Biomedical subjects

W W Morgan

Publications and source records attributed to W W Morgan.

At least 37 records · Page 2Linked to original sources

PubMed1988

Anticonvulsive activity of several excitatory amino acid antagonists against barbital withdrawal-induced spontaneous convulsions.

Several excitatory amino acid antagonists were tested for an ability to prevent spontaneous convulsions seen during the barbital abstinence syndrome in rats. Barbital-dependent animals were continuously infused intracerebroventricularly (i.c.v.) for the first 48 h following barbital withdrawal with either saline, 2-amino-7-phosphonoheptanoic acid (APH), magnesium sulfate, glutamyldiethyl ester (GDEE) or cis-2,3-piperidine dicarboxylic acid (PDA) using the highest dosages which did not affect normal behavior of the rats. All animals were observed continuously from 12 to 48 h postwithdrawal and the number of spontaneous convulsions observed in each animal was recorded. After this time, animals were killed by focused microwave irradiation and the cerebellas were collected for determination of cyclic guanosine monophosphate (cGMP) levels. While both APH and MgSO4 dramatically prevented convulsions, only APH prevented the withdrawal-induced elevation of cerebellar cGMP. PDA and GDEE had no statistically significant effect on either cerebellar cGMP levels or on convulsive activity. Although the effect of GDEE was not statistically significant, the number of convulsions was reduced to 1/3 those seen in control animals. These data implicate N-methyl-d-aspartate (NMDA) receptor-mediated pathways in seizure activity associated with the barbital abstinence syndrome and show that the withdrawal-induced elevation of cerebellar cGMP can occur without the induction of convulsions.

Amino Acids↗

PubMed1987

Light-induced stimulation of retinal dopamine: a dose-response relationship.

Light stimulates dopamine (DA) release in the retina. The purpose of this study was to determine the threshold and dose-response relationship between ocular light exposure and retinal DA synthesis in vivo. Groups of dark-adapted rats were exposed to 0, 1, 3, 5, 10, 25, 50, 100 or 1000 microwatts per square centimeter (microW/cm2) of white light for 15 min. Retinal DA and dihydroxyphenylalanine (DOPA) were subsequently quantified by liquid chromatography with electrochemical detection. Both the DA and DOPA data fit hyperbolic curves significantly (P less than 0.01). Exposure to white light at 25 microW/cm2 or greater appears to elicit the maximum response of these neurons. Threshold irradiation is calculated to be 3-5 microW/cm2. These results indicate that retinal DA synthesis and presumably DA neuron activity have a graded response to increasing irradiances of white light.

Animals↗

PubMed1987

Behavioral and biochemical studies in monkeys made hemiparkinsonian by MPTP.

Monkeys were required to press a lever rapidly for food, using either the right or the left hand. After stable baseline performance was established, MPTP (N-methyl-4-phenyl-2,3,5,6-tetrahydropyridine) was injected into the internal carotid of one side via a transfemoral catheter. The onset and time course of clinically severe, Parkinson-like symptoms were paralleled by a significant decrease of bar-pressing activity in the side contralateral to injection, while the forelimb in the unaffected side continued normal pressing. The unilaterality of effects was confirmed biochemically after sacrifice by a 95% drop in striatal dopamine (DA) levels of the injected compared to the uninjected hemisphere. The results show that hemiparkinsonism achieved by carotid injection is very stable; that normal motor behavior is maintained on the unaffected side and that goal-achieving strategies remain active, but that the affected side is unable to execute the task unless extrinsic levodopa is provided.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1987

Cultured cerebellar cells as an in vitro model of excitatory amino acid receptor function.

Primary cultures of neurons from 8-day-old rat pups were grown for 10 days in vitro in antibiotic-free media and then analysed for changes in cyclic guanosine monophosphate (cGMP) in response to several excitatory amino acid (EAA) agonists or related antagonists. Kainic acid (KA), N-methyl-D-aspartic acid (NMDA) and quisqualic acid (QA) produced dose- and calcium-dependent increases in cGMP with KA producing the largest and QA the least increase in this cyclic nucleotide. The increase induced by NMDA was additive with both KA and QA; however, KA and QA were not additive with each other. In fact, QA completely antagonized the effects of KA and to a much greater degree than did the EAA antagonists, glutamylaminomethylsulfonic acid (GAMS) or cis-2,3-piperidine dicarboxylic acid (PDA). 2-Amino-7-phosphonoheptanoic acid completely prevented the NMDA-induced elevations of cGMP yet had little effect on either the KA- or QA-induced elevations of this parameter. GAMS and PDA, on the other hand, were more effective in blocking the effects of KA and QA than of NMDA. These data show that cGMP levels in cerebellar granule cells provide an excellent model for studying the subtypes of EAA receptors.

Animals↗

PubMed1987

Activity-induced elevation of cerebellar cyclic GMP occurs in the absence of climbing fiber pathways.

The inferior olivary nuclei (ION) of Sprague-Dawley rats were chemically lesioned with 3-acetylpyridine (3-AP), and the completeness verified by the lack of retrograde labeling of the ION following the injection of horseradish peroxidase (HRP) into the cerebellum. The effects of locomotor activity or of immobilization on cerebellar cyclic guanosine monophosphate (cGMP) levels were determined in control saline-treated and experimental, 3-AP-treated rats. Three subgroups of rats from both the control and the experimental groups of rats were required to swim for 60 s, immobilized for 60 s or unmanipulated before being killed by microwave irradiation, and the cerebella were collected for cGMP determination. There was no statistically significant difference in cGMP levels between immobilized and unmanipulated rats in either the experimental or control groups. Pretreatment with 3-AP reduced cerebellar cGMP levels in both the immobilized and the unmanipulated rats to 50% of those observed in the comparably treated groups of saline-treated controls. When compared to the corresponding group of unmanipulated rats, locomotor activity induced a significantly greater elevation of cerebellar cGMP in the experimental animals than in the controls (P less than 0.05). These results indicate that while inputs from the ION to the cerebellar Purkinje cells are probably important in maintaining the normal levels of cGMP seen in inactive rats, the locomotor-induced elevation of this parameter occurs in the absence of climbing fibers (from ION). The mechanisms responsible for the greater activity-induced elevation of cGMP levels seen in rats receiving 3-AP over control rats are discussed.

Animals↗

PubMed1987

2-Amino-7-phosphonoheptanoic acid, a selective antagonist of N-methyl-D-aspartate, prevents barbital withdrawal-induced convulsions and the elevation of cerebellar cyclic GMP in dependent rats.

Female Sprague-Dawley rats were maintained on a diet of barbital for 8 weeks, a period of time previously shown to result in tolerance to and dependence on the drug. After completing this course, the barbital was abruptly withdrawn and the selective antagonist of N-methyl-d-aspartate (NMDA), 2-amino-7-phosphonoheptanoic acid (APH), or saline was infused intracerebroventricularly over 48 hr. Control rats which had not received barbital, were similarly infused with either saline or APH. All animals were observed for 12-48 hr following the withdrawal of the barbital; spontaneous convulsions, previously reported to be numerous and severe after withdrawal of the drug, were counted and graded according to severity. Forty-eight hr after withdrawal of barbital, the rats were killed by focussed microwave irradiation and cerebellae were collected for later determination of levels of cGMP. Nine convulsions occurred in 29 rats withdrawn from barbital and infused intracerebroventricularly with APH, this contrasted markedly with 61 convulsions seen in 29 animals withdrawn from the drug and infused with saline. There was a 3-fold elevation of levels of cGMP in the saline-infused, barbital-withdrawn rats when compared to control rats infused with saline. This evaluation was markedly, although not completely, prevented by the intracerebroventricular infusion of APH. These data provide evidence that dicarboxylic amino acid pathways, specifically those acting through NMDA receptors, are involved in seizure activity seen following abrupt abstinence from barbital.

2-Amino-5-phosphonovalerate↗

PubMed1987

A dietary haloperidol regimen for inducing dopamine receptor supersensitivity in rats.

The induction of dopaminergic supersensitivity in rats by the administration of haloperidol in their diet for 30 days (CHAL) in three increasing concentrations (7-15 mg/kg/day) was compared to that induced by single daily subcutaneous injections (SCHAL, 0.7 mg/kg) on the basis of biochemical (radioimmunoassay of serum haloperidol levels, 3H-spiroperidol binding) or behavioral (apomorphine stereotypy, spontaneous locomotor activity) parameters. The two modes of administration produced equivalent blood levels of haloperidol by day 30. At 48 hours post treatment: spontaneous locomotor activity and stereotyped behavior were significantly increased in both groups of haloperidol-treated rats, stereotyped behavior was significantly greater in CHAL- vs. SCHAL-treated rats at 8 days post treatment and specific 3H-spiroperidol binding was increased 64% and 236% within the striatum and GP, respectively, of CHAL-treated vs. control rats. Scatchard analysis of 3H-spiroperidol binding isotherms revealed a significant increase in the Bmax of high affinity binding sites [KD approximately 55 pM] within the striatum of both CHAL- and SCHAL-treated rats at 48 hours post treatment. A second, lower affinity site was resolved within the SCHAL-treated group which was not detected within striatal homogenates of CHAL-treated or control rats.

Administration, Oral↗

PubMed1987

Neuroendocrine studies in hyperprolactinaemic male mice.

In several species, including man and the rat, hyperprolactinaemia is associated with suppression of gonadotrophin release and male sexual behaviour. However, in the hyperprolactinaemic male mouse, plasma LH and FSH levels and copulatory behaviour are increased rather than suppressed. In an attempt to identify mechanism(s) which may be responsible for these effects of hyperprolactinaemia in the mouse, we have examined the effects of two ectopic pituitary isografts on several indices of hypothalamic and pituitary function in adult DBA/2J males. Animals with pituitary grafts had markedly increased plasma concentrations of prolactin, LH and FSH and enlarged seminal vesicles, whereas testicular and pituitary weights were not affected. Content of LHRH receptors and activity of aromatase in the pituitary, as well as dopamine-beta-hydroxylase activity in the hypothalamus were nearly identical in pituitary-grafted and sham-operated males. Biosynthesis of dopamine and turnover of noradrenaline in the median eminence were significantly increased in grafted males. We suggest that the increase in the activity of hypothalamic noradrenergic neurones may mediate stimulatory action of hyperprolactinaemia on LH and FSH release in the mouse. Comparison of these results with those obtained previously in the rat suggests that species differences in the effects of prolactin on gonadotrophin release may be related to its divergent effects on noradrenaline turnover.

Animals↗

PubMed1986

2-Amino-7-phosphonoheptanoic acid, a selective N-methyl-D-aspartate antagonist, blocks swim-induced elevation of cerebellar cyclic guanosine monophosphate.

In order to explore how rapidly locomotor activity induces an elevation in cerebellar cyclic guanosine monophosphate (cGMP) content, Sprague-Dawley rats, pretrained to swim a 2.5-m course, were required to swim from one to 5 laps representing from 7 to 40s of strenuous activity. Immediately after completing the swimming task, each animal was killed by microwave irradiation and the cerebellum was collected for subsequent determination of the cGMP content. There was no difference in the cerebellar cGMP content between rats swimming one lap, i.e. for 7 s, and control rats that did not swim. However, there was a linear increase in the cGMP over control values from 1.8- to 2.4-fold in rats swimming 3 and 5 times, respectively. The first significant elevation of the cerebellar cGMP was seen at 24 s (3 laps). To determine if acidic amino acid pathways were involved in this elevation, a low dosage of a selective NMDA antagonist, 2-amino-7-phosphonoheptanoic acid (APH) was injected intracerebroventricularly 4 min before having rats swim 4 laps. This low dosage of APH, which alone had no effect on the cerebellar cGMP content, completely blocked the swim-induced elevation of this parameter. These data provide the first report of how quickly locomotor activity elevates the cerebellar cGMP content and further suggest that an NMDA receptor-mediated pathway is involved in the activity-induced elevation of this parameter.

2-Amino-5-phosphonovalerate↗

PubMed1986

Effects of treadmill activity on cerebellar cyclic GMP.

Ovariectomized, female Sprague-Dawley rats were trained to run on a treadmill for up to several minutes. On the day of the experiment the treadmill speed was adjusted to either 680, 1360 or 2720 cm/minute and separate groups of 5 rats were required to run at each of these speeds for either 15, 30, 45 or 60 seconds. Immediately after running on the treadmill, each rat was killed by microwave irradiation, and the cerebellum was collected for subsequent determination of cyclic guanosine monophosphate (cGMP). The time to the onset of an elevation of cGMP and the maximal elevation obtained were functions of the speed of running. The first significant increase in cerebellar cGMP over that observed in inactive control rats occurred within 15 seconds after the onset of running. Regardless of the speed of running, the cGMP content reached a plateau after 45 seconds.

Animals↗

PubMed1986

Is there a metabolic basis for the fibrositis syndrome?

Patients with the fibrositis syndrome experience moderately severe musculoskeletal discomfort, mood changes associated with nonrestorative sleep, and tenderness to palpation at specific body sites. There is no characteristic abnormal laboratory finding in these patients to help identify the population. A report by Moldofsky and Warsh (Pain 1978; 5: 65-71) of low serum levels of free tryptophan in patients with severe fibrositis syndrome is intriguing but remains unexplained. Those data plus the observation by Hudson et al (Am J Psychiatry 1985; 142: 441-446; Biol Psychiatry 1984; 19: 1489-1493) that patients with fibrositis syndrome exhibit an increased prevalence of anxiety and depression suggest a number of possible avenues for further study. They include potential alterations in the homeostasis of catecholamines, corticosteroids, serotonin, aromatic amino acids, platelet membrane receptor levels, and the activity of platelet membrane monoamine oxidase. Among these possibilities, evidence is now available that suggests an increased production of catecholamines in fibrositis syndrome.

Animals↗

PubMed1986

Correlation between pentobarbital suppressed cerebellar cyclic GMP and performance of a swimming task.

Ovariectomized female Sprague-Dawley rats were trained to swim a 2.5 m course. On the day of the experiment the time required for each animal to swim the course was determined, and then the animal received either saline or one of 4 dosages of sodium pentobarbital, intravenously. Four minutes after treatment the animal's swim time was again recorded, and the animal was immediately killed by microwave irradiation. The cerebellum was collected for subsequent determination of cyclic guanosine monophosphate (cGMP). Pentobarbital caused a dosage-dependent suppression of cerebellar cGMP which was highly correlated with a drug-induced increase in the time required to swim 2.5 m. These data provide the first evidence of a correlation between a barbiturate-induced effect on a neurochemical parameter and impaired performance of a learned behavior.

Animals↗

PubMed1986

Continuously infused 2-amino-7-phosphonoheptanoic acid antagonizes N-methyl-D-aspartate-induced elevations of cyclic GMP in vivo in multiple brain areas and chemically-induced seizure activity.

The effects of the chronic intracerebroventricular (i.c.v.) infusion of the potent dicarboxylic amino acid antagonist, 2-amino-7-phosphonoheptanoic acid (APH), were examined in female rats as a prelude to the use of this compound in exploring the role of dicarboxylic amino acids in barbiturate dependence and withdrawal. Doses of APH ranging from 2.7 to 54 micrograms/day were examined for signs of toxicity. Weight loss, decreased water intake and locomotor impairment were found only with the largest dose. No significant changes in consumption of food or body temperature were observed with any dose. The chronic administration of the drug (27 micrograms/day) blocked the elevation of the content of cyclic guanosine monophosphate induced by N-methyl-D-aspartate (NMDA) in all regions of the brain examined. The chronically-administered drug also blocked wild running behavior induced by the intracerebroventricular administration of two different drugs n-methyl-D-aspartic acid and cyclohexylbarbiturate acid. However, APH was ineffective in suppressing convulsions induced by the ED50 dose of pentylenetetrazol given subcutaneously.

2-Amino-5-phosphonovalerate↗

PubMed1986

Variability and functional recovery in the N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of parkinsonism in monkeys.

Fourteen macaque monkeys were injected intravenously with N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. All developed the cardinal signs of parkinsonism (akinesia, rigidity, etc.) in varying degrees; some required repeated series of injections of the drug, while others developed the syndrome readily after the first series. Most of the subjects that were kept for longer than 4 weeks after the first dose of the drug showed complete or partial recovery after that time. Measurement, in some of the subjects, of the neostriatal levels of dopamine and dihydroxyphenylacetic acid showed the expected depletion of these substances at the peak of the behavioral action of the drug, but no recovery when the animals had returned to, or near, pre-drug behavioral status. No firm conclusion can be reached at this time as to the reasons for the behavioral recovery or the variability of the effects of the drug across subjects.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1986

Effect of ovarian steroids to stimulate region-specific hypothalamic 5-hydroxytryptamine synthesis in ovariectomized rats.

Accumulations of 5-hydroxytryptophan (5HTP) and L-dihydroxyphenylalanine (L-DOPA) following decarboxylase inhibition as indices for 5-hydroxytryptamine (5HT) and catecholamine (dopamine and/or norepinephrine) synthesis, respectively, were both increased in the preoptic area-anterior hypothalamus (POA-AH) of ovariectomized rats treated with a combination of 17 beta-estradiol benzoate (E2) and progesterone (P). Similarly, an increased accumulation of L-DOPA was seen in the mediobasal hypothalamus (MBH) and median eminence (ME) of these animals although no change was observed in 5HTP accumulation in the MBH or ME of these rats. Hypophysectomy negated these steroid-induced effects on L-DOPA accumulation. However, hypophysectomy had no apparent effect on steroid-stimulated 5HTP accumulation in the POA-AH of these rats. Under the experimental conditions of our study, the results suggest that the stimulatory effect of ovarian steroids on hypothalamic catecholamine synthesis is dependent on an intact pituitary gland, that the stimulatory effect of ovarian steroids on 5HT synthesis in the POA-AH is not dependent on an intact pituitary gland, and (3) that ovarian steroids do not seem to influence 5HT synthesis in the ME or MBH. The significance of these results may lie in the function of these hypothalamic monoaminergic neurotransmitter systems to regulate gonadotrophin release and subsequent steroid feedback modulation of such central regulatory mechanisms.

Animals↗

PubMed1986

Monoamine biosynthesis in hypothalamic regions of dwarf mice: effect of replacement of deficient anterior pituitary hormones.

Female Ames dwarf and phenotypically normal female mice were killed 30 min after treatment with NSD-1015, an aromatic L-amino acid decarboxylase inhibitor. The accumulation of dihydroxyphenylalanine (DOPA) and 5-hydroxytryptophan were measured by high-performance liquid chromatography with electrochemical detection and provided estimates of the endogenous biosynthesis of dopamine (DA) in the median eminence (ME) and serotonin biosynthesis (5-HT) in all brain regions which were examined. Dopamine synthesis was markedly suppressed in the ME while 5-HT synthesis was enhanced in both the ME and mediobasal hypothalamus (MBH) of dwarfs as compared to phenotypically normal mice. Overall, catecholamine biosynthesis (DOPA accumulation) was suppressed in the MBH of the dwarf mice but was not different from that observed in normal mice in the preoptic area anterior hypothalamus (POA-AH). The biosynthesis of 5-HT was not different in the POA-AH of dwarf mice as compared to normal mice. In the second experiment dwarf mice received saline vehicle, ovine prolactin (PRL), growth hormone (GH) or thyroxin (T4) daily for 14 days. Normal mice received saline only. Replacement with PRL significantly enhanced DA synthesis in the ME and was the only hormone to suppress significantly the elevation of 5-HT synthesis normally observed in the ME and the MBH of the dwarfs. Both GH and T4 only partially reduced 5-HT synthesis in the ME and MBH so that this parameter was no longer statistically different from either saline-treated dwarfs or normal mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1986

Hyperprolactinemia attenuates ovarian steroid stimulation of region-specific hypothalamic serotonin synthesis and luteinizing hormone release in ovariectomized rats.

Hyperprolactinemia adversely affects reproductive functions, presumably through an effect at the hypothalamic level. Given the numerous published reports linking hypothalamic serotonin (5-hydroxytryptamine, 5HT) mechanisms to the regulation of gonadotrophin secretion, we sought to determine the effects of experimentally induced hyperprolactinemia on ovarian steroid-induced increases in serum LH levels and region-specific hypothalamic 5HT synthesis in ovariectomized rats. In the first study, bilaterally ovariectomized Sprague-Dawley rats either received two pituitary homografts implanted beneath the left kidney capsule or were sham-grafted. Both groups of rats were injected subcutaneously with 5 micrograms/100 g of estradiol benzoate (E2) in corn oil vehicle at 08.00 h, 1 and 2 days before serum collection and 5 mg/100 g of progesterone (P) in corn oil vehicle at 07.00 h on the day of serum collection. Blood samples were collected via chronic indwelling jugular cannulae from each rat at 10.00, 12.00, 13.00, 14.00, 16.00 and 18.00 h. A statistically significant elevation in serum LH levels was detected at 13.00, 14.00 and 16.00 h. This increase in serum LH levels was significantly attenuated in rats bearing pituitary homografts, an effect attributed to the high serum PRL levels measured in these animals. In the second study, bilaterally ovariectomized Sprague-Dawley rats were divided into three experimental groups: (1) rats bearing two pituitary homografts and injected with E2 and P on the schedule and at the dosages previously described, (2) sham-grafted rats injected with E2 and P on the schedule and at dosages previously described and (3) sham-grafted rats injected with corn oil vehicle only.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1986

Role of central catecholamines on the potentiation of the baroreflex produced with vasopressin. A study using 6-hydroxydopamine.

This study compares the effect of arginine-vasopressin and phenylephrine on renal sympathetic nerve activity, arterial pressure, and heart rate in vehicle- and intraventricular 6-hydroxydopamine-treated conscious rabbits. In addition, this study examines the involvement of forebrain structures on these variables. In vehicle-treated rabbits, compared to phenylephrine, vasopressin produces a greater decrease in renal sympathetic nerve activity and heart rate for a given increase in pressure. After administration of intraventricular 6-hydroxydopamine, the responses produced with vasopressin are similar to those produced with phenylephrine. Analysis of catecholamine content in the nucleus of the solitary tract, parabrachial nucleus, area postrema, and spinal cord indicates that the only regions of significant catecholamine depletion are in the nucleus of the solitary tract and the spinal cord. Transection at the mid-collicular level does not alter significantly the responses of vasopressin or phenylephrine on renal sympathetic nerve activity or heart rate. This indicates that forebrain structures are not involved in mediating the enhanced buffering effect produced with vasopressin.

Animals↗