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Departments of Physiology (M.B.-Y., B.O., O.B., J.T.), Oral Biochemistry (A.G.-L.), and Pharmacology (B.S.), Göteborg University, Göteborg, Sweden S-40530; Research Centre for Endocrinology and Metabolism (M.B.-Y., B.O., O.B., O.G.P.I., C.O., J.T.), Sahlgrenska Hospital, Göteborg, Sweden S-41345; and AstraZeneca Transgenic Centre (J.T.), AstraZeneca Research and Development, Mölndal, Sweden S-43183
Address all correspondence and requests for reprints to: Jan Törnell, AstraZeneca Transgenic Centre, AstraZeneca R&D, S-43183 Mölndal, Sweden. E-mail: jan.tornell{at}astrazeneca.com
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Transgenic mice, generally overexpressing bovine GH (bGH) under control of the metallothionein promoter (Mt-bGH), display an increased spontaneous activity (4), supporting data from substituted GH-deficient patients. The Mt-bGH transgenic animals also show an increased stimulatory response to amphetamine, suggesting sensitization of the mesocorticolimbic dopamine system, a part of the brain reward system that has been linked to anhedonia/hedonia and psychic drive. In addition, the Mt-bGH transgenic mice show signs of altered dopamine metabolism in mesencephalon, diencephalon, and brain stem, which could be linked to the behavioral effects observed. Alterations of brain serotonin (5-HT) neurochemistry were also noted, and this neurotransmitter has been implicated in the regulation of mood (5) and locomotor activity (6) in humans and mice, respectively. These data indicate that the enhanced locomotor activity of Mt-bGH transgenic mice could provide a useful model to study the mechanisms behind the positive psychic effects of GH.
The psychic effects of GH may be exerted by direct actions of GH in the central nervous system (CNS). Some data suggest that GH passes the blood brain barrier (BBB) from the peripheral circulation (7), and in humans GH receptors (GHRs) are present in the choroid plexus, hippocampus, hypothalamus, and pituitary gland (8). In the rat, GHRs are found in the same areas but also in capsula interna, parietal cortex, tegmentum, mamillary bodies, and the temporal cortex (9). Some of these brain regions have been implicated in emotional responses and psychic drive.
Another possibility is that the psychic effects of GH are mediated via some substance(s) produced in peripheral tissues that secondarily influences CNS. For example, serum levels of corticosteroids are elevated in GH transgenic mice (10), and corticosteroids may influence brain dopamine systems (11, 12) as well as their sensitivity to drugs of abuse (13). It is also well known that corticosteroids can increase the general well-being in humans and even produce hypomania, mania, and psychosis (14). IGF-I is another peripheral hormone with increased serum levels in the Mt-bGH transgenic mice, and this molecule may also pass the BBB. Thus, endothelial cells lining brain microvessels contain IGF receptors that may internalize IGFs, and infused 125I-IGF-I has been reported to rapidly cross the BBB and enter the brain parenchyma (15). Also interestingly, IGF-I may influence the function of brain dopamine neurons (16). Finally, placebo-controlled trials have demonstrated that GH administration stimulates the peripheral conversion of T4 to the biologically more active T3 in both normal and obese adults as well as in GH-deficient adults (17, 18). It is well established that thyroid hormones may influence psychic drive and mood (19).
To discriminate between direct effects of GH in the CNS and its peripheral effects, we designed a transgenic construct to limit the expression of GH to the CNS. The effect of CNS-specific expression of the bGH transgene on spontaneous locomotor activity and serum levels of the above mentioned hormones was studied and compared with that of normal controls and mice with a general overexpression of bGH.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). The GFAP-bGH DNA
fragment was excised by restriction enzyme cleavage using
SfiI, separated by gel electrophoresis through a 1% agarose
gel, cut out, isolated using isotachophoresis (20) and
precipitated by ethanol.
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To identify transgenic animals, DNA was extracted from 0.5-cm tail biopsies from 2-wk-old mice. The tails were digested in lysis buffer (1% SDS, 2 mg/ml proteinase K (Merck KgaA, Darmstadt, Germany), 50 mM Tris, 100 mM EDTA, 100 mM NaCl; final pH 8.0) at 56 C overnight. The DNA from the digested tails was extracted using phenol/chloroform and precipitated by ethanol.
DNA was digested with BamHI (Promega Corp., Madison, WI), separated by electrophoresis, transferred to an N+ Hybond (Amersham, Little Chalfont, Buckinghamshire, UK) nylon membrane by Southern blot (22) and hybridized with a 1.2-kb PvuII fragment digested from the bGH gene.
The environment of the animal rooms was controlled with a 12-h light-dark cycle (0730 h-1730 h, with a 1-h dawn/sunset function), a relative humidity between 45–55% and a temperature of 20 C. The mice had free access to tap water and standard pellet chow (R-34, Lactamin, Vadstena, Sweden). The study was performed after prior approval from the local ethical committee for animal experimentation at the Göteborg University, Göteborg, Sweden. The mice were anesthetized with ketamine hydrochloride (77 mg/kg; Ketalar, Parke-Davis, Detroit, MI) and xylazine (9 mg/kg; Rompun, Bayer Corp., Lever-Kusen, Germany) and killed by heart puncture. The organs used for RNA and protein preparations were excised, immediately frozen in liquid nitrogen, and stored at -135 C.
RNA analysis
Total RNA was isolated from frozen tissues as described by
Chomczynski and Sacchi (23). First-strand cDNA synthesis
was performed at 42 C for 15 min with 1 µg RNA as template in the
presence of 10 mM Tris-HCl; pH 9.0, 50 mM KCl,
0.1% Triton X-100, 5 mM MgCl2, 0.5
µg/µl oligo(dT)15 primer (Promega Corp.), 15 U/µg AMV-RT (Promega Corp.), 1 U/µl
RNAsin (Promega Corp.), and 1 mM of each dNTPs
(Promega Corp.). The reverse transcription reaction was
terminated by heat inactivation at 95 C for 5 min and then incubated at
4 C for 5 min. The second-strand PCR was performed at 94 C for 30 sec
and 30 cycles of sequential incubations at 94 C for 30 sec, 55 C for 30
sec, and 72 C for 2 min using a reaction mixture containing 10 µl of
the first-strand reaction from all tissues except brain, which
contained 2 µl, 10 mM Tris-HCl (pH 8.3), 1.5
mM MgCl2, 50 mM KCl, 0.2
mM of each dNTP, 0.5 U Taq DNA polymerase, and
0.4 µM each of primers ex2 b-GHs
(5'-TCCCTGCTCCTGGCTTTCGC-3') and ex4 b-GHa (5'-GCAGTGAGATGCGAAGCAGC).
The PCR product was analyzed by electrophoresis.
Protein analysis by Western blotting
Tissues were prepared by homogenization in PE
buffer (10 mM potassium phosphate buffer; pH 6.8, and 1
mM EDTA) containing 10 mM
3-([3-cholamidopropyl] dimethyl-ammonio)1-propanesulphonate
(Roche Molecular Biochemicals, Mannheim, Germany),
aprotinin (1 mg/ml; Roche Molecular Biochemicals),
leupeptin (1 mg/ml; Roche Molecular Biochemicals),
pepstatin (1 mg/ml; Roche Molecular Biochemicals), and
pefablock (1 mg/ml; Roche Molecular Biochemicals). The
homogenate was sonicated and centrifuged (10,000 g for 10 min at 4 C)
and protein concentrations measured using a protein assay
(Bio-Rad Laboratories, Inc., Hercules, CA). Thirty-five
micrograms total protein from each sample was mixed with sample buffer
(62.5 mM Tris-HCl, pH 6.8, 2.3% SDS, 1% glycerol, 5%
ß-mercaptoethanol, and 0.001% bromphenol blue) and loaded on
10% NuPAGE Bis-Tris (Novex, San Diego, CA) gels. The
proteins were transferred to a polyvinyldifluoride membrane
(Amersham Pharmacia Biotech) using a
Novex blotting system. The membranes were incubated with
bGH-specific antisera raised in monkey (dilution 1:1000; kindly
provided by Dr. A. F. Parlow, Pituitary Hormones and Antisera
Center, Torrance, CA). Prestained standards (SeeBlue,
Novex) were used as size markers. Immunoreactive protein
was visualized by chemiluminescence using alkaline phosphatase
conjugated secondary goat antimonkey antibodies (dilution 1:30,000)
(Sigma Chemicals Co., St. Louis, MO) and CDP-star
(Tropix, Bedford, MA) as substrate. The membrane was
exposed to ECL film (Amersham Pharmacia Biotech) at room
temperature for 1 min.
Immunohistochemistry and in situ hybridization
Brains from adult GFAP-bGH mice and control littermates were
fixed at 4 C overnight in 4% paraformaldehyde in PBS and processed for
paraffin embedding. The sections (6 µm thick) were rehydrated and
nonspecific staining was preblocked with 5% normal rabbit serum in TBS
(20 mM Tris-HCl, pH 7.6, and 150 mM NaCl)
containing 0.1% Triton X-100. Sections were then incubated overnight
at 4 C with bGH antisera raised in monkey (diluted 1:250 in TBS
containing 0.2% BSA). For detection of immunoreactivity, alkaline
phosphatase-conjugated rabbit antimonkey antibodies were used followed
by incubation with a chromogenic substrate for alkaline phosphatase,
nitroblue tetrazolium salt and 5-bromo-4-chloro-3-indolyl phosphate in
NTMT buffer (100 mM NaCl, 100 mM
Tris-HCl, pH 9.5, 50 mM MgCl2, 0.1%
Tween-20). After color development, brain sections were postfixed in
4% paraformaldehyde in PBS and mounted.
Sections adjacent to the ones processed for immunohistochemistry were used for in situ hybridization to localize bGH mRNA expression. A digoxigenin-labeled bGH antisense riboprobe was generated from a Hind-III-linearized 1.2-kb fragment of a GFAP-bGH subclone construct and in vitro transcribed with T3 RNA polymerase. Hybridization and posthybridization washes were essentially the same as described for whole-mount in situ hybridization (24). The transcripts were visualized with a horseradish peroxidase-conjugated mouse antidigoxigenin antibody (Roche Molecular Biochemicals) together with the Tyramide signal amplification kit (NEN Life Science Products Inc., Boston, MA) according to the manufacturer’s instructions.
Analyses of GH, IGF-I, corticosterone, and thyroid hormone
levels
The concentration of circulating bGH was determined in two lines
by RIA (antisera kindly provided by Dr. A. F. Parlow, Pituitary
Hormones and Antisera Center, Torrance, CA). The assay was carried out
in 200 µl PBS (pH 7.4) containing 0,5% BSA (RIA grade,
Sigma), 1.25 µl mouse serum, anti-bGH antiserum
(1:400,000), and 125I-labeled bGH. The bGH
standard (0.1–50 ng/tube) contained 1.25 µl normal mouse serum.
After overnight incubation (4 C), the bound hormone was precipitated by
adding 1 ml of a mixture of polyethylene glycol (16%, wt/vol, final
concentration), bovine 
-globulin (2 mg/ml; Cohn fraction II and III;
Sigma), and Triton X-100 (0.02% in 0.05 M
Tris-HCL, pH 8,5). The samples were further incubated for 30 min in 4
C, centrifuged, and supernatants were aspirated. The pellets were
counted for -radioactivity.
The IGF-I concentration in serum was determined by RIA (Nicols Institute Diagnostics, San Juan Capistrano, CA) after acid-ethanol extraction, according to the manufacturer’s protocol in a double assay.
Serum corticosterone levels were determined by RIA (ICN Biomedicals, Inc., Diagnostics Division, Costa Mesa, CA) according to the manufacturer’s protocol. All samples were collected between 1020 h and 1145 h.
FT3 and FT4 were measured in serum using the Amerlex-MAB kits as described (25).
Locomotor activity studies
Locomotor activity was measured using activity meters (Digiscan
animal activity monitor, model AZYCCM Tao, Omnitech Electronics, Columbus, OH) that were placed in eight identical
sound- and light-attenuating boxes containing a weak light and fan. The
activity meter was equipped with three rows of infrared photosensors,
each row consisting of 16 sensors placed 2.5 cm apart. Two rows were
placed in a 90-degree angle along the front and side of the floor of
the cage, and the third row was placed 10 cm above the floor to measure
vertical activity. The activity meters were connected to an analyzer
system (Omnitech Electronics), and the data were collected
using LabVIEW (National Instruments, Austin, TX) computer
software.
Six-month-old GFAP-bGH, Mt-bGH transgenic mice and control littermates were placed in transparent plastic boxes and put into the activity meters. Locomotor activity was recorded for 60 min. All experiments were performed between 0900 h and 1600 h in a randomized (regarding the individual mouse) but balanced order, with respect to groups, boxes, and time of day.
Three types of experiments were performed: one with Mt-bGH mice and their littermate controls, a second with one line of the GFAP-bGH mice and their littermate controls, and a third with another line of the GFAP-bGH mice and littermate controls. The activity of littermate controls, in absolute terms, differed slightly among the three experiments, whereas the overall pattern of activity (i.e. an initial high activity followed by a gradual decline) was identical in all experiments. To facilitate comparisons among the three experiments, the cumulated locomotor activity at each time point is expressed in percent of the locomotor activity displayed by the controls during the first 5 min. The pattern of activity was judged on the basis of the habituation of the animals to the new environment. The pattern in control animals is that an initial high activity if followed by a decrease.
Statistics
The locomotor activity data were statistically evaluated using a
two-factor ANOVA for repeated measures; all other comparisons among
groups were made by unpaired t test. Values presented as
mean ± SEM P < 0.05 was
considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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mRNA analysis by RT-PCR
RNA was isolated from 10 different organs and RT-PCR was used to
examine expression of bGH. Specific mRNA for bGH was strongly expressed
in the brain and showed weak expression in lung and kidney in two lines
(data not shown). The third line expressed bGH only in the brain (Fig. 2).
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, A, C, and E). Sections from
littermate control brains showed only staining at background levels
(Fig. 4, B, D, and F).
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, G and I). No signal above background was detected in brain sections
from littermate control mice (Fig. 4, H and J). Astrocyte expression of
the bGH protein and mRNA was found in the gray (protoplasmic
astrocytes) as well as in the white matter (fibrous astrocytes).
Furthermore, although bGH mRNA in astrocytes was confined to the
perinuclear region (Fig. 4, I and K), immunostaining for bGH
protein showed a starlike shape owing to immunoreactivity of the long,
highly branched processes (Fig. 4, L and M).
Hormone levels
Serum bGH levels were significantly increased in GFAP-bGH
transgenic mice from the two analyzed lines. The serum levels of bGH in
line 3 were 334 ± 53 ng/ml (n = 8) and line 2 were 207
± 21 ng/ml (n = 8) (P < 0.05 vs.
littermate controls). This was considerably lower than previously
reported for the Mt-bGH transgenic animals (26).
No difference in serum IGF-I levels was observed in GFAP-bGH transgenic
mice, compared with the littermate controls, whereas Mt-bGH transgenic
mice displayed significantly elevated levels, compared with the
littermate controls (Table 1).
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In GFAP-bGH transgenic mice, the serum levels of
T3 were significantly decreased (28%), but the
serum levels of T4 did not differ from the
littermate controls. In the Mt-bGH, the levels of
T3 were significantly increased (25%), and the
T4 levels were significantly decreased (47%).
The conversion of T3 to T4
in the Mt-bGH transgenic mice were significantly increased (49%)
(Table 1).
Locomotor activity of Mt-bGH and GFAP-bGH transgenic mice
The spontaneous locomotor activity of Mt-bGH transgenic mice
during 60 min was significantly increased, compared with littermate
controls (Fig. 5; two-factor
repeated-measure ANOVA, group effect). F(1,22) = 5.6;
P = 0.0273). There was a decay of locomotor activity
over time in the whole material (time effect: F(11,242) = 14.5;
P < 0.0001), but the pattern of locomotor activity was
different in the two groups, as indicated by a significant interaction
term (F(11,242) = 2.5; P = 0.0053). Thus, whereas
there was a gradual decline over time in the littermate controls,
Mt-bGH transgenic mice maintained approximately the same degree of
locomotor activity during the first 40 min, after which they gradually
became less active but, however, never reached the same low activity
level by 60 min as the littermate controls. Line 2 of GFAP-bGH mice
displayed patterns and degrees of locomotor activity that were almost
identical to those of their littermate controls (Fig. 5; group effect;
F(1,14) = 0.0005; P = 0.9830; time effect;
F(11,154) = 19.3; P = 0.0001; interaction term;
F(11,154) = 0.8; P = 0.6649). Line 3 of GFAP-bGH
mice did not significantly differ from their controls as regards the
amount of locomotor activity displayed during 60 min (group effect;
F(1,14) = 0.5; P = 0.4951; time effect;
F(11,154) = 12.4; P < 0.0001), whereas they
differed as regards their locomotor activity pattern (interaction term;
F(11,154) = 2.7; P = 0.0034). These mice displayed
an almost constant intermediate-low activity level over time.
Altogether, both the amount and patterns of locomotor activity of both
lines of GFAP-GH mice differed clearly from those of Mt-bGH transgenic
mice.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The mice differ in size that could potentially result in altered locomotor activity. However, arguing for an effect unrelated to size is the locomotor activity pattern of the Mt-bGH transgenic mice. If the difference in locomotor activity had been an effect of size, one would have expected a higher initial degree of activity followed by a decline in parallel with that of controls. Neither of these was observed. Furthermore, no correlation between size and locomotor activity score has previously been observed with this method among control mice (weight range 25–45 g) (27).
Three tentative peripheral factors involved in mediating the increased locomotor activity of Mt-bGH transgenic mice were examined in the present study: corticosterone, IGF-I, and thyroid hormones. Studies have indicated that corticosterone may influence both dopamine release (12) and dopamine receptor sensitivity (11). Brain dopaminergic systems are heavily implicated in regulation of locomotor activity (13). Indeed, supporting previous observations (10), serum corticosterone levels were markedly increased in generally overexpressing Mt-bGH transgenic mice. However, a similar increase was observed in GFAP-bGH transgenic mice expressing bGH limited to the CNS, in which no difference in locomotor activity, compared with the littermate controls, was observed. This suggests that the locomotor stimulatory effects of GH are not mediated by corticosteroids but via some other peripheral factor. Furthermore, these findings indicate that the enhanced corticosterone secretion observed in Mt-bGH transgenic mice may be owing to a CNS action of GH, suggesting that central GHR may be involved in the regulation of the hypothalamic-pituitary-adrenal axis.
IGF-I levels were increased in Mt-bGH transgenic mice, but no difference was observed in GFAP-bGH transgenic mice, compared with littermate controls. It has been demonstrated that IGF-I crosses the BBB and supports dopaminergic neurons (16). Moreover, in vivo studies have shown that IGF-I promotes the survival of dopamine and noradrenaline neurons when exposed to neurotoxins (28). It has also been demonstrated that a local infusion of IGF-I may stimulate axonal regeneration, enhance functional recovery, and increase nerve sprouting in association with peripheral nerve injury (29, 30, 31, 32, 33), whereas no effects on composite motor function or in the learning ability of uninjured animals has been observed (34). It is therefore unclear whether IGF-I produces any trophic effects in the uninjured situation, as is the case in the present study. However, IGF-I could alter the locomotor activity through its documented induction of catecholamine synthesizing enzymes (35). IGF-I could be produced in the brain (36) and potentially also as response to the local GH production in our transgenic model. However, we could not detect any statistically significant changes in IGF-I mRNA levels among the brains from GFAP-bGH, Mt-bGH transgenic mice, and littermate controls (data not shown). Furthermore, the weight of the brains of GFAP-bGH transgenic mice were not increased in relation to body weight (data not shown) in contrast to transgenic mice overexpressing IGF-I (37).
Supporting previous findings that GH increases the conversion of T4 into T3 (38), a clear increase in the T3/T4 conversion ratio was observed in the Mt-bGH transgenic animals. In contrast, in GFAP-bGH transgenic mice that did not display locomotor hyperactivity, no alteration in the conversion of T4 to T3 was observed. Thus, the increased locomotor activity seen in the Mt-bGH transgenic mice may, at least in part, be related to an increased conversion of T4 into the more biologically active T3 and an increased signaling through the thyroid hormone system. When T3 is given to mice, the spontaneous activity is increased (39), further supporting the hypothesis that the elevated T3 levels may be important for the increased locomotor activity in the Mt-bGH transgenic mice.
Indeed, both T3 and T4 cross the BBB when peripherally injected, and both acute and chronic T3 administration increases the concentration of serotonin in the rat frontal cortex but not in the hippocampus (40, 41, 42). This T3-induced increase of 5-HT levels is produced either by modifying 5-HT reuptake and turnover rate or by acting on the neurotransmitter metabolism (43, 44). The effects of thyroid hormones on the levels of serotonin metabolites may be species specific because, in the hyperthyroid rat, 5-HIAA levels are decreased (45) but an increase is seen in the hyperthyroid mouse (46). Interestingly, serotonergic agonists markedly enhance behavioral activity in hyperthyroid rats (47), and serotonin has also been suggested to stimulate locomotor activity in mice (6). In the Mt-bGH transgenic mice, enhanced levels of 5-HT and 5-HIAA were previously observed in the striatum, mesencephalon, and cortex. Novelty- and amphetamine-induced hyperactivity were also observed in Mt-bGH transgenic mice (4). In this context it should be recalled that amphetamine releases not only dopamine but also serotonin, and both transmitters appear to contribute to the behavioral activation produced in mice by pharmacological manipulations that raise their synaptic levels (48). Also, more recent studies suggest that amphetamine-induced locomotor stimulation involves activation of postsynaptic 5-HT2A receptors (49, 50). One hypothesis could therefore be that in the Mt-bGH transgenic mice, high circulating levels of GH increase the conversion of T4 to T3 that secondarily enhances the function of the brain serotonin system. This in turn promotes locomotor activity in response to challenges that increase 5-HT release, such as exposure to amphetamine or, possibly, novelty stress.
Also, the thyroid status in humans is of great importance for psychic well-being. Thus, hyperthyroidism and hypothyroidism may be associated with anxiety and depression, respectively (51), and these disorders are related to brain monoamine function (5, 52). T3 supplementation has been shown to have a beneficial effect on depression in several studies. For instance, among patients refractory to tricyclic antidepressant drug therapy, those treated with T3 augmentation were twice as likely to respond as controls (53). Taken together with the present results, it may be suggested that Mt-bGH mice could be a useful model for studying mechanisms underlying the interaction between thyroid hormones and monoaminergic systems. This could be of value not only for understanding the positive psychic effects of GH but also for optimization of treatment of affective disorders.
In conclusion, the present results indicate that the enhanced spontaneous locomotor activity in Mt-bGH mice is not primarily owing to activation of GHR in the CNS but involves some peripheral factor(s). Furthermore, the data suggest that especially T3 but also IGF-I are two major candidates in this context. However, a firm determination of whether either or both of these are involved requires further experimentation. It should also be pointed out that the present data do not rule out an involvement of direct GHR-mediated effects, other than on spontaneous locomotor activity, in the CNS.
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Acknowledgments |
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Footnotes |
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Abbreviations: BBB, Blood brain barrier; bGH, bovine GH; CNS, central nervous system; GFAP, glial fibrillary acidic protein; GHR, GH receptor; 5-HT, brain serotonin; Mt-bGH, overexpression of bGH under control of the metallothionein promoter.
Received March 28, 2001.
Accepted for publication June 27, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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1. EMBO J 17:455–461[CrossRef][Medline]
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