The only psychostimulant treatment option in Turkey is methy
The only psychostimulant treatment option in Turkey is methylphenidate (Çetin et al., 2015). It is broken down by carboxylase enzyme (CES1) (Sun et al., 2004). From the point of pharmacokinetics, it may be suggested that CES1 gene polymorphisms may be the key responsible factors in patients resistant to treatment, or in the ones that experience adverse effects (Zhu et al., 2008). On the other hand, pharmacogenetic researches of ADHD mostly focused on MPH target receptors and transporters, and investigations on MPH metabolism are only small in number (Nemoda et al., 2009). It may be suggested that limited data on MPH metabolism compared to data on mechanism of action MPH is related to this (Froehlich et al., 2010).
Material and methods
Conflict of interest
Acknowledgements This research has been supported by Turkish Psychiatry Society's (grant number: 11/2014, grant date: 20.01.2014) Ankara branch office.
Introduction Fluoxetine (FLU) is one of the most prescribed pharmaceuticals acting as a selective serotonin reuptake inhibitor (SSRI) (Mennigen et al., 2011, Winder et al., 2012) indicated in the treatment of human depression, anxiety, compulsive behaviour and eating disorders (Dulawa et al., 2004). SSRIs act on the serotonergic system of the tolbutamide sale inhibiting the reuptake of serotonin (monoamine serotonin, 5-hydroxytryptamine, 5-HT) by serotonin transporter (SERT, 5-HTT) in the presynaptic membrane (Kreke and Dietrich, 2008, Valenti et al., 2012). This inhibition leads to the accumulation of serotonin in the synaptic clefts, increasing the serotonergic neurotransmission through postsynaptic serotonin receptors (Raap and Van der Kar 1999; Bisesi et al., 2014). In the absence of inhibitors, serotonin is recycled and stored in a vesicular monoamine transporter (VMAT), a non-specific monoamine transporter, or degraded by monoamine oxidase (MAO) enzymes located in the outer mitochondrial membrane (Hoffman et al., 1998, Maximino, 2012). FLU has been detected in the environment in concentrations ranging from 3.5 × 10−5 to 0.0027 μM (Metcalfe et al., 2010, Metcalfe et al., 2003; Santos et al., 2010, Styrishave et al., 2011; Silva et al., 2012). The presence of FLU in aquatic environment increases the risk of negative effects in aquatic organisms, namely in fish, as the neurotransmitter pathways are phylogenetically conserved with mammals (Kreke and Dietrich, 2008, Valenti et al., 2012). In line with this assumption are the results from previous studies on aquatic organisms (Santos et al., 2010, Schultz et al., 2011, Lacaze et al., 2015) showing alterations of several biological functions and behavioural changes upon exposure to FLU and to other psychopharmaceuticals, with direct impacts on fitness and general population dynamics (Monpelat et al., 2009, Lister et al., 2009, Santos et al., 2010, Schultz et al., 2011). In aquatic invertebrates FLU exposure resulted in genotoxicity and cytotoxicity as well as effects in the locomotion and burrowing movements, although at higher concentrations than those found in the environment (Lacaze et al., 2015, Fong et al., 2015, Hazelton et al., 2014). In fish FLU seems to compromise the antipredator behaviour (Martin et al., 2017, Saaristo et al., 2017) making individuals less reactive and also inhibited egg production (Lister et al., 2009). Fish embryos, due to their vulnerable condition, could be more sensitive to SSRIs exposure since serotonin is known to play an important role in vertebrate embryonic development (Buznikov et al., 2001, Levin, 2006). In previous studies it was shown that zebrafish embryo development is impacted by FLU, at concentrations reported in aquatic environments (Ribeiro et al., 2015, Cunha et al., 2016). Nevertheless, and despite some previous studies there is still a lack of knowledge regarding the interaction of FLU with the neurotransmitter system. Hence, the main aim of this study was to assess the effects of FLU on mRNA transcription of serotonin, dopamine and adrenergic transporters and receptors in early stages of development of zebrafish embryos.