Epigenetic Effects Induced by Methamphetamine and Methamphetamine‐Dependent Oxidative Stress

Abstract

Methamphetamine is a widely abused drug, which possesses neurotoxic activity and powerful addictive effects. Understanding methamphetamine toxicity is key beyond the field of drug abuse since it allows getting an insight into the molecular mechanisms which operate in a variety of neuropsychiatric disorders. In fact, key alterations produced by methamphetamine involve dopamine neurotransmission in a way, which is reminiscent of spontaneous neurodegeneration and psychiatric schizophrenia. Thus, understanding the molecular mechanisms operated by methamphetamine represents a wide window to understand both the addicted brain and a variety of neuropsychiatric disorders. This overlapping, which is already present when looking at the molecular and cellular events promoted immediately after methamphetamine intake, becomes impressive when plastic changes induced in the brain of methamphetamine-addicted patients are considered. Thus, the present manuscript is an attempt to encompass all the molecular events starting at the presynaptic dopamine terminals to reach the nucleus of postsynaptic neurons to explain how specific neurotransmitters and signaling cascades produce persistent genetic modifications, which shift neuronal phenotype and induce behavioral alterations. A special emphasis is posed on disclosing those early and delayed molecular events, which translate an altered neurotransmitter function into epigenetic events, which are derived from the translation of postsynaptic noncanonical signaling into altered gene regulation. All epigenetic effects are considered in light of their persistent changes induced in the postsynaptic neurons including sensitization and desensitization, priming, and shift of neuronal phenotype.

Interdependency Between Autophagy and Synaptic Vesicle Trafficking: Implications for Dopamine Release

“…The intimate interplay between Autophagy (ATG), Ubiquitin Proteasome (UP) and neurotransmission has assumed increasing interest in the context of several neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD), which fit the definition of “synaptopathic proteinopathies.” A common hallmark underlying the physiopathology of parkinsonism is the early disruption of dopamine (DA) neurotransmission, which is also implicated in numerous neuropsychiatric disorders including schizophrenia and drug addiction (Belujon and Grace, 2017 ; Weinstein et al, 2017 ; Limanaqi et al, 2018 ). It is well established that in DA-related disorders the highly reactive nature of DA provides per se a basis for the high vulnerability of DA-containing neurons to oxidative stress-related damage, a context in which the proteolytic role of ATG and UP is crucial (Lazzeri et al, 2007 ; Pasquali et al, 2008 ).…”

Autophagy-Based Hypothesis on the Role of Brain Catecholamine Response During Stress

“…A number of CNS disorders are characterized by dysregulated autophagy and related synaptic alterations, and/or oxidative and inflammatory processes connected with neuronal loss (51,69). In line with this, autophagy provides neuroprotection in general, and for catecholamine neurons, which are mostly susceptible to oxidative-related alterations, in particular (49,52,53,68). In fact, autophagy grants the survival of both DA-and NE-containing neurons during a variety of stressful conditions (49,51,52,68,70).…”

mTOR-Related Cell-Clearing Systems in Epileptic Seizures, an Update

“…These findings are also key in the context of epileptic seizures which sporadically occur following administration/intake of strong DA-releasing abused drugs/psychostimulants such as amphetamines. In fact, amphetamines produce an abnormal DA release featuring peaks and drops of extracellular concentration, which in turn lead to abnormal pulsatile stimulation of D1DRs in the brain [28,144]. It is remarkable that abnormal stimulation of D1DRs, as it occurs following amphetamine administration, leads to noncanonical intracellular pathways, which produce mTOR hyperactivation and autophagy suppression [145,146].…”

“…It is remarkable that abnormal stimulation of D1DRs, as it occurs following amphetamine administration, leads to noncanonical intracellular pathways, which produce mTOR hyperactivation and autophagy suppression [145,146]. These, in turn, may produce maladaptive plastic changes including altered cortical excitability and abnormal NMDA and AMPA receptor stimulation up to glutamate-induced excitotoxicity [144].…”