Biomedical subjects

W W Morgan

Publications and source records attributed to W W Morgan.

At least 55 records · Page 3Linked to original sources

PubMed1985

The effect of long-term diethylstilbestrol treatment or hyperprolactinemia on the response of the tuberoinfundibular dopamine neurons to elevated prolactin.

Adult male rats were rendered hyperprolactinemic by two different methods. Some animals received subcutaneous implants of diethylstilbestrol (DES) or empty capsules. After 2 months the capsules were removed. Other rats received 3 anterior pituitary homografts under the kidney capsule or had sham surgery. The DES-treated rats were killed 8 months after capsule removal, while pituitary-grafted rats were killed 4 or 12 months after surgery. The DES-treated rats had hyperplastic anterior pituitaries, and both the DES-treated rats and the rats with anterior pituitary homografts were hyperprolactinemic. The activity of the TIDA neurons, as evidenced by dopamine (DA) synthesis in the median eminence (ME), was markedly and comparably elevated in both of these experimental groups of rats when compared to their respective controls. These data: show that the maintenance of hyperplastic pituitaries 8 months after DES withdrawal is not due to impaired function of the TIDA neurons; and provide no evidence for a neurotoxic effect of prolonged hyperprolactinemia on the response of the TIDA neurons to elevated PRL.

Animals↗

PubMed1985

Hypothalamic catecholamine histofluorescence in dwarf mice.

Brains of growth hormone (GH)- and prolactin (PRL)-deficient Ames (df/df) and Snell (dw/dw) dwarf mice and normal mice of the same strains were examined for catecholamine (CA) histofluorescence, with particular emphasis upon the hypothalamic tuberoinfundibular (A12) (arcuate nucleus/median eminence) region, which plays a role in the regulation of both GH and PRL. Dwarfs and normal animals of both types also were treated with a drug regimen to deplete sequentially neuronal CA stores (reserpine), inhibit CA oxidation (nialamide) and load dopaminergic A12 cells with exogenous transmitter (norepinephrine), in order to test viability and axonal transport capacity of A12 neurons. In both types of dwarfs, compared with normals, fluorescence was markedly reduced in the zona externa of the median eminence, which is normally rich in terminals from A12 neurons. Fluorescence in the median eminence was particularly weak in Ames dwarfs, and A12 perikarya were difficult to discern in this group. Snell dwarfs showed reduced fluorescence of A12 perikarya when compared with the brightly fluorescent perikarya seen in normal mice. In supraoptic and paraventricular nuclei, and in the zona interna of the median eminence, CA fluorescence attributable to NE was comparable among dwarfs and normals; fluorescence of dopaminergic perikarya in substantia nigra was also unaffected in dwarfs. Exogenously administered NE effected enhanced fluorescence of A12 perikarya in normal mice and in Snell dwarfs; NE treatment in the Ames dwarf, however, failed to increase significantly the faint fluorescence of A12 cell bodies. The results indicate that dopaminergic A12 neurons in Snell dwarf mice are present and viable.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1985

Hamster and rat pineal gland beta-adrenoceptor characterization with iodocyanopindolol and the effect of decreased catecholamine synthesis on the receptor.

Rat and hamster pineal glands were used in binding studies to characterize their beta-adrenoceptors with a new specific antagonist ligand, iodocyanopindolol. The receptors were saturable, and the ligand was selective and demonstrated stereospecificity for both species. The rat pineal had a 20-fold greater density of beta-adrenoceptors, while the affinity was one-third that of the hamster pineal. utilizing this radioligand, we examined the effects of decreased sympathetic input to the pineal on beta-adrenergic receptors in both species. Decreased noradrenergic input to the pineal gland of the hamster was accomplished by superior cervical ganglionectomy, or by exposing the animals to continuous light for 36 hours. Parallel studies were conducted with hamster pineal gland in which catecholamine synthesis was measured. The results indicate that a selective decrease in catecholamine synthesis in the hamster pineal does not change the beta-adrenoceptor density or affinity. In contrast, a concomitant increase in beta-adrenoceptor density but not affinity occurs in the rat pineal gland after similar decreased sympathetic input.

Animals↗

PubMed1985

Altered sensitivity to an opiate antagonist, naloxone, in hyperprolactinemic male rats.

An increase in endogenous opiatergic tone has been suggested as a mechanism for suppression of gonadotropin release in hyperprolactinemia (hyperPRL). In an attempt to evaluate this possibility in hyperprolactinemic males, we have examined the effects of a specific opiate antagonist, naloxone, on plasma LH levels in adult male rats rendered hyperprolactinemic by transplanting two pituitary glands underneath the kidney capsule. Naloxone was administered intravenously (i.v.) at different dose levels (0.2,2, or 20 mg/kg body weight) and blood samples were collected at intervals ranging from 15 to 60 min after naloxone administration. In all experiments, plasma LH levels in the sham-operated controls were significantly increased after naloxone administration, while those in the pituitary-grafted group remained unaltered. Injecting naloxone daily for 3 or for 10 days failed to alter plasma LH levels in both sham-operated and pituitary-grafted animals. Administration of LHRH induced a 7-fold increase in plasma LH levels in both the pituitary-grafted animals and the sham-operated controls. These studies demonstrate that hyperPRL interferes with the naloxone-induced rise in circulating LH levels in the male rat.

Animals↗

PubMed1985

Time course of induction of prolactin-secreting pituitary tumors with diethylstilbestrol in male rats: response of tuberoinfundibular dopaminergic neurons.

3,4-Dihydroxyphenylalanine (Dopa) accumulation and dopamine (DA) and noradrenaline levels were measured in the median eminence (ME) of Fisher 344-derived inbred male rats. These animals had been treated with Silastic capsules containing 8-9 mg diethylstilbestrol (DES) or with empty capsules for 3, 7, 14, or 30 days and had the pellets removed 22 days before killing. In an additional group of rats, the DES pellets were continuously present until killing. Blood was collected before treatment was started, at pellet removal, 2 days before killing, and at killing. All rats received 50 mg/kg hydroxybenzylhydrazine (NSD-1015), an L-aromatic amino acid decarboxylase inhibitor, iv 30 min before killing, and the subsequent accumulation of Dopa provided an indirect measure of DA synthesis. Treatment with DES for 7, 14, or 30 days produced an elevation of circulating PRL. Although this elevation of PRL levels was substantially reduced after pellet removal, this parameter was still elevated in the 30-day DES-treated rats at the time of killing. Pituitary levels of PRL and PRL secretion in vitro were elevated in both the 14- and the 30-day DES-treated rats. Rats treated continuously with DES had markedly elevated circulating PRL levels, and the pituitary content and in vitro release of this hormone were also enhanced. DA synthesis, as evidenced by the accumulation of Dopa after NSD-1015 treatment, was significantly elevated in the ME of rats treated with DES for 14 or 30 days while the concentration of DA was reduced in the 30-day treated rats. DA synthesis in the ME was not different from controls in rats treated continuously with DES, although DA levels were markedly suppressed. Pituitary weights were elevated, and BWs were reduced in rats continuously treated with DES. Pituitary weights were also elevated in rats treated with DES for 30 days although not as much as in rats treated continuously with DES. A progressive reduction in seminal vesicles and testes weights was observed with longer periods of DES treatment. Testosterone levels were suppressed in rats treated continuously with DES. In a second study in which rats received DES pellets for 2 months and then the pellets were removed for 4 months, 1 mg bromocriptine sc markedly suppressed the elevated levels of circulating PRL. Collectively, these results show that 14 to 30 days of DES treatment are sufficient to induce PRL-secreting adenohypophysial tumors in adult male rats, although considerable involution of the tumor appears to occur after pellet removal.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1985

Effect of hypophysectomy and subsequent prolactin administration on hypothalamic 5-hydroxytryptamine synthesis in ovariectomized rats.

Increased levels of PRL whether of natural or experimentally induced cause result in an increased turnover of the putative PRL-inhibiting factor dopamine (DA) within tuberoinfundibular neurons, suggesting that PRL can regulate its own release via a short loop feedback mechanism. Although it is known that activation of the hypothalamic 5-hydroxytryptamine (5HT) system stimulates PRL release, the possibility that PRL could alter metabolism or release of this amine within the hypothalamus has not been examined. In the first experiment, bilaterally ovariectomized adult Sprague-Dawley rats were divided into three groups: hypophysectomized rats (HYPOX), HYPOX rats injected sc with 0.5 mg kg-1 ovine PRL (oPRL) at 1000 h and 1800 h on the day before killing the rats (HYPOX + PRL), and rats without further surgical manipulation (controls: NON-HYPOX). Three weeks after surgical manipulation, the rats were injected iv with 100 mg kg-1 NSD-1015 and killed 15 or 30 min later. 5-Hydroxytryptophan accumulation was measured by HPLC with electrochemical detection as an index for the rate of 5HT synthesis. The rate of 5HT synthesis was increased in the median eminence (ME) and mediobasal hypothalamus (MBH) but not anterior hypothalamus of HYPOX rats in comparison to the rate of synthesis of this amine in these areas of control rats. This effect was reversed in the ME and MBH of HYPOX + PRL rats. If 5HT stimulation of PRL release were achieved by 5HT inhibition of the tuberoinfundibular DA system as has been proposed previously, then it is also conceivable that the PRL short loop feedback on hypothalamic 5HT synthesis as suggested by the results of the first experiment is mediated via this DA system. To test this hypothesis in the second experiment, adult Sprague-Dawley rats were injected at 1000 h and 1800 h on the day before their killing with 0.5 mg kg-1 oPRL; 0.5 mg kg-1 oPRL, and 10 mg kg-1 pimozide (PIM) a DA receptor antagonist; 10 mg kg-1 PIM; or, on the day of their killing, with 1 mg kg-1 apomorphine (APO), a DA receptor agonist. An additional group of ovariectomized-HYPOX as well as a group of ovariectomized-NON-HYPOX rats were also included in this experiment. On the day of the experiment the rats were injected iv with 100 mg kg-1 NSD-1015 and killed 30 min later. 5-Hydroxytryptophan accumulation was measured by HPLC with electrochemical detection as an index of the rate of 5HT synthesis.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1985

Development of tolerance to chronic barbital treatment in the cerebellar cyclic guanosine monophosphate system and its response to subsequent barbital abstinence.

Female Sprague-Dawley rats were placed on a 6-week barbital feeding regimen, previously documented to result in drug tolerance and dependence. Groups of animals were sacrificed on the 2nd and 5th day of each week, up to week 5, or at various time points following drug withdrawal. Cerebellae and cerebral cortices were collected for cyclic GMP (cGMP) measurements. Initial suppressions of cGMP were seen in both the cerebellum and cerebral cortex during early weeks of the feeding regimen. These gradually returned essentially to control levels by the end of 5 weeks, a finding consistent with the development of tolerance to chronic barbiturates in the cGMP system. Barbital was withdrawn after 6 weeks of chronic administration. Four hours after withdrawal, a dramatic elevation of cerebellar cGMP was seen. This elevation was coincident with a significant decline in serum barbital levels and preceded the onset of weight loss, spontaneous seizures and locomotor depression. The elevation of cGMP was less dramatic but still apparent at 72 hr postwithdrawal when all other evaluated parameters had returned to control values. Alterations of cGMP during chronic barbital treatment and subsequent to abrupt barbital withdrawal may reflect aberrations in the function of neurotransmitter pathways involved in regulating cGMP in the cerebellum. Further, the elevation of cGMP after barbiturate withdrawal may itself play a functional role in the manifestation of barbital abstinence.

Animals↗

PubMed1984

Ontogeny of mechanisms which regulate light/dark differences in retinal dopamine synthesis.

The ability of bicuculline, a GABA antagonist, to enhance dopamine (DA) synthesis in retinas of rats 1, 4, 7, 15 and 60 days after eye opening was assessed and compared to the time course of postnatal development of the light-induced increase in DA synthesis. The accumulation of dihydroxyphenylalanine (DOPA) following administration of the L-aromatic amino acid decarboxylase inhibitor, NSD 1015, was used to estimate DA synthesis. In dark-adapted rats, neither bicuculline nor light enhanced DOPA accumulation 1 day after eye opening, but on the remaining days either treatment significantly augmented DA synthesis, and by day 15 the effects were as great as those observed in adult retinas. At each time point, the magnitude of the drug effect on DA synthesis in the dark was similar to that observed following light exposure. These results suggest that an endogenous GABAergic input to the DA neurons appears at the same time as the acquisition of the dopaminergic response to light. The effect of bicuculline treatment on DA synthesis in light-exposed animals was also assessed. At 4 and 7 days the drug significantly enhanced DOPA accumulation over that produced by exposure to light alone, but on later days bicuculline exerted no such additive effect. These data imply that early in the maturation of the light response mechanisms other than removal of an inhibitory GABAergic tone may be partially responsible for excitation of the DA neurons.

Adaptation, Physiological↗

PubMed1984

Depression of cerebellar cGMP by barbiturates. Relationship to locomotor activity.

The intravenous administration of pentobarbital, phenobarbital or barbital produced a dose-related depression of the levels of cyclic guanosine monophosphate (cGMP) in the cerebellum of male Sprague-Dawley rats. This depression of cGMP occurred with doses of pentobarbital and barbital which did not reduce locomotor activity. Further, the time-course of the recovery of locomotor activity following the administration of an anesthetic dose of pentobarbital preceded that for the recovery of the levels cGMP in the cerebellum. In a separate study, pretreatment with picrotoxinin reversed the significant depression of cGMP in the cerebellum produced by the smallest dose of pentobarbital. Collectively, these data suggest that the effects of the barbiturates on cGMP in the cerebellum are not exclusively or predominantly the result of a drug-related depression of locomotor activity and may be, at least partially, mediated via a barbiturate-induced potentiation of a GABA receptor-mediated mechanism.

Animals↗

PubMed1984

The effects of chronic oral administration of barbital on cerebellar cyclic GMP.

Female Sprague-Dawley rats received increasing dosages of barbital mixed with ground LabBlox for 7 weeks. At the end of this period, the rats were given doses of barbital acutely, and the effects of this treatment on levels of cyclic guanosine monophosphate (cGMP) in the cerebellum were determined. Chronic administration of barbital resulted in a slight depression of cGMP compared to control values. The acute injections of barbital produced a dramatic, dose-related decrease in levels of cerebellar cGMP in both control (C) and barbital-dependent (BD) animals. This depression of cGMP is of particular interest because the barbital-dependent animals had considerably higher levels of serum barbital than matched controls. The overall effect of chronic administration of barbital was right shift in the dose-response curve for levels of cGMP following acute injections of barbital. No differences in motor activity were noted between the dependent and control animals. It is believed that these results indicate that a high degree of tolerance is developed in the cGMP system of the cerebellum after chronic oral administration of barbital. Further investigation of this neurochemical parameter may provide useful information in the study of mechanisms mediating the dependence and the abstinence syndrome to barbiturates.

Administration, Oral↗

PubMed1984

24-Hour changes in catecholamine synthesis in rat and hamster pineal glands.

The purpose of this study was to examine the 24-hour variation in endogenous tyrosine hydroxylase (TH) activity and thus catecholamine (CA) synthesis in the hamster and rat pineal gland. To determine CA synthesis a time course of the accumulation of dihydroxyphenylalanine (DOPA) after DOPA decarboxylase inhibition with m-hydroxybenzylhydrazine (NSD-1015) was measured at 0, 15 and 30 min by liquid chromatography with electrochemical detection. Animals were under long photoperiods (LD 14:10; lights on at 06.00 h). In the hamster pineal gland, CA synthesis was greater in the dark (24.00 h) (0.017 ng/pineal/min) than in the light (12.00 h) (0.008 ng/pineal/min). Similarly, CA synthesis in the rat pineal was 0.037 ng/pineal/min (dark) and 0.005 ng/pineal/min (light). In a 24-hour study, animals were injected with NSD-1015,30 min prior to killing to determine if 24-hour changes were present in CA synthesis. In the hamster, DOPA in the dark (p less than 0.001) was significantly greater than in the light (1.33 +/- 0.42 ng/pineal at 06.00 h; 0.33 +/- 0.07 at 13.00 h) in this study. No significant difference was measured in norepinephrine (NE) concentration during this 24-hour period. In the rat, DOPA accumulation was significantly different (p less than 0.001) in the dark as compared to the light (0.86 +/- 0.09 ng/pineal at 03.00 h; 0.21 +/- 0.08 at 12.30 h). Within this 24-hour period, NE concentration fluctuated significantly between 2.28 +/- 0.33 ng/pineal (15.30 h) to 4.65 +/- 0.59 (05.30 h). These results indicate for the first time a definite 24-hour rhythm in endogenous TH activity and NE synthesis in the hamster pineal gland even though NE content does not change. In addition, a 24-hour change in CA synthesis and content is present in the rat pineal gland.

Animals↗

PubMed1984

Effects of estrogen-induced hyperprolactinemia on endocrine and sexual functions in adult male rats.

Chronic estrogen treatment can lead to development of prolactin (PRL) secreting pituitary tumors. We have tested the ability of diethylstilbestrol (DES) to produce persistent hyperprolactinemia (hyperPRL) in adult male rats and examined the effects of this treatment on hypothalamic-pituitary-testicular function, adenohypophyseal structure, copulatory behavior and fertility. Silastic capsules containing approximately 5 mg DES were subcutaneously implanted into adult male CDF (F-344)/CrlBR rats and removed 15 or 20 weeks later. Extreme hyperPRL, as well as suppression of plasma LH and FSH levels, persisted after DES capsules were removed. In contrast, plasma testosterone levels increased rapidly after removal of DES capsules and reached normal levels within 4-6 weeks. Copulatory behavior was assessed on two occasions between 7 and 14 weeks after removal of the DES capsules and was found to be suppressed in DES-treated rats, as evidenced by significant increases in latencies to mount, to intromit and to ejaculate. Moreover, when the animals were placed with normal females, the interval until conception was significantly greater in DES-treated than in control males. In spite of these differences in copulatory behavior, 10 of 11 DES-treated males were fertile. At autopsy, 44 weeks after capsule implantation (i.e. 24 or 29 weeks after capsule removal), DES-treated rats had marked enlargement of the anterior pituitary, increased weights of the lateral prostate and the adrenals, increased levels of testicular hCG-binding sites, reduced concentration of dopamine and norepinephrine in the median eminence and increased concentration of LHRH in the preoptic area.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Glands↗

PubMed1983

Effect of strychnine and of bicuculline on dopamine synthesis in retinas of dark-maintained rats.

The intravitreal administration of strychnine produced a significant elevation of dopamine (DA) synthesis in the retinas of dark-adapted rats. Strychnine had no antagonistic effect on the ability of muscimol to suppress the normal increase in retinal DA synthesis observed after exposure of rats to light. This latter observation suggests that strychnine is not merely acting in a non-selective fashion to suppress the inhibitory GABAergic tone exerted on the DA neurons in darkness. These results suggest that there may be a direct or indirect strychnine-sensitive input to the retinal DA neurons in the dark. This input may not be glycinergic, however, as even high dosages of glycine did not suppress the light-mediated enhancement of DA synthesis in the retina.

Animals↗

PubMed1983

Extended exposure to continuous low intensity light abolishes the photosensitivity of retinal dopamine neurons.

Male Sprague-Dawley rats were divided into 2 groups. One group (experimental) was housed for 6 months in continuous low intensity light while the other (control) was exposed to standard 14 hr light: 10 hr dark cyclic lighting conditions for the entire time. For both the control and experimental groups the light intensity was 350-700 Lux. After 6 months, the experimental rats were returned to cyclic lighting. At one week and again at 2 months the light aversion behavior of all rats was tested in a light/dark test box. The experimental rats chose the dark side of the box only 58% of the time while control animals preferred the dark 79% of the time. Since rats normally are nocturnal and avoid light, these results suggest that the experimental rats may have permanently lost a functionally significant portion of the ability to detect light. After the second behavioral test all rats were dark adapted and 15 hr later the effect of short term (30 or 60 min) exposure to light on DA turnover in one retina from each rat was assessed. The other retina from each rat was fixed and examined histologically. Light significantly enhanced the alpha methyl-p-tyrosine induced decline of DA in the retinas of the control rats but exerted no similar effect in the experimental animals. The retinal DA contents of the experimental rats were substantially depleted. Histological examination suggested that the outer nuclear layers of the experimental retinas were more severely damaged than those from rats exposed to continuous light for 4 months but still contained a few pycnotic photoreceptor nuclei and nearly normal looking inner neural layers. These results indicate that extended exposure to light eventually abolishes light aversion behavior and at this time there is also a loss of the photosensitivity of the dopaminergic amacrine neurons.

Animals↗

PubMed1983

Effects of excitatory amino acids on dopamine synthesis in the rat retina.

Intraocular administration of quisqualate but not of N-methyl-D-aspartate or kainate augments dopamine synthesis in the retinas of dark-maintained rats. The effect of quisqualate is dosage-dependent but not blocked by the glutamate antagonist, glutamate diethyl ester. These results are the first to show that the quiescent dopamine neurons of the dark-adapted rat retina can be activated by an excitatory amino acid analogue of the putative endogenous neurotransmitter, glutamate.

Amino Acids↗

PubMed1983

Use of gamma-aminobutyric acid (GABA)-transaminase inhibitors and a GABA uptake inhibitor to investigate the influence of GABA neurons on dopamine-containing amacrine cells of the rat retina.

The effects of inhibiting gamma-aminobutyric acid-transaminase (GABA-T) with aminooxyacetic acid or with gabaculine and inhibiting GABA uptake with nipecotic acid on dopamine (DA) synthesis in the retina of light-exposed rats were studied. 3,4-Dihydroxyphenylalanine (Dopa) accumulation after the inhibition of L-aromatic amino acid decarboxylase with NSD-1015 was used as an index of DA synthesis. The GABA-T inhibitors significantly increased GABA levels in the retina but had no effect on retinal Dopa accumulation in the light. Dopa accumulation was significantly inhibited at a high dosage by nipecotic acid alone and by low dosages of nipecotic acid in rats pretreated with either aminooxyacetic acid or gabaculine. The dosages of nipecotic acid which inhibited Dopa accumulation in the light also inhibited [3H]GABA uptake in the retina. The inhibitory effects of gabaculine and nipecotic acid on Dopa accumulation appeared to occur at least partially via GABA receptors because their action was significantly reversed by the GABA antagonist bicuculline methiodide. These experiments thus suggest that endogenous GABA can suppress the light-evoked increase in DA synthesis in the rat retina and support previous studies which concluded that an inhibitory GABA input may at least partially regulate the activity of the DA neurons in the retina of rats.

4-Aminobutyrate Transaminase↗

PubMed1982

Adaptation of retinal dopamine neuron activity in light-adapted rats to darkness.

The activity of the retinal dopamine neurons was studied in light-adapted rats exposed to darkness for periods ranging from 10 min to 15 h. Dihydroxyphenylalanine (DOPA) accumulation, following inhibition of L-aromatic amino acid decarboxylase with NSD-1015, was used as an index of dopamine neuronal activity. After only 10 min of darkness, DOPA accumulation had decreased to levels found in rats dark-adapted for 15 h.

Acclimatization↗

PubMed1982

Benzodiazepines suppress the light response of retinal dopaminergic neurons in vivo.

Sedative dosages of the benzodiazepine, diazepam (76 micro mol/kg, i.p.), reduce the light-evoked increase in retinal dopamine turnover, while intraocular applications of the water-soluble benzodiazepine, flurazepam (0.50 or 1.0 micro mol/eyeball), produce a dose-dependent suppression of light-enhanced dopamine synthesis. These results provide the first evidence that the benzodiazepines alter a physiologically important retinal response in vivo. They also suggest that some the visual effects produced by the benzodiazepines may have an intraretinal locus of action.

Animals↗