Influence of Amphetamine-type stimulants in the Central Nervous System: abuse and neurotoxicity

Amphetamines are synthetic drugs characterized by their psychostimulants effects on the central nervous system (CNS), and include a wide range of substances such as alpha-methylphenethylamine or amphetamine (AMPH), N-methylamphetamine or methamphetamine (METH) and 3,4 methylenedioxymethamphetamine (MDMA) also known as “ecstasy”. The ATS, structurally, are a group of substances related to the compound known as β-phenethylamine (β-PEA), a naturally neurotransmitter in the body. Structural modifications on the aromatic ring of β-PEA create multiple synthetic derivatives with different pharmacological properties. Various hypotheses regarding the mechanism responsible for METH and MDMA-induced neurotoxicity, have been proposed, including high release of monoamines (Dopamine (DA), serotonin (5-HT)), DA quinones formation synthesized by oxidation of the catechol ring of DA, excitatory amino acid glutamate (GLU) release and hyperthermia (Cadet et al., 2003; Miyazaki et al., 2006). It is likely that interactions between these factors trigger neurotoxicity induced by METH or MDMA. In addition, METH causes substantial changes in gene expression in some brain regions including the cortex, the dorsal caudate-putamen (CPu), and the midbrain (Cadet et al., 2009). These molecular changes include transient increases and decreases in the expression of various transcription factors, neuropeptides, and genes that participate in several biological functions (cell cycle, cell differentiation, signaling transduction), (Jayanthi et al., 2005). In order to better understand the molecular mechanism that control the compulsive drug use, in collaboration with National Institutes on Drug abuse (NIDA, Baltimore) we have used the Self-administration (SA) paradigm in association with footshocks to induce negative consequences during METH SA. We investigated whether the compulsive METH taking under punishment can increase the expression of immediate early genes (IEGs) in the rat Nucleus Accumbens (NAc) and Prefrontal cortex (PFC), that are important areas involved in reward, memory, executive function, motivation and contribute to some of the differences in the circuit of addiction (Volkow & Morales 2015; Volkow et al., 2012; Adinoff 2004). In the second and third study, performed at the University of Cagliari, we focused on MDMA treatment in mice in order to clarify the role played by this drug on neurotoxicity and motor behavior resulting from MDMA administration. Specifically, in the second study, considering the influence of the Ras Homolog enriched in striatum protein (Rhes) very important in the striatal functions, we studied the age-related survival of DA neurons in the substantia nigra (SNc) after MDMA treatment and the implication of this protein in neurodegenerative disease such as Parkinson Disease (PD). We have investigated the basal and the MDMA-induced neurotoxic effects in Rhes knock-out mice, male and female at different ages. Moreover, in an attempt to link neurochemical changes with behavioural modifications, this study investigated the motor activity. The third study investigated the possible neuroprotective effect of metformin, an antidiabetic drug, against short and long-term neurotoxicity induced by MDMA, together with its role on MDMA-induced hyperthermia.