Pharmacological Characterization of 4-Methylthioamphetamine Derivatives

Amphetamine derivatives have been used in a wide variety of pathologies because of their pharmacological properties as psychostimulants, entactogens, anorectics, and antidepressants. However, adverse cardiovascular effects (sympathomimetics) and substance abuse problems (psychotropic and hallucinogenic effects) have limited their use. 4-Methylthioamphetamine (MTA) is an amphetamine derivative that has shown to inhibit monoamine uptake and monoamine oxidase. However, the pharmacological characterization (neurochemical, behavioral, and safety) of its derivatives 4-ethylthioamphetamine (ETA) and 4-methylthio-phenil-2-butanamine (MT-But) have not been studied. In the current experiments, we show that ETA and MT-But do not increase locomotor activity and conditioned place preference with respect to MTA. At the neurochemical level, ETA and MT-But do not increase in vivo DA release in striatum, but ETA and MT-But affect the nucleus accumbens bioaccumulation of DA and DOPAC. Regarding cardiovascular effects, the administration of MTA and ETA increased the mean arterial pressure and only ETA significantly increases the heart rate. Our results show that the pharmacological and safety profiles of MTA are modulated by changing the methyl-thio group or the methyl group of the aminoethyl chain.

Satiation State-dependent Dopaminergic Control of Food Seeking in Drosophila

Hunger evokes stereotypic behaviors that favor the discovery of nutrients. The neural pathways that coordinate internal and external cues to motivate food seeking behaviors are only partly known. Drosophila that are food deprived increase locomotor activity, are more efficient in locating a discrete source of nutrition, and are willing to overcome adversity to obtain food. Here we developed a semi-naturalistic assay and show that two distinct dopaminergic neural circuits regulate food-seeking behaviors. One group, the PAM neurons, functions in food deprived flies while the other functions in well fed flies, and both promote food seeking. These satiation state-dependent circuits converge on dopamine D1 receptor-expressing Kenyon cells of the mushroom body, where neural activity promotes food seeking behavior independent of satiation state. These findings provide evidence for active food seeking in well-fed flies that is separable from hunger-driven seeking.