The organization of serotonin in the central nervous system is evolutionarily well conserved in the vertebrates (Lillesaar, 2011). In the brain of teleosts, three major serotonergic neural groups exist: (i) pretectal population, (ii) posterior tuberculum/hypothalamic populations, and (iii) raphe populations (Kah and Chambolle, 1983; Ekström and Van Veen, 1984; Frankenhuis-van den Heuvel and Nieuwenhuys, 1984; Margolis-Kazan et al., 1985; Johnston et al., 1990; Corio et al., 1991; Ekström et al., 1992; Batten et al., 1993; RodrıìGuez-Gómez et al., 2000; Lillesaar, 2011). In addition, serotonin-positive cells are also present in the pineal gland, area postrema, medulla oblongata and spinal cord in the brain of teleosts (Lillesaar, 2011). In teleost, serotonergic fibers from the brain directly project to the pituitary (Kah and Chambolle, 1983; Corio et al., 1991; Khan and Thomas, 1993; RodrıìGuez-Gómez et al., 2000). In some teleosts species, serotonin-immunoreactive cells also present in the pituitary (Kah and Chambolle, 1983; Ekström and Van Veen, 1984; Margolis-Kazan et al., 1985; RodrıìGuez-Gómez et al., 2000).

In mammals, serotonin is synthesized from the essential amino acid, L-tryptophan with help of catalysis by two enzymes: tryptophan hydroxylase (TPH) and amino acid decarboxylase (Fitzpatrick, 1999), whereas knowledge about mechanism of the control of brain serotonin synthesis in teleosts is still limited (Höglund et al., 2005). However, teleosts fish also preserve the molecules that are involved in homeostasis of serotonin such as TPH, serotonin transporter (SERT), which reuptakes serotonin into the presynaptic serotonergic nerve terminals to recycle serotonin (Murphy et al., 1998), and monoamine oxidase (MAO), the enzyme for degradation of serotonin (Bortolato et al., 2010).

Most teleosts have two TPH genes (tph1 and tph2), two SERT genes (slc6a4a and slc6a4b) but only one type of MAO gene (mao) (Chen et al., 1994; Setini et al., 2005; Norton et al., 2008; Rahman and Thomas, 2009). In some teleosts, such as zebrafish, stickleback and medaka, there are three genes (tph1a, tph1b, and tph2) encoding TPH (Lillesaar, 2011). In the brain of zebrafish, tph1a is present in the posterior tuberculum and hypothalamus, and also in the pineal organ, in amacrine cells of the retina, and tph1b is transiently expressed in a preoptic cell cluster during late embryonic stages (Bellipanni et al., 2002), and tph2 is mainly expressed in serotonergic neurons of the raphe nuclei (superior raphe and inferior raphe) (Lillesaar, 2011) (Figure 1). In some teleosts, TPH is expressed in the pituitary (Boularand et al., 1998; Rahman and Thomas, 2009), indicating that serotonin may be locally produced in the pituitary. In the zebrafish, slc6a4a is expressed in the superior raphe and pretectal diencephalic cluster, and slc6a4b is seen only in the paraventricular organ and caudal zone of periventricular hypothalamus (Wang et al., 2006; Norton et al., 2008). In the serotonergic raphe nuclei, serotonergic neurons in the superior raphe project to the forebrain and midbrain, and the serotonergic cells in the inferior raphe project to hindbrain-spinal cord region in the teleosts brain (Lillesaar, 2011).

In teleosts, serotonin receptors have been identified and characterized in several species such as zebrafish, European flounder (Platichthys flesus), Gulf toadfish (Opsanus beta), and puffer fish (Yamaguchi and Brenner, 1997; Lu et al., 2007; Best and Alderton, 2008; Mager et al., 2012). Additionally, in silico analysis have predicted gene sequences encoding serotonin receptors in several other species such as the tilapia (Oreochromis niloticus), cichlid fish (Haplochromis burtoni), southern platyfish (Xiphophorus maculatus), and rainbow trout (Oncorhynchus mykiss). In the zebrafish, three serotonin receptors subtypes (5-HT1, 5-HT2, and 5-HT7) have been identified, among which three subgroups of 5-HT1 (5-HT1aa, 5-HT1ab, 5-HT1bd) and two subgroups of 5-HT2 (5-HT2A and 5-HT2C) have been identified (Norton et al., 2008; Schneider et al., 2012). In the brain of zebrafish, 5-HTr1aa and 5-HTr1ab are mainly expressed in the preoptic area and hypothalamus, and 5-HTr1bd is expressed in the hypothalamus (Norton et al., 2008). In the Gulf toadfish, 5-HT2A is widely expressed in the brain including the telencephalon, midbrain, cerebellum, hindbrain and in the pituitary (Mager et al., 2012). In the zebrafish, 5-HT2C is expressed in the telencephalon, diencephalon, rhombencephalon, and spinal cord (Schneider et al., 2012).

Serotonin receptors are also expressed in peripheral tissues including gonadal tissues in teleosts. In the zebrafish, 5-HT2C receptor gene is expressed in the ovary (Schneider et al., 2012). In the toadfish, 5-HT2A is expressed in the ovary and testes (Mager et al., 2012).

Serotonin modulates fish reproductive function via multiple pathways including through central (preoptic-hypothalamic area and pituitary) and peripheral (gonads) actions. In the hypothalamus, GnRH neurons play major role in the control of vertebrate reproduction. Immunohistochemical study in the Atlantic croaker have demonstrated close association of serotonin fibers with olfactory bulbular and hypothalamic GnRH neurons (Khan and Thomas, 1993). However, in the Atlantic croaker, central administration of serotonin has no effect on preoptic GnRH1 mRNA levels (Thomas et al., 2007), indicating that serotonin may stimulate GnRH release but not synthesis. Indeed, serotonin stimulates GnRH release from the hypothalamus of the seabream and goldfish (Yu et al., 1991; Senthilkumaran et al., 2001). In the zebrafish, expression of serotonin receptors are seen in several brain regions containing GnRH neurons (Norton et al., 2008), which suggests possible co-expression of serotonin receptors in GnRH neurons as in mammals (Bhattarai et al., 2013).

Kisspeptin, a ligand for G-protein coupled receptor GPR54, has recently emerged as a key player for GnRH release (Tena-Sempere, 2006; Gopurappilly et al., 2013). However, no report has described the involvement of serotonin in the regulation of the kisspeptin system in any vertebrates to date.

In Atlantic croaker increasing serotonin concentrations are associated with levels of gonadotropin release from the pituitary (Khan and Thomas, 1994). In several teleost species, serotonin stimulates release of gonadotropin in vivo and in vitro (Somoza et al., 1988; Somoza and Peter, 1991; Khan and Thomas, 1992). In vitro and in vivo studies in teleosts have shown the involvement of 5-HT1 or 5-HT1 receptor subtypes in stimulating gonadotropin secretion (Somoza and Peter, 1991; Khan and Thomas, 1994; Wong et al., 1998). These studies suggest that serotonin plays a prominent role in gonadotropin secretion in teleosts as demonstrated in mammals.

In the Atlantic croaker, serotonin combination with GnRH stimulates LH secretion (Wong et al., 1998). In the goldfish, serotonin stimulates release of GnRH from the cultured brain preoptic-anterior hypothalamic region and pituitary fragments (Yu et al., 1991). However, a recent in vivo study in Prussian carp (Carassius gibelio Bloch) demonstrated that serotonin alone had no influence on the spontaneous LH release, but the additive effects of serotonin was observed when GnRH analog was co-administered (Sokolowska-Mikolajczyk et al., 2015). These observations indicate functional interaction between serotonin and GnRH system in teleosts. However, an in vitro study in the red seabream demonstrated that serotonin stimulates the release of GnRH from the hypothalamus but not from the pituitary of immature fish (Senthilkumaran et al., 2001). Therefore, in teleosts, the mode of action of serotonin on gonadotropin release could be changed reproductive-stage dependently. Additionally, serotonin is also known to modulate growth hormone (GH) release in goldfish (Somoza and Peter, 1991; Wong et al., 1998). In the goldfish, GnRH-stimulated GH secretion is interfered by serotonin with PKC and Ca²⁺ signaling pathways in pituitary cells (Yu et al., 2008). Those signaling pathways could also be involved in GnRH-primed gonadotropin secretion in teleosts.

In addition to its central action on the reproductive axis, serotonin directly acts on gonads. In the Gulf killifish (Fundulus grandis), 10 days of daily injection of serotonin precursor with dopamine precursor increases gonadosomatic index in male (Emata et al., 1985). An in vitro study in the Japanese medaka (Oryzias latipes) has shown stimulatory effect of serotonin on oocyte maturation in a dose-dependent manner, which is modulated via stimulation of the synthesis of estrogen and the maturation-inducing steroids (MIS: 17α,20β-dihydroxy-4-pregnen-3-one) by the granulosa cells (Iwamatsu et al., 1993) On the contrary, in the mummichog (Fundulus heteroclitus), serotonin inhibits oocyte maturation, especially oocyte meiosis (Cerdá et al., 1995, 1997, 1998).

Although the expression of serotonin receptors in the testis has not been reported in teleosts, in freshwater catfish (Channa punctatus Bloch), MAO activity has been noted in the testis (Katti and Sathyanesan, 1986), and MOA activity and serotonin contents in testis represents correlative changes with testicular maturation (Joshi and Sathyanesan, 1980). These results suggest that locally produced serotonin may participate in testicular maturation.

The role of serotonin in social behavior has been well demonstrated in fish (Winberg and Nilsson, 1993), while no report has demonstrated the involvement of serotonin in sexual behavior. As social status and reproductive activity are closely related, alteration of serotonin during different social status may directly influence reproductive activities. In teleosts fish, serotonin plays primary inhibitory role in aggressive behavior (Munro, 1986; Adams et al., 1996; Winberg et al., 2001; Perreault et al., 2003). In the fighting fish Betta splendens, serotonin decreases aggression via 5-HT1A receptors (Clotfelter et al., 2007). On the contrary, higher levels of serotonin metabolite are found in the brain of subordinate compared with dominant fish (Winberg and Lepage, 1998; Lorenzi et al., 2009). In a cichlid fish Astatotilapia burtoni, subordinate males have higher serotonergic turnover and higher expression of two serotonin receptor genes (5-HT1A and 2A) in the telencephalon (Loveland et al., 2014), indicating a correlation between social status and the serotonin system. In the Arctic charr (Salvelinus alpinus L.), higher brain serotonergic levels and activity is socially induced in subordinates (Winberg et al., 1991, 1992).

In teleosts, serotonin levels in the brain and pituitary are modulated by reproductive cycles and gonadal steroids (Subhedar et al., 1997; Hernandez-Rauda and Aldegunde, 2002b). In the tilapia, estrogen alters the brain serotonin content during the early brain development stage, which is mediated by decreasing TPH activity and increasing MAO activity (Tsai and Wang, 1999). In the adult male marine yellow snapper (Lutjanus argentiventris), serotonin levels in the telencephalon reach the peak during the prespawning period, and are lowest during the spawning period (Hernandez-Rauda and Aldegunde, 2002a). Furthermore, blocking serotonin synthesis alters brain aromatase activity during the critical period of sexual differentiation in the tilapia (Tsai et al., 2000), suggesting possible involvement of serotonin in brain sex determination.

Endocrine disruptors such as polyaromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs) can modulate serotonergic activity (Stephanou et al., 1998; Gesto et al., 2006; Clotfelter et al., 2010; Rahman et al., 2011). Some of these endocrine disruptors have a significant influence on fish reproductive function through the serotonin system. For example, PAHs such as naphthalene and benzo[α]pyrene disrupt the reproductive axis in teleosts (Hose et al., 1981; Yarahmadi et al., 2013). PCB inhibits serotonergic and TPH activity as well as disrupts GnRH and gonadotropin secretion in the Atlantic croaker (Khan and Thomas, 2000, 2006). Similarly, para-chlorophenylalanine (PCPA) reduces hypothalamic serotonin levels and impairs GnRH and LH secretion in the Atlantic croaker (Khan and Thomas, 2001). These results suggest that the serotonin system is one of the major targets for neuroendocrine disruption, which may lead to inhibition of reproductive functions.

In teleosts, the brain serotonergic activity displays diurnal or seasonal variations (Khan and Joy, 1988; Senthilkumaran and Joy, 1993), which may have significant effects on the reproductive functions. In teleosts, serotonin concentrations in the brain are higher in the morning than evening (Fingerman, 1976; Khan and Joy, 1988). In the Channa punctatus, there are diurnal variations in the serotonin content (Khan and Joy, 1988) as well as MAO activity in the hypothalamus (Khan and Joy, 1987, 1988), suggesting diurnal variation of the hypothalamic serotonin levels. Seasonal variation of hypothalamic serotonin content has also been noted in the catfish, Heteropneustes fossilis (Senthilkumaran and Joy, 1994). These seasonal changes in serotonin levels could also be due to environmental factors such as water temperature and photoperiod. In the tilapia, the hypothalamic serotonin content is lower in fish exposed to higher water temperature than those in lower temperature group (Tsai and Wang, 1997). In contrast, expression of serotonin receptors (5-HT1A and 1D) in the brain are increased by low temperature in the tilapia during the sexual differentiation (Wang and Tsai, 2006). In several fish species, photoperiods alter hypothalamic serotonin content and turnover (Olcese et al., 1980; Senthilkumaran and Joy, 1994), which can be modulated by melatonin levels (Joy and Khan, 1991). In the goldfish, pinealectomy and melatonin administration have a significant effect on hypothalamic serotonin content and serotonergic activity (Olcese et al., 1981). These results indicate environmental factors may influence reproductive functions via diurnal and seasonal change of serotonin activity.

In the protogynous fish, Hawaiian saddleback wrasse (Thalassoma duperrey), serotonin inhibits both initiation and completion of sex reversal (Larson et al., 2003a). Furthermore, in the same fish, serotonin levels in the brain are altered by socially induced sex reversal, which could be associated with territorial acquisition (Larson et al., 2003b). These results suggest that serotonin is also regulated by social behaviors.

Selective serotonin reuptake inhibitors (SSRIs) are widely used as antidepressants in the treatment of major depressive disorder and anxiety disorders (Lesch, 2001; Homberg et al., 2010). SSRIs have been detected as pharmaceutical contaminants in surface waters and sewage effluents (Kreke and Dietrich, 2008; Oakes et al., 2010) as well as in fish brain tissue (Schultz et al., 2010) owing to their widespread and increasing rates of administration. SSRIs block the presynaptic SERT and prevent the clearance of synaptic serotonin, which causes an elevation of extracellular serotonin concentrations (Tollefson and Rosenbaum, 1995). Chronic exposure to SSRIs cause significant decrease of serotonin content in the fish brain (Gaworecki and Klaine, 2008; Winder et al., 2009; Bisesi et al., 2014), which can influence the neuroendocrine control of reproductive function. Among the SSRIs, fluoxetine (also known as PROZAC) has been widely used to investigate the serotonergic modulation of the teleosts endocrine system (Somoza and Peter, 1991; Kreke and Dietrich, 2008). In female fish, fluoxetine treatment significantly reduces egg production and ovarian levels of estrogen, and gene expression levels of aromatase, FSH- and LH-receptors (Lister et al., 2009; Forsatkar et al., 2014). Conversely, fluoxetine has stimulatory effects on GnRH and LH release in some fish species (Somoza et al., 1988; Yu et al., 1991).

SSRIs also have influence on not only endocrine system, but also behaviors. In male fathead minnows (Pimephales promelas), exposure to sertraline, a SSRI decreases shelter-seeking behavior, suggesting that sertraline elicits an anxiolytic effect (Valenti et al., 2012). In hybrid striped bass (Morone saxatilis × M. chrysops), fluoxetine exposures decrease in ability of fish to capture prey (Gaworecki and Klaine, 2008). In the bluehead wrasse (Thalassoma bifasciatum), fluoxetine treatment decreases territorial aggression. However, in male B. splendens, there was no effect of chronic intramuscular injections of fluoxetine on aggressive behavior (Clotfelter et al., 2007). These observations suggest that environmental SSRIs may have significant impact on reproductive capability of fish via behavioral disruption.

A variety of influences of SSRIs on fish reproduction could be due to different doses, administrations, duration of SSRI treatments and physiological, reproductive status and sex of fish treated and species differences (Sumpter et al., 2014). However, it is still unclear how SSRIs act on the HPG axis via the serotonin system. In addition, most antidepressant drugs are specifically designed for humans (mammals), but not for fish. Therefore, the effects of these drugs may not be specific in teleosts. In fish, SSRIs are suggested to interact with and inhibit some P450 isozymes that are responsible for steroid metabolism (Kreke and Dietrich, 2008), which might have effect on the reproductive neuroendocrine control.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.