A review of the interactions between alcohol and the endocannabinoid system: implications for alcohol dependence and future directions for research.
- Authors
- Pava, Matthew J; Woodward, John J
- Year
- 2012
- Journal
- Alcohol (Fayetteville, N.Y.)
- PMID
- 22459871
- DOI
- 10.1016/j.alcohol.2012.01.002
- PMCID
- PMC3327810
Over the past fifty years a significant body of evidence has been compiled suggesting an interaction between the endocannabinoid (EC) system and alcohol dependence. However, much of this work has been conducted only in the past two decades following the elucidation of the molecular constituents of the EC system that began with the serendipitous discovery of the cannabinoid 1 receptor (CB1). Since then, novel pharmacological and genetic tools have enabled researchers to manipulate select components of the EC system, to determine their contribution to the motivation to consume ethanol. From these preclinical studies, it is evident that CB1 contributes the motivational and reinforcing properties of ethanol, and chronic consumption of ethanol alters EC transmitter levels and CB1 expression in brain nuclei associated with addiction pathways. These results are augmented by in vitro and ex vivo studies showing that acute and chronic treatment with ethanol produces physiologically relevant alterations in the function of the EC system. This report provides a current and comprehensive review of the literature regarding the interactions between ethanol and the EC system. We begin be reviewing the studies published prior to the discovery of the EC system that compared the behavioral and physiological effects of cannabinoids with ethanol in addition to cross-tolerance between these drugs. Next, a brief overview of the molecular constituents of the EC system is provided as context for the subsequent review of more recent studies examining the interaction of ethanol with the EC system. These results are compiled into a summary providing a scheme for the known changes to the components of the EC system in different stages of alcohol dependence. Finally, future directions for research are discussed.
Biochemistry of the EC System in the CNS. ECs are synthesized in the post-synaptic membrane and produce most of their actions via activation of the CB1 receptor which decreases neurotransmitter release from the pre-synaptic terminal (for details, see text). Synthetic enzymes in the post-synaptic membrane are in red, and degradative enzymes are shown in blue. Abbreviations: 2-AG = 2-arachidonylglycerol, AC = adenylate cyclase, AEA = anandamide, ATP = adenosine triphosphate, Ca2+ = calcium ion, cAMP = cyclic adenosine monophosphate, CB1 = cannabinoid receptor 1, DAG = diacylglycerol, DAGL = diacylglycerol lipase, ECs = endocannabinoids, EMT = endocannabinoid membrane transporter, ER = endoplasmic reticulum, FAAH = fatty acid amide hydrolase, IP3 = inositol triphosphate, IP3R = inositol triphosphate receptor, K+ = potassium ion, lyso-PLC = lyso-specific isoform of phospholipase C, lyso-PLD = lyso-specific isoform of phospholipase D, MAGL = monoacylglycerol lipase, mGluR5 = metabotropic glutamate receptor 5, Na+ = sodium ion, NAPE = N-arachidonyl phosphotidylethanolamine, NAPE-PLD = NAPE-specific isoform of phospholipase D, NAT = N-acyl transferase, NMDAR = N-methyl-D-aspartate receptor, PEtAM= phosphotidylethanolamine, PKA = protein kinase A, PLA1 = phospholipase A1, PLA2 = phospholipase A2, PLC = phospholipase C, PLCΞ² = Ξ²-isoform of phospholipase C, RyR = ryanodine receptor, TRPV1 = transient receptor vanilloid 1, VGCC = voltage-gated calcium channel.
Summary of ethanol-induced alterations in the EC system and a putative model of the generalized changes in EC signaling observed in different stages of chronic alcoholization. Acute ethanol consumption is associated with a CB1-dependent increase in dopamine neuron activity and dopamine release in the nucleus accumbens as well as reduced output from frontal cortical structures and the hippocampus. These effects are reversed by pre-treatment with rimonabant. In most brain structures, chronic ethanol treatment is associated with reductions in CB1 expression and FAAH activity that are paralleled by increased concentrations of anandamide. These changes normalize as the duration of chronic treatment is extended. The hyper-excitability associated with the initial phase of withdrawal results in a large increase in EC release and concomitant reductions in CB1 expression. Over time EC levels remain elevated and CB1 expression is up-regulated to compensate. For details see text. Green arrows denote glutamate or excitatory connections. Red arrows denote GABA or inhibitory connections. Blue arrows indicate dopamine projections. Thick lines represent enhanced output while hashed lines represent diminished connection strength. Text symbols and abbreviations: β= increase in concentration/expression/activity, β = decrease in concentration/expression/activity, ? = unknown effect/no data, 2-AG = 2-arachidonyl glycerol, 5-HT = 5-hydroxytryptamine, AEA = anandamide, AMG = amygdala, BLA = basolateral amygdala, CB1 = cannabinoid receptor 1, DA = dopamine, DStr = dorsal striatum, ECs = endocannabinoids, EtOH = ethanol, FAAH = fatty acid amide hydrolase, GABA = Ξ³-amino-butyric acid, Glu = glutamate, HC = hippocampus, NAc = nucleus accumbens, NE = norepinephrine, PFC = prefrontal cortex, SK = Small conductance calcium-activated potassium channel, SR = rimonabant, VTA = ventral tegmental area.
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