Distinct functions of endogenous cannabinoid system in alcohol abuse disorders

Abstract

Δ⁹ -tetrahydrocannabinol, the principal active component in Cannabis sativa extracts such as marijuana, participates in cell signalling by binding to cannabinoid CB₁ and CB₂ receptors on the cell surface. The CB₁ receptors are present in both inhibitory and excitatory presynaptic terminals and the CB₂ receptors are found in neuronal subpopulations in addition to microglial cells and astrocytes and are present in both presynaptic and postsynaptic terminals. Subsequent to the discovery of the endocannabinoid (eCB) system, studies have suggested that alcohol alters the eCB system and that this system plays a major role in the motivation to abuse alcohol. Preclinical studies have provided evidence that chronic alcohol consumption modulates eCBs and expression of CB₁ receptors in brain addiction circuits. In addition, studies have further established the distinct function of the eCB system in the development of fetal alcohol spectrum disorders. This review provides a recent and comprehensive assessment of the literature related to the function of the eCB system in alcohol abuse disorders.

Figure 1

Representative sagittal cross section of a rodent brain showing the reward circuitry affected by alcohol‐induced alterations in eCB functions and highlighting signalling to and from the nucleus accumbens (NAc) and ventral tegmental area (VTA). Glutamatergic transmission drives signalling via the reward and reward‐related circuitry. GABAergic transmission from NAc and other regions suppresses neuronal activity in target regions. The release of dopamine from the VTA and substantia nigra (SN) regulates synaptic output in other target regions (dopaminergic transmission). 2‐AG, 2‐arachidonyl glycerol; AA, acute alcohol; AEA, anandamide; AMY, amygdala; AW, alcohol withdrawal; BNST, bed nucleus of the stria terminalis; CA, chronic alcohol; CB₁, CB₁ receptor; CeA, central nucleus of the amygdala; CPu, caudate putamen; dagla, DAG lipase‐α; DS, dorsal striatum; FAAH, fatty acid amide hydrolase; HP, hippocampus; LDTg, laterodorsal tegmentum; LHb, lateral habenula; LH, lateral hypothalamus; magl, monoacylglycerol lipase; PFC, prefrontal cortex; RMTg, rostromedial tegmental nucleus; SN, substantia nigra; VP, ventral pallidum

Figure 2

Graphic representation of CB₁ receptor function in the development of neurobehavioural deficits induced by developmental alcohol exposure. Postnatal alcohol exposure enhances AEA levels in postsynaptic neurons through the transcription activation of the genes encoding the enzymes NAPE‐PLD and GDE1. AEA, acting through CB₁ receptors on presynaptic neurons, results in decreased glutamate release, which causes NMDA receptor (NMDAR) hypofunction and CDK5, ERK1/2, and CREB hypophosphorylation, leading to inhibition of Arc and Rac1 expression followed by neonatal neurodegeneration. Earlier studies have shown that activation of CB₁ receptors inhibits NMDAR function in several experimental models (Twitchell, Brown, & Mackie, 1997) and alcohol has been shown to reduce glutamatergic neurotransmission via activation of CB₁ receptors (Basavarajappa et al., 2008). These CB₁ receptor events during postnatal development may disrupt the refinement of neuronal circuits (Wilson, Peterson, Basavaraj, & Saito, 2011) and cause long‐lasting deficits in synaptic plasticity and memory in adult animals. The inhibition of CB₁ receptors (AEA tone) prevents CDK5 activation, pERK1/2 and CREB hypophosphorylation, the loss of MeCP2, DNMT1/2 and DNA methylation, deficits in Arc and Rac1 expression, and neonatal neurodegeneration (through tau and caspase‐3 cleavage), leading to normal neurobehavioural function in adult mice. The genetic ablation of CB₁ receptors does not affect NMDAR antagonist‐induced apoptosis but does protect against alcohol‐induced neonatal neurodegeneration and synaptic and memory deficits in adult mice. Thus, the putative AEA/CB₁/CDK5/pERK1/2/pCREB/Arc/Rac1 signalling mechanism may have a possible regulatory role in neuronal function in the developing brain and may be a valuable therapeutic target for FASD. The effects of alcohol are shown in red or with red arrows