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Bovine Growth Hormone Transgenic Mice Display Alterations in Locomotor Activity and Brain Monoamine Neurochemistry¹

Institute of Physiology and Pharmacology, Departments of Pharmacology (B.S., M.E., J.A.E.) and Physiology (M.B., J.T.), Göteborg University, SE 405 30 Göteborg, Sweden

Address all correspondence and requests for reprints to: Dr. Bo Söderpalm, Institute of Physiology and Pharmacology, Department of Pharmacology, Göteborg University, Box 431, SE 405 30 Göteborg, Sweden. E-mail: bo.soderpalm{at}pharm.gu.se

	Abstract

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Recent clinical and experimental data indicate a role for GH in mechanisms related to anhedonia/hedonia, psychic energy, and reward. In the present study we have investigated whether bovine GH (bGH) transgenic mice and nontransgenic controls differ in spontaneous locomotor activity, a behavioral response related to brain dopamine (DA) and reward mechanisms, as well as in locomotor activity response to drugs of abuse known to interfere with brain DA systems. The animals were tested for locomotor activity once a week for 4 weeks. When first exposed to the test apparatus, bGH transgenic animals displayed significantly more locomotor activity than controls during the entire registration period (1 h). One week later, after acute pretreatment with saline, the two groups did not differ in locomotor activity, whereas at the third test occasion, bGH mice were significantly more stimulated by d-amphetamine (1 mg/kg, ip) than controls. At the fourth test, a tendency for a larger locomotor stimulatory effect of ethanol (2.5 g/kg, ip) was observed in bGH transgenic mice. bGH mice displayed increased tissue levels of serotonin and 5-hydroxyindoleacetic acid in several brain regions, decreased DA levels in the brain stem, and decreased levels of the DA metabolite 3,4-dihydroxyphenylacetic acid in the mesencephalon and diencephalon, compared with controls. In conclusion, bGH mice display more spontaneous locomotor activity than nontransgenic controls in a novel environment and possibly also a disturbed habituation process. The finding that bGH mice were also more sensitive to d-amphetamine-induced locomotor activity may suggest that the behavioral differences observed are related to differences in brain DA systems, indicating a hyperresponsiveness of these systems in bGH transgenic mice. These findings may constitute a neurochemical basis for the reported psychic effects of GH in humans.

	Introduction

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GH-DEFICIENT (GHD) adults have impaired quality of life (1, 2, 3, 4, 5, 6). Symptoms related to lack of energy, difficulties in concentrating or remembering, tiredness, and irritability have been presented (4, 7). When substituted, GHD patients experience improved cognitive functions (8) and marked positive effects on general well-being and psychic energy (2, 3, 7, 9).

It is not clear whether the psychic effects of GH are mediated directly in the brain or via a molecule produced in peripheral tissues. Although the question of whether GH could pass the blood-brain barrier has been controversial (10), several studies now support the concept that GH from the peripheral circulation can enter into the central nervous system (11). However, local production of GH in the brain is also possible. Messenger RNA for GH can be found in different parts of the brain, supporting this concept (12). The most abundant GH immunoreactivity is found in the amygdala, hippocampus, and hypothalamus (13). Whether peripherally administered GH by itself or via other mediators can affect the synthesis of GH in the brain is unknown.

GH receptors (GHR) are present in multiple locations in the rodent (14, 15) and human (16, 17) brain. In the human, GHR are most frequent in the choroid plexus, hippocampus, hypothalamus, and pituitary gland (16). In the rat (15) most GH-binding sites are found in the choroid plexus, hypothalamus, capsula interna, and parietal cortex, but abundant binding is observed also in the hippocampus, tegmentum, mamillary bodies, and temporal cortex, areas that have been implicated in emotional processing. The functional significance for GHR in the pituitary gland is probably coupled to feedback regulation of GH secretion, but the physiological relevance in the other areas is not established.

It is unclear what brain neuronal systems are involved in the beneficial psychic effects observed after GH treatment. However, as extensive evidence links the brain meso-corticolimbic dopamine (DA) system and serotonin (5-HT) systems to hedonia/anhedonia, reward, and psychic drive (18, 19, 20, 21, 22), it is likely that brain monoamine systems are involved in mediating the GH-induced effects. Supporting this hypothesis, decreased levels of homovanillic acid (HVA), a DA metabolite, were found in the cerebrospinal fluid of GHD adults after GH substitution (11). The mesocorticolimbic DA system is suggested to be an important neuronal substrate for drugs of abuse, and, interestingly, GHD patients are less frequent smokers than age-matched controls (7). Experimentally, transgenic mice overexpressing GH show an increased preference for ethanol and nicotine over water in free choice models (23).

In the present study we have used transgenic mice overexpressing bovine GH (bGH) to investigate whether prolonged exposure to excessive GH levels produces alterations of spontaneous exploratory locomotor activity and/or the locomotor response to d-amphetamine or ethanol, behaviors that are related to brain DA and reward mechanisms (20, 24, 25). Furthermore, we have analyzed the tissue levels of different monoamines and their metabolites in several brain regions of GH-transgenic mice and normal controls.

	Materials and Methods

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Animals
A BstEII-EcoRI fragment was isolated from the plasmid Mt-bGH 2016 (provided by Dr. R. D. Palmiter) and used for injection. This DNA fragment contains the Mt promoter linked to a sequence encoding bGH. The isolated fragment was injected into the pronucleus of C57BL/6JxCBA-F₂ embryos (26). Mice that had integrated the transgene were identified by PCR analysis of DNA from tail biopsy specimens obtained 3 weeks after birth using one PCR primer located in the Mt promoter and another in the bGH gene. As a consequence of the elevated GH levels, these animals grow 40% larger than control mice (27). The mice were housed under controlled conditions, with lights on at 0300 h and off at 1700 h, and had free access to rat and mouse standard feed (Beekay Feeds).

Locomotor activity
Locomotor activity was measured by photocell recordings as previously described (28). The instruments (M/P 40 Electronic Mobility Meter, Motron Products, Stockholm, Sweden) were equipped with 40 photoconductive sensors (5 rows x 8; center/center distance, 40 mm) covered by a translucent floor, upon which a Plexiglas test cage (21 x 32 x 35 cm) was placed. The number of counts representing all light beam interruptions of any of the sensors was printed by external timer-controlled counters. Animals were injected with the drugs concerned and placed in the boxes without any preceding habituation period. Locomotor activity was recorded for 30–60 min depending on the treatment applied. All experiments were run in a randomized order between 1300–1600 h.

Brain dissection and determination of monoamine and metabolite levels
The animals were killed by decapitation, and their brains were rapidly taken out, put on an ice-chilled petri dish, and dissected into the corpus striatum, limbic region (containing the nucleus accumbens), hippocampus, cortex, diencephalon, mesencephalon, and brain stem. The brain parts were stored at -70 C until further analysis.

Frozen tissue was homogenized with a Sonifier B30 (Branson Sonic Power Co.) in 0.1 M HClO₄ containing Na₂-EDTA (5.3 mM), glutathione (1.63 mM), and -methyl-DOPA (1.0 ml) for the limbic region and 0.5 ml for the other brain parts. After centrifugation (10,000 x g, 4 C, 10 min), the supernatant was taken for analysis of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), HVA, 5-hydroxytryptamine (5-HT; serotonin), and 5-hydroxyindoleacetic acid (5-HIAA) by means of liquid chromatography with electrochemical detection.

The chromatography system consisted of an LDC minipump (Laboratory Data Control, Rivera Beach, FL), an automatic sampler model MSI 660 (Kontron Instruments Ltd. AG, Zurich, Switzerland), and a stainless steel column (0.45 x 15 cm) packed with Nucleosil RP18 5µ (Macherey-Nagel, Duren, Germany). A mobile phase consisting of 0.017 M K₂HPO₄, 0.033 M citric acid, sodium octyl sulfate (0.25–0.30 mM), 0.054 mM Na₂-EDTA, and 8–10% methanol was used for the separation. The flow rate was 1.0–1.5 ml/min at a somewhat constant temperature (21–23 C). Electrochemical detection was carried out by means of a thin layer cell, TL-3 (Bioanalytical Systems, Inc. BAS, West Lafayette, IN), with a glassy carbon working electrode, an Ag/AgCl reference electrode, and an amperometric detector (LC-3, BAS). The detector was operated at 0.7 V. The current produced was monitored using a integrator model SP 4270 (Spectra-Physics, San Jose, CA).

Experimental design
Male bGH transgenic animals and control mice, all approximately 8 months old at the start of the experiments, were tested for locomotor activity in the activity boxes described above once a week for 4 weeks, with different treatments being applied at each occasion. The order of treatments was: 1) spontaneous exploratory locomotor activity (first time in the boxes) without injection, 2) locomotor activity after a saline injection (0.9% NaCl, ip, 5 min before placement in the box), 3) locomotor activity after d-amphetamine (1 mg/kg, ip, 5 min before placement in the box), and 4) locomotor activity after ethanol [2.5 g/kg, ip (15% wt/vol in 0.9% NaCl), 5 min before placement in the box). The doses of the respective drugs were chosen on the basis of previous experience (22) and were expected to produce a moderate degree of locomotor stimulation with, in the case of amphetamine, a negligible risk of producing stereotypies.

Statistics
The locomotor activity data were statistically evaluated using a two-factor ANOVA for repeated measures, whereas Student’s t test was used for the neurochemical data. P < 0.05 was considered significant.

	Results

Top Abstract Introduction Materials and Methods Results Discussion References

 
Locomotor activity
When first exposed to the test apparatus, bGH animals displayed significantly more locomotor activity [by two-factor repeated measures ANOVA, group effect: F(1,37) = 11.4; P = 0.0017] during the entire registration period (1 h; Fig. 1). There was a significant decay of locomotor activity during the registration period and also a significant interaction term, indicating that the groups did not reduce their locomotor activity similarly over time [time effect: F(11,407) = 27.3; P < 0.0001; interaction term: F(11,407) = 27.3; P < 0.0001].

View larger version (23K): [in this window] [in a new window]   Figure 1. Top, Locomotor activity in male bGH transgenic mice (n = 10) and nontransgenic control mice (n = 25) at their first encounter with the locomotor activity boxes. Statistics were determined by two-factor repeated measures ANOVA: group effect, P = 0.0017; time effect, P < 0.0001; and interaction term, P < 0.0001. Bottom, Locomotor activity in bGH transgenic mice (n = 10) and nontransgenic control mice (n = 25) at their second encounter with the locomotor activity boxes. All animals received 0.9% NaCl, ip, 5 min before placement in the boxes. Statistics were determined by two-factor repeated measures ANOVA: group effect, P = 0.4048; time effect, P < 0.0001; and interaction term, P = 0.1684.

View larger version (22K): [in this window] [in a new window]   Figure 2. Locomotor activity in bGH transgenic mice (n = 9) and nontransgenic control mice (n = 25) at their third encounter with the locomotor activity boxes. Left panel, All animals received 1 mg/kg d-amphetamine, ip, 5 min before placement in the boxes. Statistics were determined by two-factor repeated measures ANOVA: group effect, P = 0.0016; time effect, P < 0.0001; and interaction term, P = 0.0002. Right panel, The calculated difference between the locomotor activity induced by d-amphetamine week 3 and that induced by 0.9% NaCl week 2 in each animal and group. Statistics were determined by two-factor repeated measures ANOVA: group effect, P = 0.0407; time effect, P < 0.0001; and interaction term, P = 0.0018.

View larger version (23K): [in this window] [in a new window]   Figure 3. Locomotor activity in bGH transgenic mice (n = 10) and nontransgenic control mice (n = 23) at their fourth encounter with the locomotor activity boxes. Left panel, All animals received 2.5 g/kg ethanol, ip, 5 min before placement in the boxes. Statistics were determined by two-factor repeated measures ANOVA: group effect, P = 0.0632; time effect, P < 0.0001; and interaction term, P = 0.1096. Right panel, The calculated difference between the locomotor activity induced by ethanol week 4 and that induced by 0.9% NaCl week 2 in each animal and group. Statistics were determined by two-factor repeated measures ANOVA: group effect, P = 0.1596; time effect, P = 0.0125; and interaction term, P = 0.4460.

View larger version (32K): [in this window] [in a new window]   Figure 4. Tissue levels of monoamines and monoamine metabolites, and quotients between metabolites and monoamines, in bGH transgenic mice and nontransgenic control mice in seven different brain regions. Data are expressed as a percentage of the control value. Shown are the mean ± SEM of n observations. Statistics were determined by Student’s t test: *, P < 0.05; **, P < 0.01; and ***, P < 0.001.

Tissue levels of 5-HT were significantly higher in the bGH transgenic mice in four of the seven brain regions investigated, i.e. in the cortex, striatum, mesencephalon, and brain stem (Fig. 4). Levels of the major 5-HT metabolite, 5-HIAA, were also elevated in transgenic mice compared with controls in the cortex, striatum, and mesencephalon. The 5-HIAA/5-HT quotient, a measure of 5-HT turnover, was not statistically significantly altered in any of the brain regions examined.

	Discussion

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The present study demonstrates that transgenic mice with elevated GH levels differ from nontransgenic control mice in DA-related behaviors and brain monoamine neurochemistry. GH transgenic mice were clearly hyperactive compared with controls when first exposed to the test apparatus. In addition, in bGH transgenics the locomotor score decreased by approximately 50% between the first and the last 5-min period recorded compared with an approximately 90% reduction in controls. On this first test occasion, transgenic mice thus appeared to habituate to the test apparatus slower than controls. On the second test occasion, after pretreatment with 0.9% NaCl, locomotor activity did not differ between the two groups. Thus, bGH transgenics were initially hyperactive compared with controls and displayed a slower habituation to the experimental cages. This indicates that bGH transgenics are hyperreactive to novelty (first test) compared with controls.

When exposed to the activity boxes after d-amphetamine challenge, GH transgenic mice were again significantly more active than controls. Indeed, compared with the locomotor activity observed after saline pretreatment, the bGH animals were clearly stimulated by this low dose of d-amphetamine, whereas the controls were not. The animals with elevated GH levels also showed a tendency for being more stimulated by ethanol than the nontransgenic controls, although this difference did not reach statistical significance (P = 0.0632).

Both exploratory locomotor activity and amphetamine- and ethanol-induced locomotor stimulation involve brain catecholamine systems (24, 25, 29). The above findings in bGH transgenic mice, therefore, indicate that brain DA and/or noradrenaline systems are hyperactive and/or hyperreactive in these animals. Interestingly, drugs of abuse, including amphetamine and ethanol, share the ability not only to activate the mesocorticolimbic DA system, and thereby stimulate locomotor activity in low doses, but also to sensitize the system upon repeated treatment (30, 31). Thus, protein synthesis-dependent alterations result in hyperreactivity of the mesolimbic DA neurons and postsynaptic DA receptor hypersensitivity after chronic, intermittent drug exposure (31, 32). Both of these processes probably contribute to the ensuing enhanced locomotor stimulatory action (behavioral sensitization) of drugs of abuse that recently has been advanced as a possible major determinant of drug-seeking behavior (30).

It may be suggested that the presently observed hyperactivity and hyperreactivity to amphetamine as well as the previously reported propensity of bGH transgenics to self-administer ethanol and nicotine (23) are due to a sensitized mesocorticolimbic DA system in bGH transgenic mice. Whether the sensitization would be mediated by GH or by secondary effects related to enhanced GH levels can only be speculated upon. However, it is interesting to note that bGH transgenic mice may have excessive plasma ACTH and corticosterone levels (33) and that corticosteroids are heavily implicated in behavioral sensitization to drugs of abuse (34). Moreover, ACTH and ß-endorphin derive from the same precursor molecule. Thus, also ß-endorphin levels may be enhanced in bGH transgenic mice, which could result in opiate-induced cross-sensitization to amphetamine (30). Furthermore, plasma degradation of GH produces peptide fragments with affinity for µ-opioid receptors (35) that possibly also could sensitize the mesocorticolimbic DA system.

Some neurochemical support for that bGH transgenic mice are altered in brain DA systems was also obtained. Thus, in the brain stem tissue levels of DA were decreased, and in the mesencephalon, where most of the cell bodies of forebrain DA neurons are located, both DOPAC and the DOPAC/DA quotient were lower in bGH mice compared with controls. However, contrary to the findings of decreased HVA levels in cerebrospinal fluid after GH substitutions to GHD adults (11, 36), no changes in brain tissue levels of this metabolite were observed in bGH mice.

How these neurochemical results relate to the behavioral findings is unclear. First, alterations of relevance for locomotor activity would perhaps have been expected in the target areas (mainly the limbic system and the striatum) rather than in the cell body areas. Secondly, decreased tissue levels of DA or DOPAC or of the DOPAC/DA quotient are most often regarded as indications of reduced, rather than enhanced, DA neurotransmission. However, low DA levels could also indicate enhanced use of the neurotransmitter. More importantly, the behavioral alterations in the bGH animals could be due to enhanced DA receptor sensitivity, and in that case, feedback down-regulation of DA synthesis, release, and turnover would indeed be expected (37). To evaluate the functional status of, for example, the mesocorticolimbic DA system in bGH mice compared with controls, future studies will have to apply in vivo microdialysis to estimate basal and drug-induced DA release as well as techniques to study DA receptor subtype responsiveness.

An alteration of brain DA systems could also be of relevance for the enhanced psychic drive and hedonic effects of GH in GHD humans. It is well known that the beneficial effects of antidepressants on anhedonia and other key symptoms of depression develop over several weeks of medication. Recently, it was demonstrated in experimental animals that, in addition to their acute and chronic effects on brain 5-HT and noradrenaline systems, antidepressants may enhance the activity of brain DA systems after chronic treatment (18).

The bGH mice displayed higher levels of both 5-HT and 5-HIAA in several brain regions. This indicates that both the synthesis and the metabolism of 5-HT are enhanced in these animals and/or that bGH mice possess a larger number of 5-HT neurons compared with controls. Both interpretations would indicate that the capacity of brain 5-HT systems is larger in bGH transgenics. Whether brain 5-HT release and net neurotransmission are indeed increased in these animals cannot be determined on the basis of these results. However, such an enhancement would offer an explanation for the antidepressant-like action of GH, as enhanced 5-HT neurotransmission has been linked to antidepressant effects (38). As regards reward-related mechanisms, decreased, rather than increased, 5-HT neurotransmission has been associated with enhanced preference for drugs of abuse in man and experimental animals (22). Hence, a larger capacity of brain 5-HT systems appears to be at variance with the findings of enhanced ethanol and nicotine intake in bGH transgenic mice. In a previous report, acute administration of bGH reduced or increased brain tissue levels of 5-HT and 5-HIAA in normal and hypophysectomized rats, respectively (39). It is unclear how these results relate to the present findings in mice chronically exposed to high bGH levels.

Interestingly, the above-described alterations in brain 5-HT and DA neurochemistry could also be related to the increased corticosterone levels previously observed in bGH transgenic mice. Thus, in mice corticosterone induces a subsensitivity of somatodendritic 5-HT_1A receptors (40, 41). As these autoreceptors normally restrain 5-HT neuronal impulse activity, release, and synthesis (42, 43, 44), increased 5-HT and 5-HIAA levels would be expected in animals with high corticosterone levels. Furthermore, as high, postsynaptic doses of 5-HT_1A agonists decrease ethanol intake as well as ethanol-induced locomotor activity in rodents (45, 46, 47), a subsensitivity of postsynaptic 5-HT_1A receptors could be involved in the enhanced ethanol consumption previously observed in bGH transgenics and in the trend for enhanced ethanol-induced locomotor activity observed here. Corticosterone is also implicated in the expression of DA D1 and D2 receptors (48). As DA D2 receptors are located both post- and presynaptically (autoreceptors), corticosterone-induced up-regulation of these might produce hyperactivity and hyperreactivity to amphetamine (via postsynaptic receptors) as well as lowered DA synthesis and turnover (via presynaptic receptors).

It is not known whether the behavioral and neurochemical differences observed are due to developmental differences occurring during intrauterine life or during the early postnatal period when monoaminergic systems develop or to influences later in life. Indeed, in the brain the highest GH receptor messenger RNA levels have been detected during the early developmental stages, indicating that brain GH is probably involved in brain growth and development (14). Studies are underway investigating whether chronic GH treatment of developmentally normal mice induces alterations similar to those observed in the present study.

In conclusion, bGH transgenic mice display more spontaneous locomotor activity in a novel environment than nontransgenic controls and, probably, a disturbed habituation process. The finding that bGH mice were also more sensitive to d-amphetamine-induced locomotor activity suggests that the behavioral differences observed are related to differences in brain DA systems, indicating a hyperresponsiveness of these systems in bGH transgenic mice. Neurochemical indications of an enhanced capacity of brain 5-HT systems were also observed. These findings may be of relevance for the propensity of bGH animals to self-administer ethanol and nicotine and, possibly, for the reported beneficial psychic effects of GH in humans.

	Footnotes

 
¹ This work was supported by grants from the Swedish Medical Research Council (no. 11583 and 4247), the Swedish Alcohol Monopoly Foundation for Alcohol Research, the Goteborg Medical Society, the Swedish Society for Medical Research, Orion Pharma Neurology, Organon Stipendium, Magnus Bergvalls Stiftelse, the Lundbecks Fond för Psykofarmakologisk Forskning, O. E. och Edla Johanssons Vetenskapliga Stiftelse, Leons minnesfond, Wilhelm och Martina Lundgrens vetenskapsfond, Åke Wibergs Stiftelse, and Åhlén-stiftelsen.

Received April 22, 1999.

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