Steven M. Gabriel

Growth hormone pulsatility and the endocrine milieu during sexual maturation in male and female rats

Although a sexually dimorphic pattern of rat growth hormone (rGH) secretion is well recognized in adult rats, episodic rGH release has been incompletely characterized in younger rats. In the present study, 28 to 113-day-old rats received jugular catheters and were housed in chambers designed for stress-free blood sampling. Three to seven days after surgery, 300 microliters of blood was withdrawn every 10 min between 16.00 and 22.00 h. Pulsatile rGH secretion before 33 days of age was similar in males and females. Low baseline rGH secretion was interspersed with infrequent, low amplitude pulses. In early puberty, between 33 and 40 days of age, rGH pulse amplitudes increased more than tenfold in both sexes. The duration of rGH pulses was significantly greater at this time in males versus females, a pattern that continued though adulthood. By late puberty, between 41 and 54 days of age, rGH pulse amplitudes similarly increased twofold in both sexes. Baseline rGH secretion increased at this time in both sexes, with females having a higher baseline compared to males. Only in adult rats over 54 days of age, was the typical pattern of low basal rGH secretion, combined with high amplitude, low frequency rGH pulses in males versus females evident. A sex difference in body weight, i.e. males weighing more than females, became evident after day 33 of age. This sex difference was preceded by an increase in testosterone in males versus females at all ages examined.(ABSTRACT TRUNCATED AT 250 WORDS)

Age-related changes in the association between serotonergic function and aggression in boys with ADHD.

The results of several studies have indicated an inverse relationship between central serotonergic (5-HT) mechanisms and aggression in animals and adults, but studies in children have yielded conflicting results. This study assessed 5-HT function, using a fenfluramine (FEN) challenge procedure, in an attempt to replicate a previously reported enhancement of the prolactin (PRL) response to FEN in aggressive relative to nonaggressive ADHD boys. The study failed to replicate the previous finding. Samples from both studies were then examined to reconcile the discrepant findings. The samples differed significantly in age. The entire group (n = 50) was then divided into older and younger subgroups and reanalyzed using a two-way (age-group x aggression) analysis of covariance (ANCOVA) controlling for plasma medication level. The ANCOVA generated a significant age-group x aggression interaction. Young aggressive boys had a significantly greater PRL response to FEN than young nonaggressive boys, but no such difference existed in the older age-group. These findings raise the possibility of different developmental trajectories in 5-HT function between aggressive and nonaggressive boys.

Neuropeptide deficits in schizophrenia vs. Alzheimer's disease cerebral cortex

Neuropeptide concentrations were determined in the postmortem cerebral cortex from 19 cognitive-impaired schizophrenics, 4 normal elderly subjects, 4 multi-infarct dementia (MID) cases, and 13 Alzheimers disease (AD) patients. Only AD patients met criteria for AD. The normal elderly and MID cases were combined into one control group. Somatostatin concentrations were reduced in both schizophrenia and AD. Neuropeptide Y concentrations were reduced only in schizophrenia, and corticotropin-releasing hormone concentrations were primarily reduced in AD. Concentrations of vasoactive intestinal polypeptide and cholecystokinin also were reduced in schizophrenia, although not as profoundly as somatostatin or neuropeptide Y. In AD, cholecystokinin and vasoactive intestinal peptide were unchanged. Neuropeptide deficits in schizophrenics were more pronounced in the temporal and frontal lobes than in the occipital lobe. The mechanisms underlying these deficits in schizophrenia and AD are likely distinct. In schizophrenia, a common neural element, perhaps the cerebral cortical gaba-aminobutyric acid (GABA)-containing neuron, may underlie these deficits.

Tissue-specific sex differences in galanin-like immunoreactivity and galanin mRNA during development in the rat

Galanin-like immunoreactivity (Gal-LI), as determined by radioimmunoassay, was detectable in the brain and gastrointestinal tract by day 15 of gestation. Concentrations of Gal-LI increased after birth in the hypothalamus but decreased in the stomach and duodenum. A sex difference in Gal-LI concentrations appeared during puberty in the median eminence, neurointermediate lobe, and the anterior pituitary (AP), where females had higher Gal-LI concentrations compared to males. This difference was most pronounced in the AP; adult females had up to 4-fold greater Gal-LI concentrations and 5-fold more abundant rGal-specific mRNA compared to males.

Galanin-like immunoreactivity is influenced by estrogen in peripubertal and adult rats

Galanin gene expression in the anterior pituitary is potently stimulated by estrogen in adult rats. To evaluate the influence of estrogen on galanin during the peripubertal period 30- to 32-day-old female rats were treated with pregnant mare serum gonadotropin (PMSG, 10 IU s.c., 10.00 h). Galanin-like immunoreactivity (galanin-LI) in hypothalamic and pituitary tissues was evaluated 1, 2 or 3 days after PMSG treatment between 17.00 and 19.00 h. The PMSG treatment stimulated 17 beta-estradiol secretion, which induced a midafternoon LH surge 2 days after the PMSG treatment. Concentrations of galanin-LI at the time of this LH surge were elevated 82% in the anterior pituitary and 58% in the hypothalamus (without the median eminence) when compared to saline-treated female rats. On the 3rd day after the PMSG injection, galanin-LI was increased 236% in the anterior pituitary, 88% in the neurointermediate lobe and 39% in the median eminence compared to saline-treated female rats. These changes in galanin-LI were not observed in similarly aged male rats or ovariectomized rats treated with PMSG. In adult male rats, daily injections with 17 beta-estradiol valerate (10 micrograms/daily s.c.) for 1 week increased galanin-LI in the median eminence and neurointermediate lobe to an extent similar to that seen in juvenile female rats following PMSG treatment. In contrast, the high serum levels of 17 beta-estradiol achieved after 17 beta-estradiol valerate treatment increased galanin-LI in the anterior pituitary 65-fold. These studies indicate that galanin-LI is influenced by estrogen in peripubertal and adult rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Galanin stimulates rat pituitary growth hormone secretion in vitro

The effect of galanin on growth hormone (GH) secretion was investigated in monolayer cultures of rat anterior pituitary cells. Galanin caused a gradual increase in GH concentrations into the culture medium that was maximal at 90 minutes and sustained after 180 minutes. The ED50 for galanin-stimulated GH secretion was approximately 200 nM compared to an ED50 for rat GH-releasing factor (rGRF)-stimulated GH secretion of 10pM. Galanin and rGRF were additive in increasing GH release into the incubation medium. These data indicate that porcine-derived galanin has a direct effect on pituitary GH secretion in vitro.

Galanin-like immunoreactivity is increased in the postmortem cerebral cortex from patients with Alzheimer's disease.

Abstract: Galanin is a peptide that is associated with cholinergic neurons of the basal forebrain and, thus, of interest for the neuropathology of Alzheimers disease. In the present study, human galanin‐like immunoreactivity was measured in postmortem human cerebral cortical tissues by using a homologous radioimmunoassay. In an initial study, six cerebral cortical regions were evaluated from nine elderly controls, 13 neuropathologically verified Alzheimers disease patients, and 19 elderly schizophrenics. A significant 65% increase in galanin was found in frontal cortex Brodmann area 8 of Alzheimers disease patients compared with controls. In contrast, cerebral cortical tissues from elderly schizophrenics were not different from those from elderly controls in any region. In a second study, 10 cerebral cortical regions were evaluated from 50 neuropathologically verified Alzheimers disease patients and nine elderly controls. Concentrations of galanin were increased significantly 26–61% in six of 10 cerebral cortical regions examined (Brodmann areas F8, F44, T20, T21, T36, and P22). Purification of brain extracts by size‐exclusion Sephadex G‐50 chromatography revealed that human galanin‐like immunoreactivity eluted in two peaks of different molecular weights. These studies reveal increased concentrations of galanin in the cerebral cortex of Alzheimers disease, similar to previous findings in basal forebrain tissue. Because galanin inhibits cholinergic neurotransmission, these findings may have important implications in the understanding of Alzheimers disease neuropathology and associated cognitive deficits.

Serotonin function in schizophrenia: Effects of meta- chlorophenylpiperazine in schizophrenia patients and healthy subjects

This study examined serotonin (5-hydroxytryptamine; 5HT) receptor responsivity in 22 chronic schizophrenic patients and 17 healthy control subjects. The 5HT agonist meta-chlorophenylpiperazine (MCPP) was used as a probe of serotonergic function. MCPP (0.35 mg/kg) or placebo was administered orally after a 3-week drug-free period in a randomized double-blind design. Hormonal (adrenocorticotropic hormone and prolactin), temperature, and behavioral responses and MCPP blood levels were assessed for 210 minutes after administration of the capsules. The schizophrenic patients had blunted temperature responses compared with those of the healthy control subjects: MCPP raised body temperature in the control subjects, but not in the patients. Behavioral responses also differed in the two groups: MCPP increased the total Brief Psychiatric Rating Scale (BPRS) score in the control subjects and tended to decrease it in the patients. In patients, MCPP decreased the BPRS psychosis subscore. Hormonal responses did not differ significantly in the two groups. These findings suggest that further exploration of 5HT function in schizophrenia is warranted.

Sexual and Developmental Differences in Peptides Regulating Growth Hormone Secretion in the Rat

Sex differences in the hypothalamic control of growth hormone (GH) secretion were investigated by measuring rat GH-releasing factor (rGRF) and somatostatin in male and female rats. Rat GRF-like immunoreactivity (rGRF-IR) was higher in the median eminence and hypothalamic tissue outside of the median eminence of adult (90-day-old) male compared to female rats. A similar pattern of rGRF-IR content was found in the median eminence of 35-day-old rats. This sex difference developed between days 25 and 35 of age, during which time serum concentrations of insulin-like growth factor (IGF-1) and body weight increased in both sexes. To a lesser extent, the content of somatostatin-like immunoreactivity (SLI) was higher in the median eminence of adult female rats compared to male rats. Whole hypothalamic rGRF-IR and SLI contents were influenced only moderately by adult gonadectomy or gonadal steroid treatments. For example, estrogen increased rGRF-IR content in castrated rats, but orchidectomy alone or orchidectomy followed by testosterone did not influence rGRF-IR content. Additionally, whole hypothalamic SLI content was unaffected by orchidectomy or orchidectomy followed by testosterone or estrogen. One month after ovariectomy, rGRF-IR and SLI in whole hypothalamic fragments were similar to their respective contents in gonad-intact males. However, ovariectomy followed by estrogen or testosterone did not restore rGRF-IR content and partially restored SLI content to levels seen in gonad-intact females.

Chronic morphine and testosterone treatment: effects on sexual behavior and dopamine metabolism in male rats

The effects of sustained delivery of morphine and/or testosterone (T) on male rat copulatory behavior, penile reflexes and dopaminergic metabolism in selected brain regions were examined. Castration was followed by (1) a decrease in the number of male rats exhibiting intromissive and ejaculatory behavior in mating tests, (2) decreased erections in ex copula tests, and (3) increases in dopamine and dihydroxyphenylacetic acid (DOPAC) concentrations in the mediobasal hypothalamus (MBH) and the preoptic area-anterior hypothalamus (POA-AH). The decreased incidence of copulatory behavior and penile reflexes seen after castration was effectively prevented by a 4-day treatment with 5-mm T-containing Silastic capsules. Chronic morphine implants, conversely, accentuated the castration-induced decrements in copulatory behavior and prevented the 5-mm-T-induced facilitation, but did not alter the number of animals displaying erection (although the number of erections displayed by testosterone-treated rats was reduced) in ex copula tests. Treatment of castrated rats with 5 mm T, but not morphine alone, nor the combination of 5 mm T plus morphine, significantly reduced dopamine and DOPAC levels in the MBH. In the POA-AH, 5 mm T was without effect, whereas morphine, alone or in combination with 5 mm T, reduced the levels of dopamine and DOPAC. These data suggest that (1) the decline in sexual behavior induced by chronic morphine is primarily due to a failure of sexual arousal, and not of erectile ability, and (2) although the decline in sexual activity seen after castration is associated with alterations in dopaminergic metabolism, the effects of morphine and testosterone on sexual activity are opposite and dissociated from alterations in dopaminergic metabolism.