding of both exogenous and endogenous cannabinoid system regulation has significantly advanced. At the presynaptic terminal, CB1R activation mediates neurotransmission through retrograde messengers, which are released from the post-synaptic terminal in response to activity-dependent signal transduction. Consequently the CB1R can be considered as a master regulator of synaptic transmission. However, compared to other GPCRs, the field of CB1R trafficking is in its infancy and the pathways and mechanisms of CB1R regulation are at best, incomplete. Using N-terminal fluorescent-tagged CB1R constructs, I have investigated the trafficking and diffusional mobility of CB1Rs in cultured hippocampal neurons. My work has revealed a crucial role for the C-terminal tail of the CB1R (ctCB1R) in regulating both its plasma membrane dynamics and surface localization. Specifically, using truncation and deletion mutagenesis I identified a 21 amino acid stretch in the ct-CB1R, which is critical for maintaining its axonal polarized surface distribution in hippocampal neurons. This region corresponds to a putative helical motif, H9, for which no known functional role has previously been identified. Moreover, I have demonstrated that the ct-CB1R . is sufficient to promote an axonal fate, presumably through interactions with specific scaffolding and adaptor proteins. Accordingly, I have performed an unbiased proteomics analysis using affinity purification mass spectrometry and have identified several candidate interactors, including a cluster of proteins associated with clathrin-mediated 'endocytosis, which , provide additional mechanistic insight into the underlying biochemical machinery regulating CB1R distribution in neurons .