Increase In Plasma Growth Hormone Levels Research Articles

Deficiency of leap2 promotes somatic growth in zebrafish: Involvement of the growth hormone system

PurposeLiver-expressed antimicrobial peptide-2 (LEAP2) is identified as an endogenous antagonist and inverse agonist of the growth hormone secretagogue receptor type 1a (GHSR1a), its effect on the GHSR1a is contrary to the role of GHRELIN. Growth hormone (GH) is a crucial hormone for early development. Previous studies report that LEAP2 dose-dependently attenuates ghrelin-induced GH secretion, and Leap2-knockout mice exhibit increased plasma GH levels after GHRELIN administration. Clinical data revealed a possible correlation between LEAP2 and height development. However, the role of LEAP2 in early development remains unclear. This study aimed to investigate the role of LEAP2 in early development using leap2 mutant zebrafish larvae as a model. MethodWe analyzed the conservation of LEAP2 peptide across multiple species and generated leap2 mutants in zebrafish by CRISPR-Cas9, dynamically observed and measured the growth and development of zebrafish larvae from fertilization to 5 day post fertilization (dpf). In situ hybridization, transcriptome sequencing, quantitative real-time PCR and Western blot were used to detect the expression levels of GH and its signaling in early stage of embryonic development. ResultOur data demonstrate that zebrafish with a knockout of the leap2 gene display a significant increase in hatching rate, body length, and the distance between their eyes, all without visible developmental defects in the early stages of development. In addition, both RNA and protein analyses revealed a significant increase in GH expression in leap2 mutant. ConclusionIn general, this study demonstrates that LEAP2 regulates the expression of GH during early development, particularly influencing body length.

Temporal patterns of increased growth hormone secretion in mice after oral administration of L-ornithine: possible involvement of ghrelin receptors.

l-Ornithine is known to stimulate growth hormone (GH) release in mammals. Here, we demonstrated that increases in plasma GH levels after oral administration of l-ornithine were first observed 150 min after administration, and the elevated levels were sustained for more than 90 min in mice. The increase was significantly delayed compared with the reported timing of plasma and tissue levels of l-ornithine after administration. The l-ornithine-induced increase in GH release was completely blocked by [D-Lys3]-GHRP-6, a ghrelin receptor antagonist, but not by cyclosomatostatin or JV-1-38, antagonists of somatostatin and GH-releasing hormone, respectively. These results suggest the involvement of ghrelin receptor-mediated pathways in l-ornithine-induced increases in GH release.

Effects of long-term cortisol treatment on growth and osmoregulation of Atlantic salmon and brook trout

Cortisol is the final product of the hypothalamic-pituitary-interrenal (HPI) axis and acts as a gluco- and mineralo-corticoid in fish. Long-term elevations of cortisol have been linked to reduced growth in fishes, but the mechanism(s) and relative sensitivities of species are still unclear. We carried out experiments to examine the relative effects of cortisol on growth and gill NKA activity in two salmonids: Atlantic salmon (Salmo salar) and brook trout (Salvelinus fontinalis). Treatment with intraperitoneal cortisol implants for 30 days resulted in reduced growth in both species, but with greater sensitivity to cortisol in brook trout. Gill NKA activity was strongly upregulated by cortisol in Atlantic salmon, and weakly upregulated in brook trout but with no statistically significant effect. Cortisol treatment resulted in reduced plasma levels of insulin-like growth factor I and increased plasma growth hormone levels in Atlantic salmon. Our results demonstrate that there are species differences in the sensitivity of growth and osmoregulation to cortisol, even among species in the same family (Salmonidae).

Pharmacological profile and clinical efficacy of anamorelin HCl (ADLUMIZ<sup>®</sup>Tablets), the first orally available drug for cancer cachexia with ghrelin-like action in Japan

Anamorelin hydrochloride (hereinafter referred to as anamorelin) is an orally active, small-molecule drug with a similar pharmacological action to ghrelin, an endogenous ligand of growth hormone secretagogue receptor type 1a (GHS-R1a). It was first approved in Japan for the treatment of cancer cachexia, characterized by weight loss and anorexia. Anamorelin stimulated the secretion of growth hormone (GH) from cultured rat pituitary cells and increased plasma GH levels by oral administration to rats, pigs and humans. When anamorelin was orally administered once daily for 6 days to rats, larger body weight gain associated with increased food consumption compared to the control group was observed from after the first dose. Anamorelin is a selective agonist for GHS-R1a and enhanced GHS-R1a-mediated pituitary GH secretion and increased food consumption, resulting in body weight gain. In the two Japanese phase II studies in patients with cancer cachexia associated with non-small cell lung cancer (NSCLC), improvement of lean body mass (LBM) and body weight losses and anorexia were demonstrated. The tumor types of target patients in the Japanese phase III study were colorectal, gastric, and pancreatic cancer. As a result, maintenance and increase of LBM and body weight as well as improvement of anorexia were observed, and the efficacy against cancer cachexia associated with colorectal, gastric, and pancreatic cancer was confirmed. There were no observed events considered to be significant safety risks. In conclusion, anamorelin is expected to provide a new therapeutic option for cancer cachexia for which no effective treatment has been available.

Using Baclofen to Explore GABA-B Receptor Function in Alcohol Dependence: Insights From Pharmacokinetic and Pharmacodynamic Measures.

Background: The role of GABA-B neurotransmission in addiction has recently received increased attention, with clinical trials indicating that baclofen, a GABA-B receptor agonist, may reduce alcohol consumption, craving and promote abstinence. However, the optimal dose to treat alcohol dependence is unclear with patients requesting and tolerating much higher doses of baclofen, compared with other clinical uses. We assessed the pharmacokinetics and pharmacodynamics (PK/PD) of baclofen to provide insight into GABA-B sensitivity in this patient group, relative to controls.Methods: Male healthy volunteers (controls, n = 12) and abstinent alcohol dependent individuals (AD, n = 8) received single oral doses of baclofen or placebo in a 3-way crossover design. Controls received placebo/10 mg/60 mg baclofen in a randomized, double-blind design, AD received placebo/60 mg/90 mg baclofen in a single-blind design. PK/PD measures were recorded at baseline and multiple time-points up to 6 h post-dosing, including plasma baclofen, plasma growth hormone (GH), Subjective High Assessment Scale (SHAS) and biphasic alcohol effects scale (BAES). Repeated measures ANOVA analysis explored “change from baseline” dose, time, group, and interaction effects, t-tests compared peak effects.Results: Dose-dependent effects of baclofen on PK and PD measures were observed in both control and AD groups. Whilst there were no significant group differences in any baclofen PK parameters (t1/2, tmax, Cmax, AUC), marked differences in PD effects were clearly evident. In controls, 60 mg baclofen significantly increased total SHAS and BAES scores, and significantly increased plasma GH levels compared with placebo, with peak effects at 60–120 min, in line with its PK profile. In AD, 60 mg baclofen had limited effects on these parameters; SHAS scores, BAES scores and plasma GH levels were significantly blunted compared with controls (significant group*time interactions P = 0.0014, 0.0015 and P < 0.0001, respectively).Conclusions: Our study shows blunted sensitivity to baclofen in AD relative to controls, with no difference in PK suggesting a lower GABA-B receptor sensitivity. This may explain why higher baclofen doses are requested and tolerated in the treatment of alcohol dependence. Our data has implications for choice of dose in future clinical trials in AD and possibly other substances of dependence.

Development and initial characterization of a novel ghrelin receptor CRISPR/Cas9 knockout wistar rat model.

Background/objectivesGhrelin, a stomach-derived hormone implicated in numerous behaviors including feeding, reward, stress, and addictive behaviors, acts through binding to the growth hormone secretagogue receptor (GHSR). Here, we present the development, verification and initial characterization of a novel GHSR knockout (KO) Wistar rat model created with CRISPR genome editing.MethodsUsing CRISPR/Cas9, we developed a GHSR knockout (KO) in a Wistar background. Loss of GHSR mRNA expression was histologically verified using RNAscope in wild-type WT (n = 2) and KO (n = 2) rats. We tested the effects of intraperitoneal acyl-ghrelin administration on food consumption and plasma growth hormone (GH) concentrations in WT (n = 8) and KO (n = 8) rats. We also analyzed locomotion, food consumption, and body fat composition in these animals. Body weight was monitored from early development to adulthood.ResultsThe RNAscope analysis revealed an abundance of GHSR mRNA expression in the hypothalamus, midbrain, and hippocampus in WTs, and no observed probe binding in KOs. Ghrelin administration increased plasma GH levels (p = 0.0067) and food consumption (p = 0.0448) in WT rats but not KOs. KO rats consumed less food overall at basal conditions and weighed significantly less compared with WTs throughout development (p = 0.0001). Compared with WTs, KOs presented higher concentrations of brown adipose tissue (BAT) (p = 0.0322).ConclusionsWe have verified GHSR deletion in our KO model using histological, physiological, neuroendocrinological and behavioral measures. Our findings indicate that GHSR deletion in rats is not only associated with a lack of response to ghrelin, but also associated with decreases in daily food consumption and body growth, and increases in BAT. This GHSR KO Wistar rat model provides a novel tool for studying the role of the ghrelin system in obesity and in a wide range of medical and neuropsychiatric disorders.

Effect of fish vitellogenin on the growth of juvenile catfish, Clarias gariepinus (Burchell, 1822)

The effect of heterologous fish vitellogenin (Vg)- implantation on growth performance in the juveniles of the catfish, Clarias gariepinus, was evaluated under ambient photoperiod and temperature during February–April (experiment 1) and again at May–August (experiment 2). Compared to either unimplanted (control) or bovine serum albumin (BSA)-implanted group, juveniles (average body weight: 3.5–4g) implanted (im) with Vg pellets (each containing 100μg of Clarias batrachus Vg, three per fish, at one month interval), revealed significantly (P<0.05) higher specific growth rate (SGR) at 90days during both time frames. Congruent with accelerated somatic growth due to Vg-implantation, a trend of increase in plasma level of growth hormone (GH), estradiol-17β (E2) and testosterone (T) was recorded during expt. 1. While plasma E2 and T did not vary significantly, Vg-implantation promoted significant (P<0.05) increase in plasma GH level in both the sexes during the course of expt. 2. Moreover, Vg-implantation could trigger significant alteration in gonadal growth; while control testis contained primarily spermatogonia (SG) and spermatocytes (SC), appearance of spermatozoa (SZ) was noticed in either Vg-implanted (expt. 1) or both BSA- and Vg-treated juveniles (expt. 2). Conversely, a robust increase in S III yolky oocytes was observed in Vg-implanted ovary during May–Aug; but not during expt. 1 (Feb–Apr). However, oocytes at earlier stages (S I and/or S II) of follicular growth and development were predominant in control ovary. Though the underlying mechanism is not yet clearly understood, present data indicate that implantation of Vg pellets in juvenile C. gariepinus may influence somatic growth indices; e.g., body weight gain and GH synthesis along with precocious gonadal growth in a manner sensitive to gonadal steroidogenesis.

Endocrine effects of growth hormone overexpression in transgenic coho salmon

Non-transgenic (wild-type) coho salmon ( Oncorhynchus kisutch), growth hormone (GH) transgenic salmon (with highly elevated growth rates), and GH transgenic salmon pair fed a non-transgenic ration level (and thus growing at the non-transgenic rate) were examined for plasma hormone concentrations, and liver, muscle, hypothalamus, telencephalon, and pituitary mRNA levels. GH transgenic salmon exhibited increased plasma GH levels, and enhanced liver, muscle and hypothalamic GH mRNA levels. Insulin-like growth factor-I (IGF-I) in plasma, and growth hormone receptor (GHR) and IGF-I mRNA levels in liver and muscle, were higher in fully fed transgenic than non-transgenic fish. GHR mRNA levels in transgenic fish were unaffected by ration-restriction, whereas plasma GH was increased and plasma IGF-I and liver IGF-I mRNA were decreased to wild-type levels. These data reveal that strong nutritional modulation of IGF-I production remains even in the presence of constitutive ectopic GH expression in these transgenic fish. Liver GHR membrane protein levels were not different from controls, whereas, in muscle, GHR levels were elevated approximately 5-fold in transgenic fish. Paracrine stimulation of IGF-I by ectopic GH production in non-pituitary tissues is suggested by increased basal cartilage sulphation observed in the transgenic salmon. Levels of mRNA for growth hormone-releasing hormone (GHRH) and cholecystokinin (CCK) did not differ between groups. Despite its role in appetite stimulation, neuropeptide Y (NPY) mRNA was not found to be elevated in transgenic groups.

Ghrelin Stimulates Growth Hormone Secretion and Food Intake in Aged Animals

Age-related decreases in energy expenditure have been associated with the loss of skeletal muscle and decline of food intake, possibly through a mechanism involving changes of growth hormone (GH) secretion and feeding behavior. Age-related declines of growth hormone secretion and food intake have been termed the somatopause and anorexia of ageing, respectively. Ghrelin, a 28-amino-acid peptide, was isolated from human and rat stomachs as an endogenous ligand of growth hormone secretagogue receptor. Ghrelin stimulates growth hormone release and food intake when peripherally administered to rodents and humans. PURPOSE: We investigate the relationship between age-related decline of growth hormone secretion and/or food intake and ghrelin function. METHODS: Male Long-Evans rats (4-week-old) were used. All rats were housed individually in plastic cages at constant room temperature and were given standard laboratory chow and water ad libitum. Experiments were conducted on rats at 3, 12, 24, and 27 months of age. Ghrelin (10 nmol/kg body weight) was administered intravenously to rats, after which GH concentrations and 2-hour food intake were measured. The plasma concentration of GH was determined with a Rat GH RIA kit. RESULTS: Body weight increased gradually in rats from 3- to 24-month of age. The body weight in 27-month-old rats was significantly decreased compared to 24-month-old rats. Food intake for 24 hours did not change from 3- to 24-month-old rats, while 24-hour food intake in 27-month-old rats was significantly decreased compared to 24-month-old rats. An intravenous administration of ghrelin to rats increased food intake in all generations. The amounts of ghrelin-induced food intake in 27-month-old rats were significantly decreased compared to the other generations. However, the ratio of ghrelin-induced food intake to 4-hr food intake was the same among the generations. In addition to orexigenic effect by ghrelin, intravenous administration of ghrelin elicited a marked increase in plasma GH levels, with the peak occurring 15 min after administration. CONCLUSIONS: Ghrelin replacement may improve physical abilities to stimulate GH secretion and feeding in aged animals. The present study will provide novel insights into the physiological function of ghrelin in ageing process.

Effects of Homologous Ghrelins on the Growth Hormone/Insulin-like Growth Factor-I Axis in the Tilapia, Oreochromis mossambicus

Ghrelin is a gut-brain peptide synthesized mainly in the oxyntic mucosal cells of the stomach, and has potent growth hormone (GH)-releasing and orexigenic activities. Recently, two forms of ghrelin, ghrelin-C8 and -C10, were identified in the Mozambique tilapia (Oreochromis mossambicus). The present study describes in vitro and in vivo effects of these endogenous ghrelins on the GH/insulin-like growth factor-I (IGF-I) axis. Ghrelin-C8 (100 nM) stimulated GH release from primary cultures of pituitary cells after 4 and 8 h of incubation, whereas no effect was seen on prolactin (PRL) release. Stimulatory effects of ghrelin-C8 and -C10 (100 nM) on GH release during 6 h of incubation were blocked by pre-incubation with GHS receptor antagonist, [D-Lys(3)]-GHRP-6 (10 microM). Intraperitoneal injection of ghrelin-C8 (1 ng/g body weight) and -C10 (0.1 and 1 ng/g body weight) significantly increased plasma GH levels after 5 h. Significant increases were observed also in hepatic expression of IGF-I and GH receptor (GHR) mRNA following injections of both forms of ghrelin (0.1 and 1 ng/g body weight), although there was no effect on plasma levels of IGF-I. In the next experiment, both forms of ghrelin (1 ng/g body weight) significantly increased plasma IGF-I levels 10 h after the injection. No significant effect of either ghrelin was observed on plasma PRL levels. Both forms of GHS receptor (GHSR-1a and -1b) were found in the pituitary, clearly indicating that tilapia ghrelins stimulate primarily GH release through the GHS receptor. Stimulation of hepatic expression of IGF-I and GHR suggests metabolic roles of ghrelin in tilapia.

Developmental stage of Atlantic salmon parr regulates pituitary GH secretion and parr–smolt transformation

Atlantic salmon respond to increased photoperiod by elevation of plasma growth hormone (GH) levels during the period leading up to parr–smolt transformation, both under natural and farming conditions. The aim of the present study was to elucidate the ontogeny of this response, by exposing juvenile Atlantic salmon to increased daylength at different stages of development. Salmon fry were reared on 12 h light:12 h dark from first feeding and thereafter exposed to continuous light from a mean fork length of 5 cm (LL5) or 8 cm (LL8). Plasma GH increased in smolting individuals in the LL8 group, whereas in the LL5 group as well as in parr of the LL8 group, plasma GH levels remained low. Growth rate in length increased significantly in both groups in response to increase in daylength. Plasma IGF-I varied to a lesser degree, although in late July, the LL5 IGF-I levels exceeded those of the LL8 IGF-I levels. In the LL8 group, 33% of the fish smoltified 6 weeks after onset of continuous light, whereas all the fish in the LL5 group failed to smolt. At termination of the experiment, the incidence of precocious maturing males in the LL5 and LL8 group were 38% and 62%, respectively. In conclusion, based on the lack of a GH response in fish smaller than 8 cm, it is hypothesized that the development of a functional light-pituitary axis leading to an increase in plasma GH levels, sets the threshold developmental stage for successful parr–smolt transformation of Atlantic salmon.

Ghrelin stimulates growth hormone secretion and food intake in aged rats

Age-related decreases in energy expenditure have been associated with the loss of skeletal muscle and decline of food intake, possibly through a mechanism involving changes of growth hormone (GH) secretion and feeding behavior. Age-related declines of growth hormone secretion and food intake have been termed the somatopause and anorexia of ageing, respectively. Ghrelin, a 28-amino-acid peptide, was isolated from human and rat stomachs as an endogenous ligand of growth hormone secretagogue receptor. Ghrelin stimulates growth hormone release and food intake when peripherally administered to rodents and humans. Here, we investigate the relationship between age-related decline of growth hormone secretion and/or food intake and ghrelin function. Ghrelin (10 nmol/kg body weight) was administered intravenously to male 3-, 12-, 24-and 27-month-old Long-Evans rats, after which growth hormone concentrations and 2 h food intake were measured. An intravenous administration of ghrelin to rats increased food intake in all generations. In addition, to orexigenic effect by ghrelin, intravenous administration of ghrelin elicited a marked increase in plasma GH levels, with the peak occurring 15 min after administration. These findings suggest that the aged rats maintain the reactivity to administered exogenous ghrelin.

Purification and characterization of feline ghrelin and its possible role

Ghrelin, a novel 28-amino acid peptide with an n-octanoyl modification at Ser 3, has been isolated from rat and human stomach as an endogenous ligand for the growth hormone secretagogue receptor. Here, we purified feline ghrelin and examined its possible physiological role in cats. The major active form of feline ghrelin is a 28-amino acid peptide octanoylated (C8:0) at Ser 3; except for one amino acid residue replacement, this structure is identical to those of rat and human ghrelins. However, much structural divergence in peptide length and fatty acid modification was observed in feline ghrelin: peptides consisting of 27 or 26 amino acids lacking Gln 14 and/or Arg 28 were found, and the third serine residue was modified by octanoic acid (C8:0), decanoic acid (10:0), or unsaturated fatty acids (C8:1, C10:1 and C10:2). In agreement with the structural divergence, two kinds of cDNA with different lengths were isolated. Administration of synthetic rat ghrelin increased plasma growth hormone levels in cats, with a potency similar to that in rat or human. Plasma levels of ghrelin in cats increased approximately 2.5-fold after fasting. The present study indicates the existence of structural divergence in feline ghrelin and suggests that, as in other animals, ghrelin may play important roles in GH release and feeding in cats.

Different effects of physiologically and pharmacologically increased growth hormone levels on cholecalciferol metabolism at prepubertal age

The aim of the study was to investigate the influence of physiologically and pharmacologically increased plasma growth hormone (GH) levels on cholecalciferol metabolism at prepubertal age. Three groups of dogs raised on the same diet were studied from weaning till 21 weeks of age, i.e., small breed dogs ( n=7, control group); large breed dogs with 15-fold greater growth rates compared to the control group ( n=8, LB-group); and small breed dogs treated with pharmacological doses of growth hormone ( n=6, GH-group; 0.5 IU GH per kg body per day) from 12 to 21 weeks of age. Excess of GH had the expected anabolic effect on growth rate and phosphate sparing. Increased plasma GH levels in the LB- and GH-groups versus the control group were accompanied by (1) greater plasma insulin-like growth factor I (IGF-I) levels, (2) greater plasma 1,25-dihydroxycholecalciferol (1,25(OH) 2D 3) levels, and (3) lower plasma 24,25(OH) 2D 3 levels. In the LB-group, excess of GH favored plasma 1,25(OH) 2D 3 levels by decreasing the clearance of 1,25(OH) 2D 3, whereas in the GH-group by increasing the production of 1,25(OH) 2D 3. The lowered plasma 24,25(OH) 2D 3 levels in the LB- and GH-groups were likely attributed to a competitive inhibition of the production of 24,25(OH) 2D 3 by GH and/or IGF-I.

Effect of chronic treatments with ghrelin on milk secretion in lactating rats

Ghrelin, a novel acylated peptide and endogenous ligand for growth hormone (GH) secretagogue receptor, was originally isolated from rat and human stomachs. In addition to its GH-releasing activity, ghrelin plays an important role in many physiological functions, including food intake, gastric acid secretion, neonatal development, and so on. In this study, the effect of daily treatment with ghrelin on milk production was investigated in lactating rats and the development of the pups was monitored. Daily subcutaneous injection of ghrelin into nursing dams for 8 days from parturition caused a significant increase in milk yield and litter weight gain. When litters nursed by ghrelin-treated and saline-treated dams were interchanged on day 4 of lactation, the growth curves were reversed. Daily injections of ghrelin also increased plasma GH levels. Northern blot analysis revealed that daily injection of ghrelin significantly increased mammary casein mRNA expression. In addition, RT-PCR analysis showed that a ghrelin receptor was present in the mammary glands of lactating rats. These results suggest that ghrelin may play an important role in milk production in lactating dams.

Role of Ghrelin in the Control of Growth Hormone Secretion in Prepubertal Rats: Interactions with Excitatory Amino Acids

Ghrelin is a 28-amino-acid peptide, with an essential n-octanoyl modification at Ser3, that elicits growth-hormone (GH) secretion in rats and humans. At present, the mechanisms of ghrelin action and its interactions with other systems controlling GH secretion remain poorly characterized. In this context, the present study was undertaken to obtain information about ontogeny and possible gender differences in the GH-releasing activity of ghrelin, and to delineate its primary site(s) of action at the hypothalamus and/or pituitary. In addition, the interactions between ghrelin and other relevant signals in the control of GH secretion, such as excitatory amino acids (EAAs), nitric oxide (NO) and serotonin, were assessed. Experiments were carried out in infantile-prepubertal animals, when GH pulsatility is not yet established. Systemic administration of ghrelin (25 nmol/rat, i.p.) to 5-, 10- and 23-day-old male and female rats increased plasma GH levels from day 10 onwards. This action was NO dependent, since it disappeared in 23-day-old males after pretreatment with an inhibitor of NO synthase (NAME). Similarly, central infusion of ghrelin (3 nmol/rat, i.c.v.) elicited GH responses in 10- and 23-day-old animals significantly higher than after systemic administration. By contrast, in vitro challenge of pituitary tissue with increasing doses of ghrelin (10^–9–10^–7M) failed to enhance GH release into the incubation medium, whereas stimulation with GH-releasing hormone (GHRH; 10^–7M) or GHRP-6 (10^–7M) was effective. Finally, effects of ghrelin were blocked by pretreatment with MK-801 and NBQX antagonists of EAA ionotropic receptors and after manipulation of endogenous serotoninergic tone. In addition, the potent releasing activity of EAA agonists NMDA and AMPA was blunted by pretreatment with D-Lys3-GHRP-6, a selective antagonist of the cognate ghrelin receptor, i.e. the GH-secretagogue receptor. In conclusion, our results demonstrate that GH-releasing activity of ghrelin appears early in the infantile period, is NO dependent and involves a primary hypothalamic site of action. The data also demonstrate for the first time the existence of a cross-talk between ghrelin and other neurotransmitter systems, such as EAAs and serotonin, in precise control of GH secretion.

Neuroendocrine and behavioral responses to dopaminergic agonists in adolescents with alcohol abuse.

Dopaminergic systems are involved in the pathophysiology of alcohol use disorders, but there is little research investigating the role of these systems in adolescents. In this study, we investigated dopaminergic systems in adolescents with alcohol abuse by determining neuroendocrine and behavioral responses to dopaminergic drug challenges. Twenty-six participants (11 with DSM IV alcohol abuse and 15 controls) were enrolled in the study. Neuroendocrine and behavioral response to the dopaminergic indirect agonist methylphenidate (10 mg) and the direct agonist pergolide (50 mcg), were examined. The primary response measures were spontaneous eye-blink rate, plasma prolactin (PRL), and growth hormone (GH). Additionally, participants completed a visual analog mood scale (VAMS). The rate of increase in plasma GH level was blunted for adolescents with alcohol abuse compared to the control group, after methylphenidate administration [ t=-2.75, P=0.0066, 95% confidence interval (CI) -0.3, -0.048]. The rate of decrease in PRL level after pergolide administration was greater in adolescents with alcohol abuse as compared to the control group ( t=-3.05, P=0.0028, 95% CI -0.01923, -0.00409). Adolescents with alcohol abuse rated themselves as less "energized" in comparison to the control group after methylphenidate (rate difference=-0.4, P=0.0231). This preliminary study suggests that adolescents with alcohol abuse may have a differential response to dopaminergic agonists, as also reported for adults with alcohol use disorders. Further studies investigating gender differences, and other neurotransmitter systems are needed to understand the differential dopaminergic response in adolescents with alcohol use disorders.

Enhanced survival and mucosal repair after dextran sodium sulfate-induced colitis in transgenic mice that overexpress growth hormone.

Growth hormone (GH) is used as therapy for inflammatory bowel disease (IBD), but the specific effects on intestine are unknown. Transgenic mice overexpressing GH (MT1-bGH-TG) were used to test whether increased plasma GH levels alter inflammation or crypt damage during dextran sodium sulfate (DSS)-induced colitis. MT1-bGH-TG and wild-type (WT) littermates were given 3% DSS for 5 days followed by up to 10 days of recovery. Colitis and epithelial cell proliferation were evaluated histologically. Plasma insulin-like growth factor (IGF)-I and colonic IGF-I, interleukin (IL)-1beta, and intestinal trefoil factor (ITF) messenger RNAs (mRNAs) were measured. DSS induced similar disease onset in MT1-bGH-TG and WT. More MT1-bGH-TG survived than WT. By recovery day 7, MT1-bGH-TG had less inflammation and crypt damage, elevated plasma IGF-I, and increased colonic ITF expression relative to WT. Colonic IL-1beta was elevated in DSS-treated MT1-bGH-TG and WT, but IL-1beta mRNA abundance correlated with disease only in WT. MT1-bGH-TG showed earlier increases in epithelial cell proliferation than WT during recovery but only WT showed atypical repair. GH does not alter susceptibility to acute DSS-induced colitis but enhances survival, remission of inflammation, and mucosal repair during recovery. GH therapy may be beneficial during active IBD by improving mucosal repair.

Growth Hormone Secretion after Baclofen Administration in Different Phases of the Menstrual Cycle in Healthy Women

Aim: The aim of this study was to investigate the effect of baclofen administration on growth hormone (GH) secretion during different phases of the menstrual cycle. Methods: Twelve healthy women (33.6 ± (SD) 2.8 years; range 23–40 years) with regular menstrual cycles were enrolled. The phases of the menstrual cycle were determined using transvaginal ultrasonography (TV-US) and detecting hormonal serum levels. Plasma GH levels were evaluated during the early follicular, periovulatory and luteal phases of the cycle before and after the baclofen challenge test. Results: After acute baclofen administration, GH levels increased significantly (p < 0.001) compared to basal values during the periovulatory and luteal phases, while no significant variation was detected during the early follicular phase. In addition, plasma GH levels resulted significantly (p < 0.001) higher during the luteal phase than during the periovulatory phase. Conclusion: Acute baclofen administration induces a significant increase in plasma GH levels in healthy females during the periovulatory and luteal phases, but not during the early follicular phase. These data suggest a modulator role of plasma sex steroids levels on GH release induced by baclofen.

Zolmitriptan (a 5-HT1B/1D receptor agonist with central action) does not increase symptoms in obsessive compulsive disorder

Non-selective serotonin (5-HT) receptor agonists like meta-chlorophenylpiperazine and MK-212 have been used to explore the role of 5-HT in obsessive compulsive disorder (OCD). The results of these studies and the findings of autoradiography and neuroimaging studies, pointed to a possible role of the 5-HT1B/1D receptor in the pathophysiology of OCD. Recently the selective 5-HT1B/1D receptor agonist sumatriptan was used to further explore the role of the 5-HT1B/1D receptor in OCD. Equivocal results with respect to the increase of obsessive compulsive symptoms in patients with OCD were reported. In one study a significant increase in plasma growth hormone (GH) concentration was observed, although sumatriptan does not pass the blood-brain barrier. In order to further explore the role of the 5-HT1B/1D receptor in the pathophysiology of OCD, we performed this study, following the same design as Ho Pian et al. (Psychopharmacology 140:365-370). In the present study we performed a randomized, double-blind, placebo-controlled, cross-over design with zolmitriptan (5 mg per os), a selective 5-HT1B/1D receptor agonist with better brain penetrating properties than sumatriptan. We could not detect any changes in obsessive compulsive symptoms, mood, or anxiety levels, although we found a (nonsignificant) increase in plasma GH levels. Based upon these findings, no evidence was found for a specific role of the 5-HT1B/1D receptor in OCD. It should be noted, however, that challenge studies in OCD are difficult to perform. Perhaps in the future better challenge paradigms will make it possible to further explore the role of specific receptor types in OCD.