Central nervous system actions of growth hormone on brain monoamine levels and behavior of juvenile rainbow trout

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Hormones and Behavior 43 (2003) 367–374

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Central nervous system actions of growth hormone on brain monoamine levels and behavior of juvenile rainbow trout Elisabeth Jo¨nsson,a,* Viktoria Johansson,a Bjo¨rn Thrandur Bjo¨rnsson,a and Svante Winbergb a

b

Fish Endocrinology Laboratory, Department of Zoology/Zoophysiology, Go¨teborg University, Box 463, SE-405 30 Go¨teborg, Sweden Evolutionary Biology Centre, Department of Comparative Physiology, Uppsala University, Norbyva¨gen 18A, SE-752 36 Uppsala, Sweden Received 17 June 2002; revised 2 October 2002; accepted 3 October 2002

Abstract Growth hormone (GH) has been demonstrated to alter the behavior of juvenile salmonids. However, the mechanisms behind this action are not yet understood. In mammals and birds, peripheral GH treatment has been shown to affect monoaminergic activity in the central nervous system, which may be a mechanism whereby GH alters behavior. To investigate if GH may influence behavior directly at the central nervous system, juvenile rainbow trout were injected with GH into the third ventricle of the brain, whereupon physical activity and food intake were observed during 2 h. Thereafter, brains were sampled and the content of serotonin, dopamine, and noradrenaline and their metabolites were measured in hypothalamus, telencephalon, optic tectum, and brainstem. The GH-treated fish increased their swimming activity relative to sham-injected controls, while appetite remained unchanged, compared with sham-injected controls. Analysis of brain content of monoamines revealed that the GH treatment caused a decrease in the dopamine metabolite homovanillic acid in the hypothalamus, indicating a lowered dopaminergic activity. It is concluded that GH may alter behavior by acting directly on the central nervous system in juvenile rainbow trout. Furthermore, GH seems to alter the dopaminergic activity in the hypothalamus. Whether this is a mechanism whereby GH affects swimming activity remains to be clarified. © 2003 Elsevier Science (USA). All rights reserved. Keywords: Growth hormone; Behavior; Locomotor activity; Food intake; Monoamines; CNS; Intracerebroventricular; Dopamine; Teleost fish; Homovanillic acid

Introduction Growth hormone (GH) is a major promoter of postnatal growth and has a key role in the metabolism of vertebrates. In addition, it is now clear that GH has a much wider range of action than previously recognized, including a function in sexual maturation, in the immune system, and in osmoregulation in both teleost fish (see Bjo¨rnsson 1997; Pe´rezSa´nchez, 2000; Peter and Marchant, 1995) and mammals (see Harvey et al., 1995). A series of studies has demonstrated that GH may affect several types of behaviors in juvenile salmonids. Peripheral GH treatment increases feeding and swimming activity (Jo¨nsson et al., 1996), stimulates dominant feeding behavior * Corresponding author. Fax: ⫹46-31-773-3807. E-mail address: [email protected] (E. Jo¨nsson).

(Johnsson and Bjo¨rnsson, 1994) and aggression (Jo¨nsson et al. 1998), whereas it reduces antipredator behavior (Johnsson et al., 1996; Jo¨nsson et al., 1996). Similar changes in behavior are seen in GH transgenic salmon (Abrahams and Sutterlin, 1999; Devlin et al., 1999). These changes in behavioral patterns are consistent with GH increasing food intake in teleost fish (Johnsson and Bjo¨rnsson, 1994; Markert et al., 1977; Wilson et al., 1988). Also in mammals, GH has been shown to modulate behavior. Somewhat inconsistent, peripheral GH treatment decreases motor activity in rats (Alvarez and Cacabelos 1993; Kelly 1983; Stern et al., 1975), while GH transgenic mice displayed higher locomotor activity in a novel environment than nontransgenic controls (So¨derpalm et al., 1999). Moreover, GH increases aggression in wild male mice (Matte, 1981). Little is known about the mechanisms whereby GH modifies behavior. In fish, one hypothesis is that GH may affect

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feeding behavior and competitive ability indirectly through a peripheral pathway, by inducing metabolic changes that feed back on the brain, thereby increasing the feeding motivation (Johnsson and Bjo¨ rnsson, 1994; Johnsson et al., 1996; Jo¨ nsson et al., 1996, 1998; Markert et al., 1977). It has also been speculated that GH may act directly at the central nervous system (CNS) to modulate behavior (Alvarez and Cacabelos, 1993; Burman et al., 1996; Johnsson and Bjo¨ rnsson, 1994; Johansson et al., 1995; Markert et al., 1977; Matte, 1981; Stern et al., 1975). In support of the latter, central administration of GH increased food intake in ring dove (Buntin and Figge, 1988). Central functions of GH in brain growth, sleep, learning, and memory have also been demonstrated in mammals (see Harvey et al., 1993; Laron and Galatzer, 1985; Nyberg, 2000). Further support for a possible direct action of GH at the CNS level is the demonstration of specific GH binding sites in various brain areas in mammals (Di Carlo et al., 1984; Fraser et al., 1990, Lai et al., 1991; Posner et al., 1974; Zhai et al., 1994), chicken (Attardo and Harvey 1990; Fraser et al. 1990), and teleost fish (Gray et al., 1990; Yao et al., 1991; Sakamoto and Hirano, 1991; Pe´ rez-Sa´ nchez et al., 1991). Recently, the GH receptor was cloned in goldfish, and found to be expressed in several tissues including the brain (Lee et al., 2001). Peripheral GH treatment has been shown to affect monoamine activity in different brain areas and the concentration of monoamine metabolites in the cerebrospinal fluid of rat, chicken, and humans (Andersson et al., 1977, 1983; Burman et al., 1996; Lea and Harvey, 1993; Johansson et al., 1995; Stern et al., 1975; Wang et al., 2000). As brain monoamines are involved in behavioral functions in both mammals and fish (see Huntingford and Turner, 1987; Mason, 1984; Winberg and Nilsson, 1993), it may be hypothesized that they mediate effects of GH on behavior. This is supported by studies in humans, where long-term systemic GH treatment improved the general well-being, which was suggested to be mediated by the accompanying changes in neurotransmitters (Burman et al., 1995, 1996; Johansson et al., 1995). In addition, it has been suggested that GH affects hypothalamic monoamines as a mechanism to regulate its own secretion from the pituitary (Andersson et al., 1977, 1983; Lea and Harvey, 1993). The aims of the present study were to investigate whether GH may affect behavior directly at the level of the CNS, and if such changes might be reflected in changes in monoaminergic activity in specific brain areas. To do this, GH was injected into the third brain ventricle of juvenile rainbow trout, whereupon the swimming and the feeding activity of the fish were observed for 2 h. Thereafter, brains were removed and the content of serotonin, dopamine, and noradrenaline and their metabolites were measured in hypothalamus, telencephalon, optic tectum, and brainstem.

Materials and methods Fish and holding conditions The experimental work was approved by the Ethical Committee of Animal Research in Go¨ teborg (license 169/ 98). The study was conducted from September to November 2000. Juvenile rainbow trout weighing from 20 to 40 g were obtained from a local hatchery (Laxforsens Fiskodling AB), transported to the Department of Zoology, Go¨ teborg University, and allowed to acclimatize for at least 10 days in tanks with aerated recirculating fresh water. During the experiments, the water temperature was kept at 10°C, and a 12-h light: 12-h dark photoperiod regimen was maintained. During acclimatization, fish were fed commercial food pellets (BioMar, size 2) at a rate of 2% body weight (bwt) per day. Experimental design The experiments were conducted in nine replicate series and each series consisted of two parts, an acclimatization period and the behavioral study. Final sample sizes were 20 control fish and 21 GH-treated fish. Six fish that did not feed and had lost weight during the acclimatization period were excluded from the experiment. At the start of each experimental series, four to eight fish were randomly netted, anesthetized in 2-phenoxyethanol (0.05%), and body weights recorded. Thereafter, each fish was transferred to a separate 50-L aquarium compartment. The aquaria were covered with black plastic to prevent disturbance. The fish were allowed to acclimatize to this environment for 5 days. During the first 4 days, the fish were fed once daily at 1200 h at a rate of 2% bwt without disturbing the fish. On the fifth day, the fish were deprived of food, and the aquaria cleaned. The next day, the behavioral experiment was conducted. Starting at 1100 h, each fish was anesthetized in 2-phenoxyethanol (0.05%) and the body weight recorded, whereupon an injection into the CNS was made. After injection, the fish were returned to their aquaria, where they recovered from the anesthesia within 2 min. On four different occasions, 20, 40, 90, and 110 min post injection, each fish was observed during 5-min periods through a small opening in the plastic cover. During observations, the fish were given 30 pellets (0.2 g) every 75 s (four times per observation period). Thus, the total amount of food given to each fish was 3.2 g. During each observation period, the physical activity of the fish was recorded every third second. The following three main behaviors were observed: (1) swimming (the fish actively moves forward), (2) feeding (the fish grasps a pellet and swallows it), and (3) holding position. On occasions, fish could reject, miss, or spit out food; however, these behaviors were very rare and not further analyzed. After the last observation, the fish were removed from the aquaria and brains were sampled for

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monoamine analysis. Thereafter, the remaining food in each aquarium was collected to assess total food intake. CNS injections Each fish was placed on a wet towel on a polyvinylchloride board, and its body position secured. Then an injection of salmon growth hormone (sGH) into the third ventricle was carried out as described by De Pedro et al. (1993), using a 30-gauge Microlance needle (0.3 mm) coupled to a 10-␮l Hamilton syringe with an 18P cannula. Injections were carried out between the two optic tecta, which are visible from outside, in line with the base of the eyes. GH-treated fish received a single dose of 0.1 ng sGH kg bwt⫺1 (GroPep Pty Ltd., North Adelaide, Australia) in a volume of 1 ␮l. The sGH was dissolved in 10 mM NaCl with 2 mM Na2CO3 in an appropriate concentration. Control fish received vehicle only. To minimize leakage from the injection site, 15 s were allowed to elapse before the needle was withdrawn. Prior evaluation on 50 fish using methylene blue for injections, whereupon the brains were dissected, indicated a 90% success rate for delivery to the third ventricle. Brain sampling Directly after the last observation, the fish were rapidly anesthetized in 2-phenoxyethanol (0.1%) and thereafter decapitated. The brain was dissected out and divided into telencephalon, hypothalamus, optic tectum, and brainstem. The tissues were wrapped in aluminium foil and immediately frozen in liquid nitrogen and then kept at ⫺80°C until analysis. Brains were sampled from 12 fish of each treatment. Monoamine analysis All brain tissues were weighed and homogenized in 4% (wt/vol) 0°C perchloric acid containing 40 ng ml⫺1 epinine as internal standard. The brainstem and optic tectum were homogenized by using a Potter-Elvehjem homogenizer, whereas the other brain parts were sonicated by using an MSE 100-W ultrasonic disintegrator. Samples were then centrifuged at 27,000 g for 10 min at 4°C, and the supernatants used for analyses. Monoamines and monoamine metabolites were quantified by using high performance liquid chromatography with electrochemical detection according to Øverli et al. (1999). The following monoamines and metabolites were analyzed: noradrenaline and its metabolite 3-methoxy-4-hydroxyphenylglycol, dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and serotonin (5-hydroxytryptamine) and its metabolite 5-hydroxyindoleacetic acid. The monoamines were quantified by using standard solutions and corrected for recovery of the internal standard using HPLC software (CSW, DataApex Ltd., the Czech Republic).

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Calculations and statistical analysis The monoamine or metabolite content of the tissues is expressed per wet weight. In addition, metabolite/monoamine ratios were calculated, as they are less sensitive than the metabolite content itself to changes in neural processes other than release rate, and are also less sensitive to variance related to tissue sampling and weight determination. However, when observed, changes in metabolite content in most cases considered to be a more accurate indicator of changed monoamine utilization (Fillenz, 1993; Stanford, 1993). All data were analyzed by using SPSS 10.0 software. For repeated measures of feeding and swimming activity, the GLM repeated measures procedure was used. The repeated measures analysis revealed that GH-treated fish had a higher swimming activity compared with control fish (F ⫽ 5.948, df ⫽ 1, P ⫽ 0.019), but there was no difference in swimming activity between the different observation periods (F ⫽ 0.518, df ⫽ 3, P ⫽ 0.67), neither was there any interaction between treatment and time effects F ⫽ 0.283, df ⫽ 3, P ⫽ 0.84). The repeated measures analysis showed also that feeding activity did not vary significantly between the four observation periods (F ⫽ 1.919, df ⫽ 3, P ⫽ 0.13), or between treatment groups (F ⫽ 0.901, df ⫽ 1, P ⫽ 0.35). There was no interaction between observation and treatment effects on feeding activity (F ⫽ 0.294, df ⫽ 3, P ⫽ 0.83). Therefore, swimming and feeding activity were analyzed by pooling the data from the four observation periods, so that the average of the four measurements for each fish was used as an independent data point. For comparisons between control and GH group means, a two-tailed t test was applied. When variance was not homogenous (Levene’s test for equality of variance), data were log-transformed before performing the t test analyses. Spearman rank test was used for correlation analyses between behavioral parameters and monoaminergic activities. Statistical significance was set at P ⬍ 0.05. Data are presented as means ⫾ standard error of means (SEM).

Results Sham- and GH-treated fish did not differ in body weight at the time of acclimatization (33.0 ⫾ 2.8 and 36.4 ⫾ 2.7 g, respectively), or at the time of injection (35.0 ⫾ 2.8 g and 38.5 ⫾ 2.7 g, respectively). One of the 42 fish showed signs of disorientation after the injection and was immediately removed from the behavioral experiment. Mean time spent swimming was higher in GH-treated fish than in control fish (P ⬍ 0.05, Fig. 1A). Mean feeding activity did not differ between treatment groups (Fig. 1B). There was no difference in total food intake between shamand GH-treated fish during the 2 h after injection (Fig. 2C), neither was there any difference between sham- and GH-

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Fig. 1. Behavior of juvenile rainbow trout during 2 h after growth hormone (GH) or vehicle injections into the third ventricle. (A) time spent swimming, (B) time spent feeding, and (C) total food intake. See Materials and methods for details. Data are presented as means ⫾ SEM. A t test was used to assess difference between treatment groups. *P ⬍ 0.05.

treated fish in regard to the time it took them to initiate feeding (71.3 ⫾ 17.1 and 90.8 ⫾ 23.8 s, respectively). GH-treated fish had lower hypothalamic HVA content than the sham-treated controls (P ⬍ 0.05, Fig. 2A), but there were no differences in DA, DOPAC, or the ratios HVA/DA, DOPAC/DA between the two groups (Fig. 2A). There were no differences in any of the other hypothalamic monoamine

Fig. 2. Contents of dopamine (DA) and its metabolites homovanillic acid (HVA), and 3,4-dihydroxyphenylacetic acid (DOPAC), and the ratios between the DA metabolites and DA in (A) hypothalamus, (B) telencephalon, (C) brainstem, and (D) optic tectum, 2 h after an injection of growth hormone (GH) or vehicle into the third brain ventricle. See Materials and methods for details. Data are presented as means ⫾ SEM; n ⫽ 10 –12. A t test was used to assess difference between treatment groups. *P ⬍ 0.05.

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levels or monoamine metabolites between the two treatment groups (data not shown). Neither were there any significant differences between control and GH-treated fish in respect to the hypothalamic monoamine metabolite/monoamine ratios (data not shown). In the telencephalon, optic tectum, and brainstem, there were no significant differences in any of the monoamines or monoamine metabolites measured, nor were there any differences in the metabolite/monoamine ratios, between control and GH-treated fish (Fig. 2 for dopamine results; for noradrenaline or serotonin data are not shown). However, there was a tendency for lower DOPAC levels in telencephalon in GH-treated fish compared with controls (P ⫽ 0.06, Fig. 2B). Telencephalic HVA levels were excluded due to a technical problem. No significant correlations were found between food intake, feeding, or swimming activity and monoamine levels, monoamine metabolite levels, or metabolite/monoamine ratios in the different brain areas.

Discussion In the present study, GH administered directly into the third ventricle increased swimming activity in juvenile rainbow trout, which indicates that GH may act directly on the CNS to influence behavior. A similar GH-induced increase in swimming activity has previously been observed in rainbow trout after intraperitoneal GH injections (Jo¨ nsson et al., 1996), suggesting that peripherally administered GH may reach the CNS. This in agreement with studies on mammals (see Coculescu, 1999) and studies on salmonid fish (Johansson, V., Bjo¨ rnsson, B.T., unpublished results), which indicate that GH may pass the blood-brain barrier. Further, peripheral GH treatment decreases monoamine levels in diencephalon and pons-medulla in rats already after 15 min, which indicates that GH is rapidly taken up in the brain tissue (Stern et al., 1975). Peripheral GH treatment also decreases locomotor activity within 30 min in rats (Alvarez and Cacabelos, 1993). Together, these results imply that GH affects motor activity, but in opposite directions, in rats compared with fish. However, GH-transgenic mice display increased motor activity compared to nontransgenic controls (So¨ derpalm, 1999). In the present study, the lack of effect of the central GH injections on food intake or on time to first feeding differs from previous findings on fish after peripheral GH injections, which increased appetite (Johnsson and Bjo¨ rnsson, 1994; Markert et al., 1977; Wilson et al., 1988). Thus, while peripheral GH treatment increases both appetite and swimming activity in fish, the present results indicate that at the central level, there is dissociation between these GH-mediated effects. It also indicates that the mechanisms behind the peripheral effects of GH on appetite and swimming activity may differ. Hence, the increased appetite in fish after intraperitoneal GH administration is probably mediated by some secondary peripheral factor(s) other than GH itself. How-

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ever, based on this study, it cannot be entirely discarded that GH may act directly at the CNS to alter appetite by increasing/decreasing the local production of secondary factor(s), but it may take more than 2 h for this effect to take place. Data on birds indicate that peripheral and central GH injections have different effects on food intake. In peripherally GH-treated chicken, food intake was suppressed (VasilatosYounken, 1995; Wang et al., 2000), with hypothalamic adrenaline and neuropeptide Y probably involved in mediating the effect, whereas food intake was increased in centrally GH-treated ring dove (Buntin and Figge, 1988). However, these discrepancies in GH effects may not only be due to the different routes of administration, but may also depend on the protocol used. In addition, although GH has similar stimulatory effects on growth in most vertebrates examined so far, the underlying causes may vary among species. Factors such as increased feed intake, increased feed conversion efficiency and increased foraging efficiency may, to a varying degree, contribute to the growth increase. Thus, the relationship between GH, growth, and behavior is also likely to differ among species. Central GH injections reduced the hypothalamic HVA levels, indicating a lowered dopaminergic activity, while serotonergic and noradrenergic activities were not affected. The present results thus partly corroborate findings in rats after peripheral GH treatment (Andersson et al., 1977, 1983; Stern et al., 1975), and in birds after central and peripheral GH treatments (Lea and Harvey, 1993; Wang et al., 2000), where GH decreases the activity of all monoamines in the hypothalamus. In humans, peripheral GH treatment decreases the HVA levels in the cerebrospinal fluid, but not the levels of 5-hydroxyindoleacetic acid and 3-methoxy-4hydroxyphenylglycol (Burman et al., 1996; Johansson et al., 1995). This is consistent with the results of the present study, although here, GH was injected into the CNS. The GH-induced change in monoamines in rats and birds has been interpreted as a possible mechanism behind GH autoregulation (Andersson et al., 1977, 1983; Lea and Harvey, 1993). This may also be the case in teleost fish, where dopamine has been shown to stimulate GH secretion in ´ gu´ stsson et al., 2000; Bosma et al., 1997; several species (A Chang et al., 1985, 1990; Lin et al., 1993a, 1993b; Melamed et al., 1995, 1996, 1997; Wong et al., 1993, 1998). Furthermore, dopaminergic innervation of the anterior pituitary has been demonstrated for goldfish (Kah et al., 1987) and rain´ gu´ stsson et al., 2000). In the present study, bow trout (A however, there was also a tendency for lower concentrations of the dopamine metabolite DOPAC in the telencephalon of the GH-treated fish. This is consistent with the demonstration of specific GH-binding sites in telencephalon of rainbow trout (Pe´ rez-Sa´ nchez et al., 1991). In rats, GH decreases both the serotonergic and noradrenergic activities in telencephalon, pons-medulla, as well as in hypothalamus, while dopaminergic activity was not measured (Stern et al., 1975), suggesting that GH may have a function in brain areas other than the hypothalamus.

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How GH acts in the CNS to increase swimming activity in fish remains to be resolved. In rat and mice, there are indications that GH may influence the effect of d-amphetamine, which in turn is related to DA, on motor activity (So¨ derpalm et al., 1999; Stern et al., 1975). However, in the present study there was no clear correlation between dopaminergic activity and swimming, and also, there was a decreased dopaminergic activity in the GH-treated fish. In cichlids, DA seems to stimulate motor activity (Mok and Munro, 1998; Munro, 1986), as is generally the case in mammals (see Mason, 1984). In mammals, the DA system has two major circuits, the mesostriatal system and the mesolimbic system (Butler and Hodos, 1996). While these two systems are interconnected, the mesostriatal system appears to be mainly involved in motor control whereas the mesolimbic system is important in the control of motivational and emotional behavior. In teleosts, dopaminergic cells are not present in the midbrain, but several cell groups appear within the posterior tubercle (Butler and Hodos, 1996; Meek, 1994). In the zebra fish (Danio rerio) brain, two populations of dopaminergic cells can be recognized within the posterior tubercle, but it is still not clear whether these are homologous to the mesostriatal and mesolimbic systems of mammals (Rink and Wullimann, 2002). Moreover, due to the everted telencephalon in teleosts, the subpallial subdivisions are still a matter of debate, and brain areas homologous to the striatum and nucleus accumbens of tetrapods have still not been clearly identified in teleosts (Bradford, 1995). Juvenile freshwater-living salmonids, as the rainbow trout of the present study, switch between periods of physical activity and inactivity. The sedate periods, combined with the use of hiding places and cryptic coloration, represent a mechanism of predator avoidance, while the periods of active swimming represent the defense of a territory and/or foraging within this territory. Thus, swimming is associated with both costs and benefits, and can be defined as risky but growth promoting. Peripheral GH treatment increases swimming activity and food intake, together with a decreased predator avoidance (Jo¨ nsson et al., 1996) and it can be postulated that this effect may be mediated through a systemic and/or a central action of the hormone. The systemic physiological effect of GH on growth is in itself well established and includes stimulation of tissue growth with related changes in both protein and lipid metabolism (Bjo¨ rnsson, 1997; Harvey et al., 1995). It can be hypothesized that such an effect will in turn be “detected” by the CNS, e.g., through changes in plasma nutrient/metabolite levels, and this would lead to changes in behavior, something that could be termed as “growth-driven behavior.” This is in contrast with “behaviorally driven growth” that could occur when the hormone acts on the CNS. The present study is a direct test of the latter hypothesis, and the increase in swimming activity of juvenile rainbow trout following central GH injections strengthens the view that GH can modulate behavior through direct effects at the

CNS. The central GH injections also decreases the dopaminergic activity in the hypothalamus, which may be interpreted as a mechanism for GH autoregulation and/or one of the mechanisms whereby GH modifies behavior. However, it is clear that further research is needed to establish the functional mechanisms behind the effects of GH in the CNS.

Acknowledgments The authors thank Øyvind Øverli and Olivier Lepage for valuable help during the HPLC analyses. This work was supported by grants from the Swedish Council for Agricultural and Forestry Research, the Wallenberg Foundation (the VIRTUE project), the Adlerbertska Foundation, the Royal Swedish Academy of Sciences, La¨ ngmanska Kulturfonden, the Helge Axson Johnson Foundation, and the Wilhelm and Martina Lundgren Foundation.

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