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Review
. 2016 Oct 5;36(40):10230-10238.
doi: 10.1523/JNEUROSCI.1712-16.2016.

Drug-Induced Alterations of Endocannabinoid-Mediated Plasticity in Brain Reward Regions

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Free PMC article
Review

Drug-Induced Alterations of Endocannabinoid-Mediated Plasticity in Brain Reward Regions

Natalie E Zlebnik et al. J Neurosci. .
Free PMC article

Abstract

The endocannabinoid (eCB) system has emerged as one of the most important mediators of physiological and pathological reward-related synaptic plasticity. eCBs are retrograde messengers that provide feedback inhibition, resulting in the suppression of neurotransmitter release at both excitatory and inhibitory synapses, and they serve a critical role in the spatiotemporal regulation of both short- and long-term synaptic plasticity that supports adaptive learning of reward-motivated behaviors. However, mechanisms of eCB-mediated synaptic plasticity in reward areas of the brain are impaired following exposure to drugs of abuse. Because of this, it is theorized that maladaptive eCB signaling may contribute to the development and maintenance of addiction-related behavior. Here we review various forms of eCB-mediated synaptic plasticity present in regions of the brain involved in reward and reinforcement and explore the potential physiological relevance of maladaptive eCB signaling to addiction vulnerability.

Keywords: THC; addiction; cocaine; drugs of abuse; endocannabinoid; nucleus accumbens; plasticity; reward; ventral tegmental nucleus.

Figures

Figure 1.
Figure 1.
Density of CB1 receptor distribution across brain reward areas. Presynaptic CB1 receptors are Gi/o-coupled metabotropic receptors that are located throughout reward regions of the brain with varying levels of expression. Distribution of other components of the eCB system, such as the eCB synthetic enzymes N-arachidonoyl-phosphatidylethanolamine (NPLD) (Egertová et al., 2008) and DAGL (Suárez et al., 2011), follow a similar pattern, and mechanisms of CB1 receptor-mediated synaptic plasticity have been measured in mesocorticolimbic and corticostriatal pathways crucially involved in the pathophysiology of addiction.
Figure 2.
Figure 2.
General mechanism of retrograde eCB signaling. Upon release of neurotransmitter (e.g., glutamate, GABA), postsynaptic depolarization results in elevations in intracellular calcium levels through activation of ionotropic receptors, Gq-coupled metabotropic receptors (e.g., Group I mGluRs, M1/M3 mAChRs, D2Rs), and/or voltage-gated calcium channels. The eCBs AEA and 2-AG are not stored in vesicles but instead are synthesized de novo from phospholipid precursors through calcium-dependent and -independent mechanisms. NAPE is hydrolyzed by N-arachidonoyl-phosphatidylethanolamine-specific phospholipase D (NPLD) to yield AEA, and DAG is converted to 2-AG by DAGL. Both eCB species traverse the synaptic cleft and activate presynaptic Gi/o-coupled CB1 receptors, thereby inhibiting adenylyl cyclase, regulating ion channels, and ultimately suppressing neurotransmitter release. eCB signaling is terminated following degradation by hydrolytic enzymes in the presynaptic and postsynaptic compartments. Primarily, AEA is converted to arachidonic acid (AA) and ethanolamine (EtOHamine) by fatty acid amide hydrolase (FAAH) localized to the postsynaptic cell, whereas 2-AG is hydrolyzed presynaptically into AA and glycerol by monacylglycerol lipase (MAGL).
Figure 3.
Figure 3.
Summary of drug-induced disruptions of eCB-mediated long-term plasticity in the VTA and NAc. a, b, Although the specific mechanism differs by brain region, eCB-LTD induction under normal conditions is primarily governed by activity-dependent release of eCBs from the postsynaptic cell and CB1 receptor stimulation on active afferents. a, Within the VTA, eCB-LTDi at GABAergic synapses permits adaptive dopamine cell firing, and induction involves additional coordination between presynaptic (e.g., D2 dopamine receptors) and postsynaptic (e.g., Group I mGluRs) metabotropic receptors. b, Control over accumbal glutamate release from cortical and limbic afferents through the induction of eCB-LTDe relies on activation of postsynaptic metabotropic receptors (e.g., mGluR5) and release of calcium from intracellular stores. c, d, Following exposure to drugs of abuse, such as THC or cocaine, parallel disturbances in eCB-LTD mechanisms that normally provide inhibitory control over VTA dopamine neuron activity and curb excitation of NAc MSNs instead promote activation of reward circuitry. c, Drug exposure facilitates the induction of eCB-LTDi in the VTA, removing GABA-mediated inhibition of dopamine neurons and enhancing their excitability. d, Drug-induced loss of eCB-LTDe at glutamatergic synapses in the NAc prevents control over excitation of MSNs.

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