Amphetamine-related drugs neurotoxicity in humans and in experimental animals: Main mechanisms

Abstract

Amphetamine-related drugs, such as 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine (METH), are popular recreational psychostimulants. Several preclinical studies have demonstrated that, besides having the potential for abuse, amphetamine-related drugs may also elicit neurotoxic and neuroinflammatory effects. The neurotoxic potentials of MDMA and METH to dopaminergic and serotonergic neurons have been clearly demonstrated in both rodents and non-human primates. This review summarizes the species-specific cellular and molecular mechanisms involved in MDMA and METH-mediated neurotoxic and neuroinflammatory effects, along with the most important behavioral changes elicited by these substances in experimental animals and humans. Emphasis is placed on the neuropsychological and neurological consequences associated with the neuronal damage. Moreover, we point out the gap in our knowledge and the need for developing appropriate therapeutic strategies to manage the neurological problems associated with amphetamine-related drug abuse.

Dissecting the Influence of Two Structural Substituents on the Differential Neurotoxic Effects of Acute Methamphetamine and Mephedrone Treatment on Dopamine Nerve Endings with the Use of 4-Methylmethamphetamine and Methcathinone

“…In mouse studies, this toxicity primarily impacts dopaminergic axons in the forebrain (Moratalla et al, 2015). METH elicits a pronounced depletion in both tissue DA content and in protein markers of dopaminergic terminals, including the dopamine transporter (DAT) and the synthetic enzyme tyrosine hydroxylase (TH) (McConnell et al, 2015).…”

Neurotoxicology of Synthetic Cathinone Analogs

“…Studies have demonstrated that glial activation participates in the events that induce neuronal damage, since chronic neuroinflammation elevates the levels of glia-derived cytokines that exert neurotoxic effects on vulnerable neurons [2]. Microglia and astrocytes are the primary modulators of inflammation in the CNS and have been associated with the toxicity induced by administration of methamphetamine [3], amphetamine and parachloroamphetamine [4], and 3,4-methylenedioxy-methamphetamine (MDMA) [5].…”

“…Methamphetamine’s ability to flood the intracellular medium with DA is thought to be the first step in a cascade that leads to mitochondrial dysfunction, enhanced excitatory neurotransmission, increases in oxidative stress, nerve ending damage, and apoptosis [74]. Similar to the other amphetamines, metabolism of MDMA also results in the formation of ROS, which ultimately induce long-term neurotoxic effects [2]. However, none of the β-ketoamphetamines (methcathinone, mephedrone, methylone, and MDPV) showed cytotoxicity at the highest concentrations tested in functional assays [36].…”

Pleiotrophin overexpression regulates amphetamine-induced reward and striatal dopaminergic denervation without changing the expression of dopamine D1 and D2 receptors: Implications for neuroinflammation

“…Despite widespread use of amphetamine-type stimulants, the long-term medical consequences of these drugs abuse and dependence have not been addressed until recently. During the past two decades, preclinical studies have demonstrated that this type of psychostimulants damages dopaminergic neurons, causing striatal dopaminergic denervation and dopaminergic cell death in the substantia nigra among other effects (Moratalla et al, 2015). However, clinical correlation was not studied until Callaghan and colleagues (2012) probed a ~77% increased risk of Parkinson's disease (PD) in amphetamine-type drug abusers (Callaghan et al, 2012).…”

“…To overcome these limitations, we have now studied the rewarding and neurotoxic effects of amphetamine in mice with transgenic neuronal PTN overexpression in the brain (PTN-Tg mice). In addition, it is interesting to note that overstimulation of dopamine D1 (D1R) and D2 receptors (D2R) significantly contributes to the neurotoxic effects of amphetamine (Moratalla et al, 2015). Furthermore, dopamine is a crucial transmitter in the neuroimmune network (Kustrimovic et al, 2014) and D2R is identified as an important component controlling innate immunity and inflammatory response in central nervous system (Shao et al, 2013).…”