S. Kaleem Quadri

Interleukin-1 stimulates the release of dopamine and dihydroxyphenylacetic acid from the hypothalamus in vivo☆

Push-pull perfusion technique was used to infuse IL-1 beta into and collect perfusate from the medial basal hypothalamus of freely moving male rats. Dopamine (DA) and its metabolite, dihydroxyphenylacetic acid (DOPAC), were measured in the perfusate using high performance liquid chromatography with electrochemical detection. In the control group, release rates of DA and DOPAC decreased and were 62% and 40%, respectively, below pretreatment levels after 325 min. In contrast, treatment with 50 ng of IL-1 beta produced substantial reductions in these decreases, and treatment with 100 ng of IL-1 beta produced increases of up to 118% and 89% in the release rates of DA and DOPAC, respectively. It is concluded that IL-1 beta affects the metabolism of catecholamines (and probably other neurotransmitters) in the brain, which, in turn, mediate its central and neuroendocrine actions.

Interleukin-1 stimulates catecholamine release from the hypothalamus

During a 60-min period, the in vitro release of norepinephrine (NE) from the hypothalami of male rats decreased by 28%. The presence of 50 or 100 ng of interleukin 1-beta (IL-1 beta) in the incubation medium prevented this decrease and raised the release by 17% or 45% respectively (P less than 0.05). The average release of dopamine (DA) decreased by 55% in the control group but 50 ng of IL-1 beta cut this decrease to 25%, and 100 ng of IL-1 beta not only completely prevented the decrease but raised the release by 44% (P less than 0.05). In a following 60-min period, when the hypothalami from the treatment groups were incubated without IL-1 beta, it resulted in sharp declines in the release of NE and DA, confirming that IL-1 beta was the stimulus for the increases in catecholamine release in the previous incubation period. It is concluded that IL-1 beta stimulates the release of catecholamines (and probably other neurotransmitters) in the brain which, in turn, mediate its central and neuroendocrine actions.

Cyclic changes in the release of norepinephrine and dopamine in the medial basal hypothalamus: effects of aging

Push-pull perfusion and HPLC were used to measure the release of norepinephrine (NE) and dopamine (DA) in the medial basal hypothalamus of young (4-5 months old), middle-aged (8-10 months old), and old (22-24 months old) rats. In the young animals, the afternoon of proestrus was characterized by a gradual increase in NE release and a simultaneous gradual decrease in DA release. The peak in NE release and the nadir in DA release occurred at about the time when the proestrous surges in serum LH and PRL are known to occur. No changes in NE and DA releases occurred in the afternoon of diestrus when serum LH and PRL are known to remain stable. In the middle-aged proestrous animals, the patterns of NE and DA releases were similar to those in the young proestrous animals, but the peak in NE release was attenuated and did not reach statistical significance. This corresponded with the reported attenuation in the LH surge in middle age. In the old persistently diestrous animals, NE and DA were released at constant rates, which correlated with the well-documented constant levels of serum LH and PRL in old age. These data provide an explanation for the simultaneous proestrous surges of LH and PRL and lead us to conclude that NE plays a facilitatory role in the LH surge, while DA, through its inhibitory action, regulates the PRL surge.(ABSTRACT TRUNCATED AT 250 WORDS)

Tyrosine hydroxylase messenger RNA in the hypothalamus, substantia nigra and adrenal medulla of old female rats

The effects of aging in the female rat were analyzed in terms of tyrosine hydroxylase (TH) gene expression and serum prolactin levels. The number of tuberoinfundibular dopaminergic (TIDA) neurons and the concentration of TH mRNA per cell was greater in 16- to 18-month-old rats than in 25-month-old rats. The amount of TH immunostaining was more intense in the median eminence of the 18-month-old rats compared to either younger or older rats. Plasma prolactin levels were moderately elevated in 18-month-old rats compared to 4-month-old rats, and extremely elevated in 25-month-old rats due to the occurrence of pituitary prolactinomas. There were no detectable changes in TH mRNA levels in the substantia nigra with age, whereas adrenal TH mRNA increased with age. We propose that prolactin initially exerts a stimulatory effect on the TIDA neurons as the rat ages, but eventually causes a loss in neuronal number and neuronal function as the pituitary prolactinoma secretes increased amounts of prolactin.

Plasma Thyroxine and Cortisol under Basal Conditions and during Cold Stress in the Aging Dog

Abstract The effects of aging on plasma concentrations of thyroxine (T4) and cortisol and on responses of these hormones to low ambient temperatures were determined in the dog. Female beagle dogs were divided into three age groups: old, adult, and puppies. The mean (±SD) ages were 11.4 ± 0.2 years, 3.0 ± 0.4 years, and 7.6 ± 0.2 weeks, respectively. All dogs came from a genetically homogeneous colony and were free from any disease. The adult and old dogs were used during anestrus. Based on four daily blood samples, the mean (±SE) T4 level in the old dogs (2.8 ± 0.1 μg/dl) was significantly (P < 0.001) lower than that in the adults (4.2 ± 0.2 μg/dl) and puppies (4.4 ± 0.2 μg/dl). By contrast, mean plasma cortisol levels in the old dogs (21.1 ± 3.1 ng/ml) and adults (15.4 ± 2.4 ng/ml) were significantly higher than those in the puppies (7.2 ±1.1 ng/ml). No significant changes in plasma T4 and cortisol occurred in any of the three age groups at 22°C or during exposure to 10 or 4°C. Exposure to −5°C, however, produced significant increases in T4 (>130% by 5 hr) and cortisol (>280% by 1 hr) in adult dogs. This temperature produced only a modest increase in T4 (70% by 3.5 hr) and no change in cortisol in the old dogs. The puppies showed no change in T4 and cortisol during exposure to —5°C. The results demonstrate that with advancing age, plasma T4 and cortisol concentrations change in opposite directions, thus supporting the hypothesis of a negative relationship between these two hormones. These results also show that the responses of these hormones to the stress of cold decline during aging and are not yet developed in the very young.

Effects of aging on the pituitary-thyroid axis in the dog☆

The effects of advancing age on basal serum concentrations of thyroxine (T4) and thyrotropin (TSH), on T4 responses to TSH, and on TSH responses to thyrotropin-releasing hormone (TRH) were studied in beagle dogs. A total of 27 female dogs belonging to four age-groups were used: prepubertal (11.4 +/- 0.2 (SD) weeks), adult (2.1 +/- 0.3 years), middle-aged (6.5 +/- 0.2 years), and old (12.4 +/- 0.3 years). There was no significant difference between serum T4 concentrations of prepubertal (4.3 +/- 0.1 microgram/dl, mean +/- SE) and adult dogs (4.1 +/- 0.1 microgram/dl). Also, the decreases between adulthood and middle age (16.01%) and between middle age and old age (23.5%) were not significant, but serum T4 levels in the old dogs (2.6 +/- 0.2 micrograms/dl) were significantly (p less than 0.01) lower than those in the adult dogs. Serum cortisol levels showed a progressive increase with advancing age and were significantly higher in old animals (20.1 +/- 2.4 ng/ml) compared to those in the adults (13.4 +/- 1.2 ng/ml). There were no significant differences in serum TSH concentrations among the four age-groups. A single i.v. injection of TSH (0.15 IU/kg B.W.) raised serum T4 levels in the prepubertal animals by more than 45% in 1 h and by more than 100% in 2 h. T4 responses to TSH in the adult dogs were similar to those in the prepubertal dogs but were greatly delayed and subdued in the middle-aged and old animals. A single i.v. injection of TRH (5 micrograms/kg B.W.) increased serum TSH levels in the prepubertal animals by more than 120% in 15 min. These increases were less in the adult (74.8%) and middle-aged (21.3%) animals, and a significant increase (24.6%) in the old animals did not occur until 30 min after TRH treatment. This study demonstrates that, with advancing age, marked alterations occur in the regulation of the T4-TSH system in the dog.

L-Deprenyl inhibits tumor growth, reduces serum prolactin, and suppresses brain monoamine metabolism in rats with carcinogen-induced mammary tumors

Previously, we have reported thatL-deprenyl decreased the incidence of mammary tumors and pituitary tumors in old acyclic rats. The objective of the present study was to investigate the effects ofL-deprenyl, a monoamine oxidase-B (MAO-B) inhibitor, treatment on the development and growth of tumors and on the metabolism of catecholamines and indoleamine in the medial basal hypothalamus (MBH) and the striatum (ST) of rats bearing 7,12-dimethylbenzanthracene (DMBA)-induced mammary tumors. Female Sprague-Dawley rats with DMBA-induced mammary tumors were injected (sc) daily with 0.25 mg or 5.0 mg of deprenyl/kg BW or the vehicle (saline; control) for 12 wk. Tumor diameter, tumor number, body weight, and feed intake were measured every week of the treatment period. Serum PRL and the concentrations of catecholamines, indoleamine, and their metabolites were measured by RIA and HPLC, respectively. Treatment with 5.0 mg deprenyl decreased the tumor diameter, tumor number,and serum prolactin (PRL) level. Although the body weight increased in all three groups, the body weight gain in the 5.0 mg group was smaller than that in the control and 0.25 mg groups. Deprenyl treatment had no effect on feed intake. The concentrations of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were decreased in the MBH and the ST, and the concentration of 5-hydroxy-indoleacetic acid (5-HIAA) was decreased in the MBH of deprenyl-treated rats. Treatment with 5.0 mg deprenyl enhanced the concentrations of norepinephrine (NE) and serotonin (5-HT) in the MBH and in the ST, and the concentration of dopamine (DA) in the MBH. These results suggest that the suppression of the development and growth of DMBA-induced mammary tumors by chronic deprenyl treatment may be mediated through alterations in the synthesis and metabolism of catecholamines and indoleamine in the MBH and inhibition of PRL secretion.

Effects of Chronic Hyperprolactinemia on Tuberoinfundibular Dopaminergic Neurons

Abstract Prolactin (PRL) secretion is under the inhibitory regulation of the tuberoinfundibular dopaminergic (TIDA) system. Short-term elevation in PRL levels has been shown to increase the activity of TIDA neurons, however, the responsiveness of TIDA neurons to chronically elevated serum PRL levels is controversial. The purpose of this study was to investigate the effects of prolonged elevations of serum PRL on TIDA neuronal activity. Female Sprague-Dawley rats (2–3 months old) were ovariectomized and implanted (sc) with haloperidol (HAL), a dopamine receptor antagonist for 6 or 9 months to produce hyperprolactinemia. Ovariectomized, sham-implanted rats were used as controls. Other groups of intact rats were implanted with HAL or shamimplanted for 9 months and then were implanted with PRL-producing MMQ cells for 6 weeks to further increase circulating PRL levels. TIDA neuronal activity was measured in terms of tyrosine hydroxylase (TH) activity in the stalk-median eminence and was correlated with changes in serum PRL levels. After 6 months of treatment, TH activity in HAL-treated rats was 130% higher than that in the control rats. After 9 months of treatment, TH activity in HAL-treated rats was 81% higher than that in control rats. This increase was significantly less than the increase that occurred after 6 months of treatment. Nine months of HAL-induced hyperprolactinemia followed by implantation of PRL-producing MMQ cells, which resulted in very high levels of PRL, did not increase TH activity in the stalk-median eminence. These results demonstrate that hyperprolactinemia over a prolonged period reduces the responsiveness of TIDA neurons, and these effects vary depending on the duration and intensity of hyperprolactinemia.

l-Deprenyl stimulates the release of catecholamines in the rat medial basal hypothalamus in vivo

In vivo release of catecholamines in the medial basal hypothalamus (MBH) by L-deprenyl, a monoamine oxidase-B (MAO-B) inhibitor, was measured in young male Sprague-Dawley rats with stereotaxically implanted push-pull cannulae in the MBH and perfused with 0 (control), 1.5, 2.5 or 10.0 microg deprenyl in 20 microl of saline. Perfusate samples were collected at 20-min intervals and analyzed for norepinephrine (NE) and dopamine (DA) by high performance liquid chromatography (HPLC)-EC. NE release in the MBH was enhanced following perfusion with 2.5 and 10.0 microg deprenyl while DA release was augmented after infusion of 10.0 microg of deprenyl. There were no significant alterations in the release of NE and DA in the control and 1.5 microg deprenyl groups. These results suggest that deprenyl-induced in vivo release of catecholamines in the MBH may be involved in the reversal of some of the reproductive aging processes.

Failure of copulation to affect serum prolactin, LH, and estrogen levels in female rhesus monkeys.

Summary Serum concentrations of pro-lactin, LH, and estradiol-17β (E2) were measured on Day 1 (Day 8-17 of the menstrual cycle) at 30 and 0 min before and 10, 30, 60, 120, and 180 min after coitus in five intact female rhesus monkeys. Blood samples were also collected on a similar schedule on the following 2 days when the females were placed for 30 min in the mating cage alone (Day 2) or in the presence of a male in a separate cage (Day 3). None of the females showed an increase in serum prolactin or E2 levels on any of the 3 days. Serum LH levels increased (P < 0.05) in two of the three monkeys in which they were monitored. However, of these two monkeys, one showed a similar LH increase when she was left alone in the mating cage. In three females which refused copulation, serum prolactin, LH, and E2 levels remained unchanged. The effect of copulation on serum LH was further investigated in eight additional females which were allowed to copulate on Days 5, 12, and 22 of the menstrual cycle and in two long-term ovariectomized E2-treated females. Serum LH increased within 30 min after coitus in one female on each of the 3 days, but remained unchanged or showed inconsistent fluctuations in the remaining seven intact females and in the two ovariectomized E2-treated females. We conclude that copulation per se does not influence serum prolactin, LH, or E2 levels nor do changing ratios of circulating estrogen and progesterone before coitus account for occasional postcoital LH fluctuations in captive female rhesus monkeys after pairing with a sexually active male. We thank Terry Oyama and Margaret Stobie for excellent technical assistance and Lois Hasebe for typing the manuscript. Special appreciation is due to Dr. Charles Phoenix for use of the copulation room.