The neurotoxicity of amphetamines: Bridging drugs of abuse and neurodegenerative disorders

• Published in: Experimental neurology 2006-09, Vol.201 (1), p.24-31
• Main Authors: Iacovelli, Luisa, Fulceri, Federica, De Blasi, Antonio, Nicoletti, Ferdinando, Ruggieri, Stefano, Fornai, Francesco
• Format: Article
• Language: English
• Subjects: Amphetamine-Related Disorders - complications; Amphetamines; Animals; Anticonvulsants. Antiepileptics. Antiparkinson agents; Biological and medical sciences; Humans; Lewy body; MDMA; Medical sciences; Methamphetamine; Models, Neurological; Nervous system (semeiology, syndromes); Nervous system as a whole; Neurodegenerative Diseases - metabolism; Neurodegenerative Diseases - physiopathology; Neurodegenerative disorders; Neurology; Neuronal inclusions; Neuropharmacology; Neurotoxicity Syndromes - etiology; Neurotoxicity Syndromes - metabolism; Neurotoxicity Syndromes - physiopathology; Parkinson's disease; Pharmacology. Drug treatments; Proteasome Endopeptidase Complex - metabolism; Signal Transduction - physiology; Ubiquitin - metabolism; Ubiquitin–proteasome system; α-Synuclein; β-Arrestin
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2006.02.130

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.