Review The neurotoxicity of amphetamines: Bridging drugs of abuse and neurodegenerative disorders Luisa Iacovelli a,b , Federica Fulceri c , Antonio De Blasi a , Ferdinando Nicoletti a,d , Stefano Ruggieri a,d , Francesco Fornai a,c, ⁎ a Lab of Neurobiology of Movement Disorders, I.R.C.C.S. I.N.M Neuromed; Loc. Camerelle, Pozzilli (IS), Italy b Department of Physiology and Pharmacology, University of Rome “La Sapienza”, Roma, Italy c Department of Human Morphology and Applied Biology, University of Pisa, Pisa, Italy d Department of Neurological Sciences, University of Rome “La Sapienza”, Roma, Italy Received 17 January 2006; accepted 18 February 2006 Available online 5 May 2006 Abstract Amphetamine derivatives are the most commonly abused drugs. These compounds have been known for many years to induce neurotoxicity. However, recent findings have highlighted novel alterations produced by amphetamines in the central nervous system consisting of neuronal inclusions and the involvement of proteins belonging to a multi-enzymatic complex known as the ubiquitin–proteasome system. These ultrastructural and molecular changes are similar to those that occur during degenerative processes that affect the basal ganglia, and in particular Parkinson's disease, which is characterized by ubiquitin-containing neuronal inclusions in the subtantia nigra. This is recently confirmed by the occurrence of ubiquitin immunoreactive structures in the substantia nigra of humans abusing methamphetamines. In this article, we propose that the neurotoxicity of amphetamines and degenerative disorders share a number of steps in their mechanism of action involving the ubiquitin–proteasome system. The fine tuning of this ubiquitous proteolytic pathway is now being elucidated because G-protein-coupled receptors and signaling proteins such as β-arrestin regulate access to this catalytic machinery. The identification of the ubiquitin–proteasome pathway and β-arrestin as molecular targets of neurotoxicity is expected to provide novel therapeutic strategies both for the treatment of drug addiction and the treatment of neurodegenerative disorders. © 2006 Elsevier Inc. All rights reserved. Keywords: Amphetamines; β-Arrestin; Lewy body; MDMA; Methamphetamine; Neuronal inclusions; Parkinson's disease; Neurodegenerative disorders; α- Synuclein; Ubiquitin–proteasome system Contents Introduction ................................................................ 25 New vistas on Parkinson's disease (PD).................................................. 26 New vistas on amphetamines toxicity: neuronal inclusions as key pathological correlates ........................ 26 The role of DA .............................................................. 27 The role of α-synuclein (Fig. 2) ...................................................... 27 Focus on common mechanisms ...................................................... 28 The role of the ubiquitin–proteasome system in inclusions formation ................................ 28 The role of GPCRs signaling in inclusions formation ......................................... 29 Conclusions ................................................................ 29 Acknowledgments ............................................................. 29 References ................................................................. 29 Experimental Neurology 201 (2006) 24 – 31 www.elsevier.com/locate/yexnr ⁎ Corresponding author. Lab of Neurobiology of Movement Disorders, I.R.C.C.S. I.N.M Neuromed; Loc. Camerelle, Pozzilli (IS), Italy. E-mail address: f.fornai@med.unipi.it (F. Fornai). 0014-4886/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.expneurol.2006.02.130