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Amphetamine derivatives have therapeutic potential in diseases such as attention deficit hyperactivity disorder, narcolepsy and obesity. However, their prolonged use has been associated with cardiovascular toxicity and addiction. In recent years, we have studied the pharmacological effects of amphetamine derivatives such as methylthioamphetamine (MTA) and N,N-dimethyl-thioamphetamine, with the aim of improving their therapeutic selectivity. In this work, we show that similarly to MTA, N,N-dimethyl-thioamphetamine has effects on the dopamine system, producing a significant increase in extracellular levels of dopamine (as measured by in vivo brain microdialysis) and locomotor activity, which is a behavioural measure of dopaminergic activation. However, unlike MTA, N,N-dimethyl- thioamphetamine does not produce aortic contraction in vitro. Our results show that N,N-dimethyl-thioamphetamine is a drug that retains the dopaminergic effects of amphetamine derivatives but exhibits a lower potential for producing cardiovascular side effects., (© 2013 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

4-Methylthioamphetamine (MTA) is a phenylisopropylamine derivative whose use has been associated with severe intoxications. MTA is usually regarded as a selective serotonin-releasing agent. Nevertheless, previous data have suggested that its mechanism of action probably involves a catecholaminergic component. As little is known about dopaminergic effects of this drug, in this work the actions of MTA upon the dopamine (DA) transporter (DAT) were studied in vitro, in vivo and in silico. Also, the possible abuse liability of MTA was behaviourally assessed. MTA exhibited an in vitro affinity for the rat DAT in the low micromolar range (6.01 μM) and induced a significant, dose-dependent increase in striatal DA. MTA significantly increased c-Fos-positive cells in striatum and nucleus accumbens, induced conditioned place preference and increased locomotor activity. Docking experiments were performed in a homology model of the DAT. In conclusion, our results show that MTA is able to increase extracellular striatal DA levels and that its administration has rewarding properties. These effects were observed at concentrations or doses that can be relevant to its use in human beings., (© 2012 The Authors Basic & Clinical Pharmacology & Toxicology © 2012 Nordic Pharmacological Society.)

The lateral septum is a brain nucleus involved in various mental disorders such as anxiety and drug addiction. In the present study, we investigated whether systemic amphetamine, known to release dopamine (DA) in nucleus accumbens, will also release DA in lateral septum. Our results show that systemic amphetamine administration (2 mg/kg i.p.) induced a significant increase in DA extracellular levels in nucleus accumbens but not in lateral septum. Interestingly, intralateral septum perfusion of amphetamine through the microdialysis probe induced a significant increase in DA extracellular levels. To test if GABAergic neurotransmission in lateral septum was responsible for inhibiting the release of DA when amphetamine was administered systemically, we perfused a GABA-B selective antagonist (CGP-52432) intra lateral septum. Systemic amphetamine administration induced a significant increase in lateral septum DA release when CGP-52432 was concomitantly superfused. Our results indicate that the systemic administration of amphetamine induces an increase in lateral septum GABA release and the consequent activation of GABA-B receptors counteracting the direct effect of amphetamine on lateral septum DA release., (© 2010 The Authors. Journal Compilation © 2010 International Society for Neurochemistry.)