Lloyd J. Forman

Effects of CNS active drugs and somatostatin antiserum on growth hormone release in young and old male rats

The capacity of several potent pharmacological agents to increase growth hormone (GH) release was tested in young (3- to 4-month-old) and old (18- to 20-month-old) male Sprague-Dawley rats. Young and old animals were injected with alpha-methyl-p-tyrosine (250 mg/kg), a catecholamine synthesis inhibitor, followed 60 min later by the alpha-adrenergic receptor agonist, clonidine hydrochloride (150 micrograms/kg). Plasma GH levels increased to greater than 276 ng/ml by 30 and 50 min in young rats, whereas values never exceeded 130 ng/ml (p less than 0.01) in old rats. Piribedil methane sulfonate (1 mg/kg), a dopamine receptor agonist, significantly increased GH in young animals 60 min after injection (p less than 0.01), but had no effect in old rats. Morphine sulfate (5mg/kg) increased plasma GH concentration in young rats to greater than 400 ng/ml at 30, 50 and 70 min after injections, whereas values in old animals never exceeded 300 ng/ml (p less than 0.01). 15 min after injection of somatostatin antiserum No. 774 (5 ml/kg), plasma GH levels increased to greater than 750 ng/ml in both young and old rats. Administration of greater volumes of somatostatin antiserum (8 ml/kg) increased GH levels more in old than in young animals 30 and 45 min after injection (p less than 0.01). These results indicate that old male rats have less capacity to increase GH in response to agents that normally enhance GH release. This may be the result of a diminished number of affinity of post-synaptic neurotransmitter receptors, or to an increased release of somatostatin. Since somatostatin antiserum in creased H equally or to a greater extent on old that in young animals, aging rats may release more somatostatin or the pituitary may be more sensitive to the inhibitory effects of this hormone.

L-Dopa Restores Amplitude of Growth Hormone Pulses in Old Male Rats to That Observed in Young Male Rats

35 male Sprague-Dawley rats, 18 months old, were injected subcutaneously with the catecholamine precursor, L-dihydroxyphenylalanine (L-dopa) (100 mg/kg, twice daily), or vehicle alone, for 8 days in an attempt to increase the amplitude of growth hormone (GH) pulses in old male rats. 40% of young rats had at least one GH pulse greater than 600 ng/ml, over a 6.5 h sampling period, whereas only 22% of old vehicle-treated rats had pulses of similar amplitude. Treatment of old rats with L-dopa increased the number of animals showing elevated GH pulses to 53%. Young animals had mean GH concentrations of 136.5 +/- 14.0 ng/ml over the 6.5 h sampling period, whereas vehicle-treated old animals had mean GH levels of 95.2 +/- 7.7 ng/ml (p less than 0.05). Treatment of old animals with L-dopa increased mean plasma GH concentrations to 132.9 +/- 11.2 ng/ml (p less than 0.05) which was not significantly different from GH values in young rats. Pituitary GH concentration was less in old than in young rats (301 +/- 27.4 vs. 370 +/- 17.4 micrograms/mg protein, p less than 0.05). L-Dopa increased pituitary GH concentrations in old rats to 318 +/- 32.2 micrograms/mg protein, which was not significantly different from that in either young or old vehicle-treated animals. Hypothalamic somatostatin content in both rostral and caudal areas was lower in old than in young rats (p less than 0.01), and L-dopa had no significant effect on somatostatin content. These data indicate that L-dopa can increase the amplitude of GH pulses and elevate mean plasma GH in old male rats to levels present in young male rats, probably by increasing hypothalamic catecholamines.

Suppression by Naloxone of Rise in Plasma Growth Hormone and Prolactin Induced by Suckling

Abstract The effects of three different doses of the specific opiate antagonist, naloxone (0.2, 2.0, and 5.0 mg/kg body wt), on release of growth hormone (GH) and prolactin (PRL) induced by suckling were determined in postpartum lactating rats. Blood was collected from mother rats via an indwelling atrial cannula 8 hr after separation from their pups. Suckling for 30 min induced a 3-fold increase in plasma GH and more than a 10-fold increase in plasma PRL. Injection of naloxone into mother rats just prior to suckling by their pups produced significant inhibition of both GH and PRL release. Doses of 0.2 and 5.0 mg naloxone/kg body wt almost completely inhibited GH release, whereas an intermediate dose (2.0 mg/kg body wt) was partially effective. Inhibition of PRL release by naloxone was dose related, and the highest dose (5.0 mg/kg body wt) decreased plasma PRL values by 60-80%. These results suggest that the endogenous opioid peptides are involved in release of GH and PRL induced by the suckling stimulus in the rat.

Maintenance by L-DOPA treatment of estrous cycles and LH response to estrogen in aging female rats

Nineteen, non-cycling female rats, 13-15 months of age, were fed 125 mg L-DOPA/15 g feed daily, and nineteen control rats of the same age were provided feed without L-DOPA. Sixteen of the L-DOPA fed rats each demonstrated 1-7 (average = 3) vaginal estrous cycles during the 75-day period of treatment, whereas no cycles were observed in the untreated controls. All animals were then ovariectomized and the post-castration rise in LH was monitored. Four weeks after ovariectomy, serum LH levels in the L-DOPA treated old female rats were significantly higher than in the non-treated old female rats. A single injection of 20 micrograms of estradiol benzoate (EB) significantly lowered serum LH in the L-DOPA treated rats, but no effect was observed in the non-treated controls. A second injection of EB three days later produced a significantly greater LH surge in the old rats given L-DOPA than in the non-L-DOPA treated controls. These results indicate that prolonged L-DOPA administration can partially prevent the decline in function of the hypothalamo-pituitary-ovarian system in aging female rats.

Elevation of Plasma LH in Response to Systemic Injection of β-Endorphin Antiserum in Adult Male Rats

Abstract A single injection of β-endorphin antiserum into mature male rats produced approximately a 3-fold rise in plasma LH levels by 10 to 50 min, and declined by 90 min, but remained significantly elevated above pre-injection values. Control rats injected with normal rabbit serum showed no elevation in plasma LH values. These results indicate that β-endorphin is one of the endogenous opiates that tonically depresses basal release of LH in mature male rats.

Immunoreactive beta-endorphin in the plasma, pituitary and hypothalamus of young female rats on the day of estrus and intact and chronically castrated old constant estrous female rats

Immunoreactive beta-endorphin (IR-beta-ENDO) was compared in the plasma, pituitary and hypothalamus of young female rats on the day of estrus and old constant estrous (CE) female rats, and in intact and chronically castrated old CE female rats. The concentration of IR-beta-ENDO in the plasma and the content and concentration of IR-beta-ENDO in the neurointermediate lobe of the pituitary were significantly greater in the old CE female rats than in the young female rats on the day of estrus. The content and concentration of IR-beta-ENDO in the anterior pituitary and hypothalamus were similar in the two age groups. To determine if estrogen contributed to the increase in plasma and pituitary levels of IR-beta-ENDO observed in the old animals, a group of old CE female rats were castrated and compared to sham operated control CE rats. Thirty days after castration, levels of plasma, pituitary and hypothalamic IR-beta-ENDO were comparable in the intact and the chronically castrated old female rats. These data indicate that in old CE female rats, plasma and pituitary IR-beta-ENDO are significantly increased in comparison to young female rats on the day of estrus, and that these increased levels of IR-beta-ENDO observed in old female rats do not appear to be influenced by gonadal estrogen.

Mediation by gonadal steroids of plasma beta-endorphin and LH in castrated female and male rats ☆

Immunoreactive beta-endorphin (IR-BE) was significantly decreased and luteinizing hormone (LH) significantly increased in female rats castrated for four weeks. Forty eight hours after a single injection of estradiol benzoate (EB), IR-BE levels increased, and LH levels were reduced. On the afternoon following the administration of a second injection of EB given six hours earlier, IR-BE levels were reduced below control values, whereas LH levels were significantly elevated. There was no change in IR-BE levels during the remainder of that afternoon whereas LH levels decreased over time. Similar to female rats, IR-BE was diminished and LH increased in castrated male rats. IR-BE was increased significantly above those values observed in intact animals 24 hr after a single injection of TP and returned to control levels by 48 hr after administration of TP. Injection of TP reduced LH to levels observed prior to castration. These findings suggest that gonadal steroids exert a feedback on the release of IR-BE from the pituitary of female and male rats opposite to their feedback effect on the release of pituitary gonadotropins.

Comparison of the effects of central acting drugs on prolactin release in young and old male rats.

Abstract The effects of several central acting drugs on prolactin (PRL) secretion were compared in young (3-4 months) and old (18-19 months) Sprague-Dawley male rats. Administration of the catecholamine synthesis inhibitor, methyl-DOPA, or the dopamine receptor blocker, haloperidol, produced a significantly greater increase in plasma PRL in the old than in the young rats. Stimulation of the serotonergic system by quipazine or enhancement of opioid activity by morphine produced a significantly greater rise in plasma PRL in the young than in the old male rats. Administration of the specific opiate antagonist, naloxone, reduced plasma PRL levels more in old than in young male rats. but this difference was not significant. Measurement of pituitary content and concentration of PRL revealed that both were significantly greater in old than in young male rats. These results suggest that hypothalamic dopamine continues to be an important inhibitor of PRL release in old male rats, whereas serotonin and the opiates become relatively less effective as stimulators of PRL release.