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Biomedical subjects

W J Millard

Publications and source records attributed to W J Millard.

At least 37 records · Page 2Linked to original sources
PubMed1993

Modulation of neuropeptide Y expression in rat brain neuronal cultures.

Neuropeptide Y (NPY) and its encoding mRNA were measured in neurons co-cultured from rat basal forebrain and cerebral cortex. NPY was synthesized and released in a manner consistent with secretion-synthesis coupling; depolarization increased each in a calcium-dependent manner. The accumulation of NPY encoding mRNA was elevated by a muscarinic receptor blocker, without changes in transmitter release or peptide synthesis, thereby consistent with a membrane potential-independent mechanism. Changes in intrinsic muscarinic transmission could nonetheless be expressed rapidly as an elevation in NPY levels by depolarizing the neurons subsequent to muscarinic receptor blockade. This depolarization-induced elevation of NPY subsequent to muscarinic receptor blockade was dependent on the presence of extracellular calcium ions. Forskolin and pertussis toxin also increased NPY encoding mRNA levels in a manner that was not additive with muscarinic receptor blockade. These results suggest that one or more muscarinic receptors may tonically modulate NPY synthesis via changes in adenylate cyclase activity, providing a model for the non-homeostatic modulation of neuropeptide turnover.

Acetylcholine↗
PubMed1993

Effects of chronic stimulation or antagonism of opiate receptors on GH secretion in male and female rats.

The present study was undertaken to assess the role of endogenous opioid systems in the sexually dimorphic pattern of growth hormone (GH) secretion. To this end, male rats were treated chronically (6 to 12 h) with morphine and estrogen-exposed, ovariectomized female rats with morphine or naloxone. Chronic morphine exposure of male rats caused a 12-fold increase in basal GH levels and a modest rise in GH pulse frequency. These two changes resulted in a 3-fold increase in both mean GH concentration and total GH secretion over 6 h. In female rats, chronic morphine reduced GH pulse amplitudes but did not significantly affect other parameters of GH secretion. By contrast, chronic naloxone treatment of female rats reduced basal GH levels by 64% without affecting GH pulse amplitudes or pulse frequency. These data suggest that endogenous opioid systems are involved in the regulation of the basal GH secretion in both male and female rats.

Animals↗
PubMed1993

Influence of in vivo reproductive endocrine state on growth hormone-releasing factor stimulated adenylate cyclase activity in anterior pituitary fragments.

The growth hormone releasing factor (GRF) stimulated adenylate cyclase activity was evaluated in membrane fractions of anterior pituitary glands from male and female rats and in gonadectomized rats following in vivo gonadal steroid treatments. The baseline adenylate cyclase activity was lower in random estrous cycle female rats as compared with males. When estrous cycle phases were evaluated, diestrus 1 females had a lower basal activity as compared with males, while proestrus females were similar to males. The maximal stimulation of adenylate cyclase activity by GRF (i.e. Vmax) was lower in random estrous cycle female rats than in males. This lower Vmax, relative to males, was more pronounced in diestrus 1 than in proestrus females. There was little difference in the ED50 for GRF-stimulated adenylate cyclase activity among these groups. The adenylate cyclase activity was altered 1 week after gonadectomy or 1 week after gonadectomy plus simultaneous in vivo gonadal steroid treatment. The expression of data as a function of whole tissue (content) or as a function of protein (concentration) influenced magnitude and direction of these treatment effects. This may reflect the proliferation of nonsomatotroph cell populations and altered protein synthetic activity following reproductive endocrine manipulations. When expressed as a whole tissue content, the baseline adenylate cyclase activity was unchanged after gonadectomy when compared to same-sex, gonadal-intact cohorts. However, an increase in the Vmax for GRF-stimulated adenylate cyclase activity was found in gonadectomized rats relative to sham-operated, gonadal-intact cohorts.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1993

Developmental and sex-related changes of the growth hormone axis in lean and obese Zucker rats.

The development and sex-related changes in the hypothalamic-pituitary GH axis were examined in lean and obese Zucker male and female rats from 6 to 12 weeks of age. Pituitary GH content was not different in any phenotype/sex group at 6 weeks. GH content increased with age in male rats, but at 10 and 12 weeks content was decreased in obese male rats relative to lean rats. GH content did not increase in female rats and there was no difference in content between lean and obese female rats. Hypothalamic GHRH content was not different between the groups. Hypothalamic SS content was decreased in obese male rats compared to lean male rats (95%) and in obese female rats compared to lean female rats (78%). Individual 6-hour plasma GH profiles from rats 6-7 weeks of age showed the characteristic sexually dimorphic GH secretory patterns. However, spontaneous GH secretion was dramatically reduced in obese animals when compared to sex-matched lean rats. GH peak amplitude (25% of lean) and mean GH concentration (19% of lean) were decreased in obese male rats without a significant alteration in GH peak frequency or baseline level. In obese female rats, the number of GH peaks, peak amplitude, baseline GH, and mean GH concentration were all decreased compared to lean. The reduction in peak amplitude (14% of lean) and in mean GH concentration (20% of lean) was similar to the reduction in obese male rats. Serum IGF-I concentrations were not different among the groups at 6 weeks. IGF-I levels in male rats increased with age but were not different between lean and obese rats. IGF-I concentrations in female rats were unchanged with time and were not different between lean and obese rats. Serum insulin was increased in obese male and female rats at 6 through 12 weeks. We conclude (1) GH secretion is depressed at 6-7 weeks in obese male and female rats with the magnitude of reduction similar to previous observations in male rats 12 weeks or older; (2) pituitary GH content is depressed only in obese male rats and occurs after the defect in GH secretion; (3) hypothalamic GHRH content is unchanged and hypothalamic SS is slightly to moderately decreased in obese rats; (4) serum IGF-I is not different between lean and obese rats; (5) obese male and female rats were hyperinsulinemic.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗
PubMed1992

Cocaine in utero enhances the behavioral response to cocaine in adult rats.

The effects of cocaine exposure in utero on cocaine-induced behaviors and dopamine (DA) transmission in the nigrostriatal and mesolimbic pathways were measured in adult rats. Pregnant rats received either saline or cocaine (1 or 3 mg/kg, IV) daily throughout gestation. When offspring were 3 months of age, locomotor and stereotypic behaviors were rated after an injection of either saline or cocaine (10 mg/kg, IP). Cocaine in utero increased the response to cocaine in adult offspring and increased basal locomotion in female offspring. Cocaine in utero increased amphetamine-stimulated release in female offspring but decreased release in males. On the other hand, male rats that had received cocaine in utero exhibited greater basal tritium release. One injection of cocaine increased amphetamine-stimulated [3H]DA release from striatal slices of male rats but not female rats. Neither cocaine in utero nor in vivo affected D2 DA receptor binding in striatum nor nucleus accumbens. Thus, cocaine in utero behaviorally sensitized animals to subsequent cocaine exposure and increased [3H]DA release from nigrostriatal endings, but the relationship of these two variables depended upon gender.

Animals↗
PubMed1992

Opiate modulation of growth hormone secretion is compromised during the steroid-induced luteinizing hormone surge.

Earlier studies from our laboratory have shown that treatments with gonadal steroids which cause a surge of luteinizing hormone (LH) blunt the effects of morphine on LH secretion, locomotor activity, nociception and temperature regulation. The present study was conducted to determine if the growth hormone (GH) response to morphine sulfate (MS) was also affected during steroid-induced LH surges. Adult ovariectomized female rats were primed with estradiol benzoate (EB: -49 h prior to P4 or oil injection) and/or progesterone (P4; 10.00 h). Seven and one half hours after P4 treatment, at the time of the steroid-induced LH surge, the GH response to an intravenous dose of 0.5, 2.0 or 5.0 mg/kg MS was determined. A GH peak response occurred at 15 min after drug administration and was maximal at the dose of 2 mg/kg MS in all groups. Although the timing of the GH rise was not altered in either EB/oil- or EB/P4-treated animals, a significant blunting of MS-induced GH secretion was observed across all doses of MS with a greater reduction being observed in EB/P4-treated animals. In a second study the GH response to opiates was investigated prior to and following the steroid-induced LH surge to determine if the suppression of opiate-induced GH secretion was confined to the time of the preovulatory LH surge. Before the LH surge (2.5 h), a mild suppression of opiate-induced GH secretion was observed only in EB/oil-treated animals. After the LH surge (13 h after P4 administration), morphine-induced GH secretion was similar in all groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Opiate stimulation of prolactin secretion is reversed by ovarian hormone treatment.

Previous studies have indicated that during the estradiol- and progesterone (P4)-induced surge in luteinizing hormone (LH), the effects of opiates on behavioral, autonomic and neuroendocrine functions are altered. In the present study, we further evaluated the apparent universality of alterations in opiate-mediated function during the LH surge by investigating the effects of morphine sulfate (MS) on prolactin (PRL) secretion during both the estradiol benzoate (EB) and the EB + P4-induced LH surges. All doses of MS tested (0.5, 2.0 and 5.0 mg/kg) resulted in significant increases in PRL secretion in nonestrogen-treated animals which did not show LH/PRL surges. During the LH/PRL surge induced by EB/P4 treatment, MS caused no change in the PRL secretion, while in EB/oil treated animals, a paradoxical and dose-dependent decrease in PRL secretion was observed. The suppression of PRL was 52, 68 and 80% of baseline respectively for the 3 doses of MS. Evaluation of the time dependence of MS on PRL secretion showed that the paradoxical suppression in EB/oil-treated animals was seen only during the LH/PRL surge, occurring at 17.30 h (7.5 h post P4 injection), and not before (12.30 h) or after (23.00 h) the steroid-induced LH/PRL surge. Finally, we assessed the role of pituitary dopamine receptors on the phenomenon of MS-induced PRL suppression in EB/oil rats. Domperidone (1mg/kg), a peripherally active D2 receptor antagonist, administered prior to the morphine challenge, attenuated the opiate-induced PRL suppression in EB/oil-treated animals suggesting that a dopaminergic mechanism is involved in this paradoxical response to morphine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Comparison of efficacy of cysteamine in depleting prolactin immunoreactivity in different hyperprolactinemic animal models.

We have examined the effects of cysteamine on its ability to deplete prolactin in various states of hyperprolactinemia. Administration of subtoxic doses of cysteamine (75 and 150 mg/kg,sc) dramatically reduces serum prolactin levels as well as pituitary prolactin content in a dose-dependent manner in estrogen-primed brown Irish ACI female rats. A similar dose-dependent decrease in anterior pituitary prolactin levels was observed in two ectopic prolactin secreting pituitary tumor models (MtTW15 and 7315a). However, a significant reduction in serum prolactin levels was seen in these same tumor bearing animals at only the 150 mg/kg dose of cysteamine. Interestingly, the prolactin content of each of the prolactin secreting tumors, although reduced by cysteamine administration, the effect was neither dose-dependent nor as dramatic as that observed in the anterior pituitary gland proper. These data demonstrate that cysteamine can significantly lower prolactin concentrations in hyperprolactinemia. Further, ectopic prolactin secreting pituitary tissue appears less sensitive to the prolactin-depleting effects of cysteamine. This latter finding may explain, in part, why serum prolactin levels were not as severely reduced in the ectopic tumor bearing female rats as in estrogen-induced hyperprolactinemic animals.

Analysis of Variance↗
PubMed1991

Hormonal regulation of rat hypothalamic neuropeptide mRNAs: effect of hypophysectomy and hormone replacement on growth-hormone-releasing factor, somatostatin and the insulin-like growth factors.

Hormonal feedback regulation of hypothalamic peptides putatively involved in growth hormone (GH) regulation has been studied by measurement of steady-state mRNA levels in male hypophysectomized rats with or without thyroid hormone, corticosterone, testosterone or GH replacement. Hypothalamic GH-releasing factor (GRF) mRNA levels increased progressively following hypophysectomy to 420% of sham levels after 15 days while hypothalamic insulin-like growth factor I (IGF-I) and insulin-like growth factor II (IGF-II) mRNA levels decreased to less than 40% of sham levels. Whole hypothalamic somatostatin mRNA levels were not significantly different from sham. One week of continuous GH infusion restored hypothalamic IGF-I mRNA to levels (95%) indistinguishable from those in sham-operated controls but had no effect on either IGF-II or GRF mRNA. Thyroid hormone, corticosterone and testosterone treatment without GH had no effect on the hypophysectomy-induced reduction of either IGF-I or IGF-II mRNA levels but reversed the elevation of GRF mRNA. We conclude that hypothalamic IGF-I may be involved in GH feedback regulation and thus may function as a hypothalamic modulator of GH. In contrast, IGF-II may be regulated by one of the pituitary trophic hormones but not by GH or the target hormones tested. Finally, hypothalamic GRF mRNA regulation appears to be complex and may include target hormone feedback.

Animals↗
PubMed1991

Evaluation of the sites of opioid influence on anterior pituitary hormone secretion using a quaternary opiate antagonist.

Studies were conducted to determine the effects of a potent narcotic antagonist, nalmefene methyliodide, which does not cross the blood-brain barrier (BBB), on the secretion of anterior pituitary hormones and on the anterior pituitary hormonal response to morphine sulfate. Since the localization of opiate receptor responses to inside or outside the BBB depended upon the relative ability of nalmefene HCl and nalmefene methyliodide to penetrate the BBB, initial studies were conducted to document that nalmefene methyliodide does not block opiate receptors inside the central nervous system. While nalmefene HCl blocked morphine-induced antinociceptive responses at doses as low as 10 micrograms/kg, nalmefene methyliodide was ineffective in this regard at doses as high as 500 micrograms/kg. The luteinizing hormone (LH) suppression and prolactin (PRL) secretion induced by morphine was blocked by both nalmefene HCl and its methyliodide analogue, indicating that the opioid receptor type which mediates both responses is located outside the BBB. We observed that basal PRL levels were reduced by nalmefene HCl but not by nalmefene methyliodide indicating that basal PRL secretion is influenced by opioid neurons inside the BBB. While nalmefene HCl blocked morphine-induced suppression of thyroid-stimulating hormone (TSH) release, nalmefene methyliodide was less effective, suggesting that opiate-induced TSH suppression may be mediated by receptors located both within and outside the BBB. Nalmefene HCl caused a growth hormone (GH)-secretory response by itself, but nalmefene HCl and nalmefene methyliodide were ineffective in blocking morphine-induced GH secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesia↗
PubMed1991

Effects of gonadal steroids on clearance of growth hormone at steady state in the rat.

Gonadal steroids have been implicated in the modulation of GH secretory patterns in the rat. We have studied the effects of testosterone (T) or estradiol (E2) on the steady state clearance (Clss) and plasma half-life (t1/2) of GH in male and female rats (n = 4-6/group). A femoral and a jugular cannula were surgically implanted into adult Sprague-Dawley rats. At the time of cannulation some rats were orchidectomized, and a Silastic capsule containing E2, T, or nothing was implanted sc. After recovery from surgery, either purified rat GH or a crude extract of rat pituitary was infused iv to attain steady state plasma GH concentrations. Blood samples were taken every 30 min for 4 h during the infusion, and nine samples were taken at 2.5-min intervals immediately after stopping the infusion. The mean Clss for GH in female rats were significantly (P less than or equal to 0.001) less than that in males, whereas the t1/2 did not differ between the two groups. Neither the Clss nor the t1/2 was affected by castration in males or females. The Clss of GH in E2-treated castrated males was significantly less (P less than 0.001) than that for intact males, but the t1/2 did not differ between the two groups. The Clss for GH was greater in T-treated ovariectomized rats than in intact females, but the t1/2 did not differ with T treatment. These results suggest that 1) the Clss for GH is lower in female rats than in males; 2) 4 weeks of gonadectomy has no effect on the Clss in males or females; 3) under experimental conditions, E2 decreases and T increases the Clss for GH; and 4) the t1/2 for GH is not different in males or females. The steroid-induced changes in Clss in the absence of detectable effects on t1/2 suggest that factors affecting the volume of distribution at steady state (i.e. plasma GH-binding proteins or GH heterogeneity) are involved in the effects of gonadal steroids on GH clearance in the rat.

Animals↗
PubMed1991

Signal transduction systems in growth hormone-releasing hormone and somatostatin release from perifused rat hypothalamic fragments.

The role of signal transduction systems was examined in the secretion of GH-releasing hormone (GHRH) and somatostatin (SS) from perifused rat hypothalamic fragments. Forskolin, an adenylate cyclase activator, stimulated the release of GHRH and SS in a concentration-dependent manner (10-100 microM) with greatest stimulation for GHRH at 100 microM (mean +/- SE, 249 +/- 14%) and for SS at 30 microM (172 +/- 18%). (Bu)2cAMP also augmented GHRH and SS release. The protein kinase-C activator phorbol 12-myristate 13-acetate did not significantly stimulate basal GHRH or SS release at concentrations of 10 nM to 1 microM. The calcium ionophore A23187 enhanced the release of GHRH and SS in a concentration-dependent manner (2-20 microM), with the greatest responses of 282 +/- 50% at 10 microM and 189 +/- 24% at 20 microM, respectively. Potentiation by phorbol 12-myristate 13-acetate of forskolin-stimulated GHRH and SS release was observed. A23187 at 10 microM did not enhance forskolin-stimulated GHRH release, but did potentiate forskolin-stimulated SS release in a more than additive response. We conclude that there is 1) cAMP stimulation of hypothalamic GHRH and SS release, 2) a modulating role of protein kinase-C on cAMP-stimulated release of GHRH and SS, 3) a stimulatory role of the calcium messenger system for GHRH and SS release, 4) interaction of the signal pathways with differences in net GHRH and SS responses, and 5) a modulatory effect of protein kinase-C in perifused hypothalamic fragments which differs from the stimulation of basal GHRH and SS release reported in fetal-derived hypothalamic cell cultures. Our observations suggest an important regulatory role of interacting signal transduction systems in the hypothalamic secretion of GHRH and SS.

Animals↗
PubMed1991

Growth hormone secretion in the obese male rat: modulation by the gonadal and thyroid axes.

The present study was designed to determine if either the testes or thyroid plays a role in the blunted GH secretion observed in the obese male rat. Analysis of individual GH secretory profiles in adult lean and obese Zucker rats revealed a severe attenuation of both mean GH levels and individual GH pulse amplitudes in obese rats as well as a significant lowering of circulating testosterone levels. Normalization of the testosterone levels by the use of sc Silastic capsules elevated but did not normalize GH pulse amplitudes in obese animals. Further, the GH response to either rat GH-releasing factor (5 mu/kg) or morphine (1 mg/kg) were reduced in obese male rats. In contrast, the thyroid axis showed minimal change in obese animals. A slight reduction in free T3 levels in serum was observed while free and total T4 and total T3 were normal in obese rats. Further, mean circulating TSH levels and the TSH response to 500 ng/kg TRH were not altered in fat rats. Thus, the reduced GH secretion observed in the obese rat is not paramount to an alteration in either gonadal or thyroid function. This alteration of the GH secretory axis may not be attributable to one factor but more likely caused by a number of concomitant deficits which may act in concert to manifest impaired GH secretion.

Animals↗
PubMed1990

Effects of nucleus basalis lesions on cerebral cortical concentrations of corticotropin-releasing hormone (CRH)-like immunoreactivity in the rat.

The present study was designed to determine the effects of partial cholinergic denervation on parietal cortical corticotropin-releasing hormone-like immunoreactivity (CRH-LI) in the rat at different ages. Young adult rats received either unilateral or bilateral ibotenic acid infusions into their nucleus basalis, destroying most of the acetylcholinesterase-positive neurons in that region. Parietal cortical levels of CRH-LI were assayed 2.5, 10, 14 and 19 months after placement of nucleus basalis lesions. Parietal CRH-LI was elevated at 10, 14 and 19 months in bilaterally lesioned animals, while unilateral lesions had no effect on CRH-LI.

Aging↗
PubMed1990

Glucose modulation of skin temperature responses during morphine withdrawal in the rat.

Studies were undertaken to determine the effects of acute alterations in plasma glucose levels on the tail skin temperature (TST) response of morphine-dependent rats to naloxone-precipitated withdrawal. In morphine-dependent rats, treatment with dextrose at doses of 0.5 or 2.5 g/kg did not alter the normal 6.0 +/- 0.3 degrees C TST response to naloxone. However, treatment with 5, 10 or 20 g dextrose/kg, which increased plasma glucose to 250 mg/dl or greater, blocked the TST response during morphine withdrawal. In contrast, an IV injection of 2.5 IU insulin (Na-porcine)/kg, which reduced plasma glucose for 2 h, caused a delayed TST response of 4.7 +/- 0.4 degrees C in control rats and exaggerated the TST response normally observed in morphine-dependent rats treated with naloxone. Collectively, these data indicate that acute hyperglycemia can attenuate and hypoglycemia can enhance the skin vasodilation which accompanies precipitated morphine withdrawal. In view of our observation that naloxone-precipitated morphine withdrawal caused a marked increase in blood glucose, the sympathetic activation associated with opiate withdrawal may be intended to elevate blood glucose and thereby limit the manifestation of the withdrawal response.

Animals↗
PubMed1990

The effect of cellular glucoprivation on skin temperature regulation in the rat.

Studies were undertaken to determine the effects of cellular glucoprivation on temperature responses in morphine-addicted and placebo-treated rats and to compare these responses to those observed during naloxone-precipitated morphine withdrawal. Naloxone caused a tail skin temperature (TST) response of 5.7 +/- 0.5 degrees C in morphine-dependent rats. Intraperitoneal administration 2-deoxyglucose (2DG) caused TST responses in placebo-treated and morphine-dependent rats of 4.8 +/- 0.6 and 6.2 +/- 0.5 degrees C, respectively. These data indicate that the activation of the sympathetic nervous system by cellular glucoprivation causes a TST response which is equivalent in magnitude to that induced by precipitating withdrawal with naloxone. This effect of 2DG appears to be mediated by the brain, since icy administration of 2DG caused a TST response, similar to that induced by naloxone treatment of morphine-dependent rats. Collectively, these data suggest that a TST increase is a component of the response of rats to local brain glucoprivation induced by 2DG.

Animals↗
PubMed1990

Growth hormone (GH) secretory dynamics in animals administered estradiol utilizing a chemical delivery system.

We have utilized a redox chemical delivery system (CDS) for the brain targeting of estradiol (E2) to ascertain its effects on GH secretory patterns in adult intact male rats. The E2-CDS (1.0 mg/kg) dissolved in 20% hydroxypropyl-cyclodextrin (HPCD), E2 (1.0 mg/kg) alone in 20% HPCD, or 20% HPCD was administered intravenously. GH secretory profiles, plasma steroid levels, and anterior pituitary levels of hormones were determined 1 week following steroid injection. Whereas E2 in HPCD and HPCD treatment did not alter masculine GH secretory patterns, animals administered the E2-CDS displayed disrupted GH patterns with attenuated individual pulse amplitudes and significantly elevated GH baseline levels. Moderate pituitary hyperplasia was evident only in the E2-CDS group of animals. Plasma testosterone (T) concentrations were reduced in only the E2-CDS group. T replacement reduced E2-CDS-associated pituitary hyperplasia and preserved the masculine GH secretory profiles, with only a slight reduction in individual GH peak amplitudes being observed. T replacement did not prevent the increase in pituitary and plasma levels of PRL associated with E2-CDS treatment but did block both the increase in pituitary GH content and the hyperplasia associated with prolonged E2 exposure. E2 given alone induced a significant increase in both GH and PRL in the pituitary without establishment of pituitary hyperplasia or elevated plasma PRL levels. These data indicate that E2-CDS is an effective mode of steroid administration. Changes in GH secretory dynamics, pituitary levels of GH, and degree of hyperplasia are dependent upon the chemical design of the delivery system for E2. Concomitant T therapy can prevent some of the changes in GH secretion associated with high-dose E2 exposure.

2-Hydroxypropyl-beta-cyclodextrin↗