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Review
, 61 (7), 1070-87

Endocannabinoid-mediated Synaptic Plasticity and Addiction-Related Behavior

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Review

Endocannabinoid-mediated Synaptic Plasticity and Addiction-Related Behavior

Nimish Sidhpura et al. Neuropharmacology.

Abstract

Endogenous cannabinoids (eCBs) are retrograde messengers that provide feedback inhibition of both excitatory and inhibitory transmission in brain through the activation of presynaptic CB₁ receptors. Substantial evidence indicates that eCBs mediate various forms of short- and long-term plasticity in brain regions involved in the etiology of addiction. The present review provides an overview of the mechanisms through which eCBs mediate various forms of synaptic plasticity and discusses evidence that eCB-mediated plasticity is disrupted following exposure to a variety of abused substances that differ substantially in pharmacodynamic mechanism including alcohol, psychostimulants and cannabinoids. The possible involvement of dysregulated eCB signaling in maladaptive behaviors that evolve over long-term drug exposure is also discussed, with a particular focus on altered behavioral responses to drug exposure, deficient extinction of drug-related memories, increased drug craving and relapse, heightened stress sensitivity and persistent affective disruption (anxiety and depression).

Figures

Figure 1
Figure 1. Synaptic organization of the endocannabinoid system
AEA and 2-AG are synthesized from phospholipids in the postsynaptic cell. The most commonly accepted route for AEA synthesis involves its direct formation from N-arachidonoyl-phosphatidylethanolamine (NAPE) via catalysis by a specific phospholipase D (NAPE-PLD). Alternatively, recent evidence points to AEA formation via the ABHD4/GDE1 pathway and also through the PLC pathway via either PTPN22 or SHIP1 activity. Because the specific enzymes for AEA generation remain unclear no specific pathway is represented in this figure. 2-AG derives primarily from the hydrolytic metabolism of 1,2-diacylglycerol (DAG) via the sn-1-selective DAG lipases DAGLα and DAGLβ. Once released into the synaptic cleft AEA and 2-AG exert signaling effects through CB1 and other receptors including CB2 and GPR55 (Pertwee, 2010). CB1 receptors are expressed on presynaptic terminals, though the synaptic positions of CB2 and GPR55 in the CNS have not been confirmed. AEA also functions as a potent agonist at transient receptor potential vanilloid receptor 1 (TRPV1), though unlike GPCRs these receptors contain an intracellular lipid binding site. Termination of extracellular eCB signaling is initiated by cellular reuptake, and once inside the cell eCBs are shuttled via chaperone mechanisms (including fatty acid binding proteins (FABPs; (Maccarrone et al., 2010)) to specific enzymes for hydrolytic cleavage. Degradation of 2-AG is attributed primarily to presynaptic monoacylglycerol lipase (MAGL) that cleaves 2-AG into arachidonic acid (AA) and glycerol. Degradation of AEA occurs in postsynaptic cells through fatty acid amide hydrolase (FAAH) that cleaves AEA into AA and ethanolamine. Evidence suggests that FAAH can also conjugate AA and various neurotransmitters into n-arachidonoyl moieties such as n-arachidonoyl dopamine (NADA) (Hu et al., 2009) that have potent bioactivity at TRPV1 and CB1 receptors (Pertwee, 2010).

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