Final Activity Report Summary - SPAR (Synaptic plasticity and long-term depression in the nucleus accumbens after in vivo exposure to addictive drugs) Repeated consumption of addictive drugs initiates adaptive mechanisms that cause remodelling of brain circuits which are normally used to reinforce rewarding and learning behaviours that are necessary for the normal functions of the brain. The fact that modifications in synaptic functions induced by addictive drugs are expressed long after complete withdrawal is strongly indicative of the key role of durable changes in specific neural systems and gene expression in drug craving and relapse. A form of synaptic plasticity that is well studied is endocannabinoid dependent long-term depression. The general aim of this proposal was to understand the adaptive processes at the cellular and network levels that underlay synaptic plasticity-related addictive drug administration, with focus on the opioid drug morphine. During the course of this research project we made a striking discovery. We discovered, against all expectations, that the inhibition synaptic activity by a cannabinoid agonist was blocked by an opioid receptor specific antagonist. Likewise, the opioid-mediated inhibition was blocked by the specific cannabinoid receptor antagonist. These reciprocal effects were confirmed when tested in mice which were deficient for the cannabinoid 1 receptor in comparison to wild type littermates. These data showed for the first time functional interactions at the synaptic level between the two receptor types. This was a provocative finding that would assist explaining many discrepancies in the field. Since both receptor types were subject to desensitisation after repeated exposure to agonist, cross-desensitisation was tested. Chronic in vivo exposure to a cannabinoid agonist desensitised both cannabinoid and opioid receptors. Chronic in vivo exposure to morphine, however, only desensitised opioid receptors and did not affect the activity of cannabinoid receptors. This finding was particularly relevant in the context of multiple drugs users that consumed both cannabis derivatives and opiate drugs, such as marijuana and heroin. Altogether the data supported the idea that mu opioid and cannabinoid 1 receptors had reciprocal, however asymmetric, interactions in the brain with regard to receptor function and expression of synaptic plasticity. The data clearly indicated the involvement of the endocannabinoid system in the effect of morphine.