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Acute recombinant human growth hormone (r-hGH) administration (1-250 micrograms/kg; IP) decreased locomotor activity (LA) in a dose-dependent manner, F(5, 43) = 3.55, p < 0.009, with maximum effect at a dose of 10 micrograms/kg [control = 1655 +/- 659 inputs/outputs (I/O); r-hGH = 909 +/- 436 I/O; p < 0.05]. The daily treatment with r-hGH (10 micrograms/kg/day; 5 days; IP) reduced LA counts during the first trial, with no apparent changes in motor behavior after habituation. In contrast, growth hormone-releasing factor (GRF; 10 micrograms/rat/day; 5 days; IP) enhanced LA (control = 1045 +/- 566 I/O; GRF = 2284 +/- 894 I/O; p < 0.01) during the 5-day treatment period, inhibiting habituation. Moreover, the individual differences in LA persisted during the treatment period in response to GRF or r-hGH, but not in control rats. These results seem to indicate that the effects of GRF on LA are not mediated by the release of peripheral GH, and suggest that GRF might influence psychomotor behavior by a central mechanism.

Recent studies seem to indicate that the somatotropinergic system (STS) (GRF-SS-GH-SM axis) may be involved in the neuromodulation of higher activities of the central nervous system (CNS). In an attempt to demonstrate the influence of the STS on memory functions in humans, we have investigated the effects of acute administration of exogenous GRF vs. placebo on short-term memory (STM) in healthy young subjects. We gave GRF(1-29)NH2 (150 micrograms; i.v.) to a group of subjects (EG) (N = 17) and placebo (0.9% saline, 1 ml; i.v.) to a different group of subjects (CG) (N = 6). Prior to testing we presented a list of 20 neutral words (A1), and 2 hours after injection the same list (A2) and another list (B) of similar characteristics were presented in order to evaluate cognitive performance (CP). Basal CP (A1 list) was similar in EG and CG. Differences between EG and CG were found for both A2 (EG = 14.76 +/- 1.55 words vs. CG = 11.83 +/- 1.34 words, p less than 0.01) and B lists (EG = 12.17 +/- 1.68 words, p less than 0.005). According to the basal serum GH levels, EG subjects were divided into 2 subgroups: EG1 (N = 6), with high basal GH levels (11.57 +/- 4.47 ng/ml) and EG2 (N = 11), with low basal GH levels (1.55 +/- 1.71 ng/ml), similar to CG (1.3 +/- 1.53 ng/ml). GRF-induced GH response showed maxima 15 (28.15 +/- 11.71 ng/ml) and 30 min (28.09 +/- 17.07 ng/ml) after injection in EG1 and at 45 min (15.52 +/- 14.45 ng/ml) in EG2.(ABSTRACT TRUNCATED AT 250 WORDS)

In order to investigate the potential antagonistic actions of the two main neuroregulators of the somatotropinergic system (GRF-SS-GH-SM axis), growth hormone-releasing factor (GRF) and somatostatin (SS) at the central level, the effects of GRF and SS on locomotor activity (LA) were studied in a computerized system. Male Wistar rats (N = 6-9 per group) received i.p. or i.c.v. GRF(1-44)NH2 or SS(1-14) in doses ranging from 0.1-30 micrograms, and LA was automatically recorded in the OUCEM-86 system (Osaka University Computerized Electronic Maze) for 30-min periods. The peripheral administration of SS (1 microgram, i.p.) did not alter LA, while GRF (1 microgram, i.p.) increased LA from 20.35 +/- 4.18 to 36.25 +/- 6.98 IO/min (p less than 0.005). After central injection, SS (1 microgram; i.c.v.) decreased LA from 31.16 +/- 6.90 to 20.88 +/- 2.82 IO/min (p less than 0.005) and GRF (1 microgram, i.c.v.) increased LA to 47.60 +/- 5.35 IO/min (p less than 0.005). SS- and GRF-induced LA changes were time- and dose-dependent (SS: ED50 = 1.83 nmol, Emax = 6.10 nmol; GRF: ED50 = 99.1 pmol, Emax = 1.98 nmol). The maximum effect of GRF appeared during the first 5 min, showing activity 10-15 sec post-injection, while the lowest activity induced by SS was registered 15-30 min after injection, although a significant reduction in LA was detected 5-10 sec after i.c.v. administration. With doses higher than 10 micrograms (i.c.v.) SS provoked "barrel rotation", tremors and stereotyped behaviors. The GRF-induced hyperkinetic syndrome showed a linear pattern with doses up to 10 micrograms, and a plateau with 10-15 micrograms. Doses higher than 20 micrograms induced convulsion, uncontrolled movements and a high death rate during the following 12-24 h. In conclusion, according to the present results, GRF and SS exert antagonistic effects on LA in a time- and dose-dependent manner, the former stimulating LA, and the latter inhibiting it.

Attention-deficit hyperactivity disorder (ADHD) is a type of disruptive behavior of unknown etiology with a prevalence of 2.5-5% in school-age children. The useful evaluation of the GRF-induced GH response as a marker in some mental disorders led us to study the response of GH to the exogenous administration of GRF (1-29) NH2 (150 micrograms, i.v.) in ADHD children (N = 12, age = 7.78 +/- 1.66 years) and healthy children (N = 6; age = 8.73 +/- 2.24 years) in order to evaluate the functioning of the somatotropinergic system (GRF-SS-GH-SM axis) and using this neuroendocrine test as a potential diagnostic marker and/or a therapeutic predictor in ADHD. While controls (CS) showed a maximum GH response to GRF 15 min after injection (37.15 +/- 29.56 ng/ml; basal GH = 5.49 +/- 4.71 ng/ml), ADHD children (basal GH = 2.28 +/- 1.66 ng/ml) exhibited a lower response with a plateau from 15 (21.32 +/- 10.00 ng/ml) to 60 min (26.48 +/- 23.72 ng/ml). Serum GH levels at 90 (17.23 +/- 14.45 vs. 5.99 +/- 2.82 ng/ml, p less than 0.05) and 120 min (11.89 +/- 8.63 vs. 4.12 +/- 1.66 ng/ml, p less than 0.05) were significantly higher in ADHD than in CS. According to the GRF-induced GH response elicited in ADHD, two different populations of patients can be distinguished; one group with high response of GH (AUC = 3372.21 +/- 1127.61 ng.min/ml) and another group with a hyporeactive GH (AUC = 1567.46 +/- 726.0 ng.min/ml, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Studies on the morphological distribution of histamine (HA)-secreting neurons and their hypothalamic projections suggest that HA may play a key role in regulating neuroendocrine functions, some of which have been recently elucidated. To investigate possible interactions between the somatotropinergic and histaminergic systems in the brain, the effects of GRF-44 [0.1-10 micrograms intracerebroventricular (icv)] and somatostatin (SS-14; 0.1-10 micrograms, icv) on HA in five different parts of the hypothalamo-hypophyseal system, and in the hippocampus and frontal cortex, were studied using a highly sensitive HPLC system for determination of HA. GRF-44 (1 microgram, icv) elicited significant (P less than 0.005) increases in the concentration of HA in the anterior hypothalamus, posterior hypothalamus, median eminence, adenohypophysis, neurohypophysis, frontal cortex, and, to a lesser extent, in the hippocampus, after a clear time-dependent pattern with maxima 15 min after injection. In contrast, SS-14 (1 microgram, icv) significantly (P less than 0.005) decreased the levels of HA in all areas studied, except in the neurohypophysis. The SS-induced HA levels reached minima 30 min after injection. The antagonistic effects of GRF-44 and SS-14 on the release of brain HA were dose dependent, showing an inverse linear correlation within the range 0.1-10 micrograms in the anterior hypothalamus (r = -0.59) and posterior hypothalamus (r = -0.75). Responses of HA to GRF-44 and SS-14 (range: 0.1-10 micrograms) also exhibited an inverse linear correlation in the median eminence (r = -0.90) and adenohypophysis (r = -0.58), while in the hippocampus and frontal cortex the antagonistic effects of GRF and SS displayed an inverse curvilinear correlation. SS-14 ED50 values ranged from 0.6 to 1.75 nmol with Emax of 0.65-6.10 nmol. GRF-44 ED50 values ranged from 0.02-0.3 nmol and the Emax values oscillated between 0.2 and 1.90 nmol in the regions studied. The greatest responses of HA to GRF-44 and SS-14 were obtained in the hypothalamo-hypophyseal system. Although brain HA is present in both the neuronal and the mast cell compartments, changes induced in the concentration of HA by centrally administered GRF-44 and SS-14 appear to occur mostly in the neuronal compartment. Therefore, it is likely that the somatotropinergic and histaminergic systems reciprocally interact at the central level to regulate still unknown neuroendocrine functions.

To clarify the functional state of the somatotropinergic system at the hypothalamo-hypophyseal level in senile dementia of the Alzheimer type, the GHRH test was performed in three groups of subjects: a) healthy elderly subjects; b) early onset senile dementia patients; and c) late onset senile dementia patients. Intravenous administration of GHRH(1-44)NH2 (100 micrograms) elicited a marked plasma GH response with a maximum peak (709.54 +/- 259.0 pmol/l; P less than 0.005) 60 min after injection in patients with early onset senile dementia, but no significant response was detected in the other two groups. Electroencephalographic recording showed that GHRH modifies brain bioelectrical activity, decreasing frequency (0.52 +/- 0.15 Hz) and increasing amplitude (8.25 +/- 4.5 microV) of the electroencephalogram basic rhythm. The evaluation of mental performance and behaviour with a battery of different tests for mental assessment revealed that GHRH induces transient clinical changes in psychomotor behaviour. According to these results, it seems likely that the somatostatin deficiency reported in senile dementia of the Alzheimer type may account for the enhanced GHRH-induced GH response observed in patients with early onset senile dementia. In consequence, the GHRH test might constitute a useful antemortem marker for senile dementia of the Alzheimer type if the present results can be replicated in early stages of the disease.

Changes in the level of histamine (HA) in rat brain induced by intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) administrations of growth hormone-releasing factor (GRF1-44) were studied. HA was determined by high-performance liquid chromatography (HPLC) in the anterior hypothalamic region, posterior hypothalamic region, median eminence, adenohypophysis, neurohypophysis, hippocampus and prefrontal cortex. GRF1-44 (1-10 micrograms, i.c.v.) induced significant time- and dose-dependent increases in the concentration of HA in the hypothalamo-hypophyseal system and time-dependent decrease of HA in the hippocampus. In contrast, after i.p. administration of GRF1-44 (10 micrograms) the level of HA in the hypothalamus tended to decrease but the total amount of H-1 receptors in the hypothalamo-hypophyseal system did not change. Circadian variations in the GRF-induced HA and growth hormone responses were also observed, responses being lower in the evening than in the morning. It is concluded that GRF interacts with HA at the central level to optimize the function of the somatotropinergic system.

Administration of hypothalamic peptides has been reported to induce behavioral changes and to modify neurological functions such as locomotor activity and learning. Somatostatin (SS) and growth hormone-releasing factor (GRF) exert opposite effects on anterior pituitary secretion. Similarly, at the central nervous system (CNS) level, SS and GRF display antagonistic actions on behavioral parameters. The authors were able to confirm these effects in male Wistar rats by means of a computerized electronic maze measuring locomotor activity and learning. SS concentration is reduced in specific areas of the CNS in patients with late onset of senile dementia of the Alzheimer's type (SDAT). In early onset SDAT a GRF test elicits a growth hormone response much greater than that observed in normal controls of the same age or in patients with late onset SDAT. Thus, administration of GRF to patients with early onset SDAT has been followed by a significant improvement in locomotion, appetite, mental performance and social interaction. A possible therapeutic role of GRF in the management of patients with dementia remains to be explored.