Prior stimulation of the endocannabinoid system prevents methamphetamine-induced dopaminergic neurotoxicity in the striatum through activation of CB2 receptors

Abstract

Methamphetamine toxicity is associated with cell death and loss of dopamine neuron terminals in the striatum similar to what is found in some neurodegenerative diseases. Conversely, the endocannabinoid system (ECS) has been suggested to be neuroprotective in the brain, and new pharmacological tools have been developed to increase their endogenous tone. In this study, we evaluated whether ECS stimulation could reduce the neurotoxicity of high doses of methamphetamine on the dopamine system. We found that methamphetamine alters the levels of the major endocannabinoids, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) in the striatum, suggesting that the ECS participates in the brain responses to methamphetamine. Δ9-tetrahydrocannabinol (THC), a cannabis-derived agonist of both CB1 and CB2 cannabinoid receptors, or inhibitors of the main enzymes responsible for the degradation of AEA and 2-AG (URB597 and JZL184, respectively), blunted the decrease in striatal protein levels of tyrosine hydroxylase induced by methamphetamine. In addition, antagonists of CB2, but not of CB1, blocked the preventive effects of URB597 and JZL184, suggesting that only the former receptor subtype is engaged in neuroprotection exerted by ECS stimulation. Finally, we found that methamphetamine increases striatal levels of the cytokine tumor necrosis factor alpha, an effect that was blocked by ECS stimulation. Altogether, our results indicate that stimulation of ECS prior to the administration of an overdose of meth-amphetamine considerably reduces the neurotoxicity of the drug through CB2 receptor activation and highlight a protective function for the ECS against the toxicity induced by drugs and other external insults to the brain. This article is part of the Special Issue entitled ‘CNS Stimulants’.

Neuroprotective Effect of JZL184 in MPP+-Treated SH-SY5Y Cells Through CB2 Receptors

“…The neuroprotective effect of JZL184 has been demonstrated in animal models of Parkinson's disease [28,11] and in methamphetamine-induced toxicity in mice [29] both affecting the dopaminergic system. However, no neuroprotective effect has been reported in an animal model of malonateinduced neurotoxicity and in M-213 cells, which have a phenotype similar to striatal neurons [30,31].…”

“…This could be due to the effect of rimonabant in mitochondrial CB 1 receptors that regulate energy metabolism in neurons [38]. CB 2 receptors are involved in neuroprotection under different pathological conditions [39][40][41][42]29] including an animal model of Parkinson's disease [16]. In general, the protective role of CB 2 receptor activation is mostly attributed to its ability to reduce deleterious microglial activation [43,44,39,40], although CB 2 -mediated regulation of astroglial phenotype could also support the neuroprotective effect [45].…”

Recent Advances in Methamphetamine Neurotoxicity Mechanisms and Its Molecular Pathophysiology

“…Converging evidence suggests that endogenous cannabinoids also play a neuroprotective role in pathological situations [ 143 ]. Indeed, administration of a toxic dose of methamphetamine alters striatal levels of endocannabinoids, the endogenous ligands of CB 1 and CB 2 receptors, and inhibition of the hydrolysis of these compounds prevents METH-induced reduction of tyrosine hydroxylase levels, a hallmark of dopamine terminal loss in the striatum [ 144 ]. Recent research found that METH altered the levels of the major endocannabinoids, anandamide (AEA), and 2-arachidonoyl glycerol (2-AG) in the striatum, suggesting that the ECS participated in the brain responses to METH [ 7 ].…”

Enhanced microglial activity in FAAH−/− animals

“…It was suggested that the neuroprotective effect of AEA is mediated by CB1 and CB2 receptors [15] , whereas both cannabinoid receptor dependent [10] and independent [16] effects of AEA on microglial activity were reported. Increased AEA levels were observed in neurodegenerative and neuroinflammatory disorders [17] , which is probably neuroprotective, since cannabinoid system activity is thought to be anti-inflammatory and protective in Parkinson disease [18] , Alzheimer disease [19] , multiple sclerosis [20] and traumatic brain injury [21] .…”