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Biomedical subjects

R A Mueller

Publications and source records attributed to R A Mueller.

At least 109 records · Page 6Linked to original sources
PubMed1984

Comparison of the CNS effects induced by TRH and bicuculline after microinjection into medial septum, substantia nigra and inferior colliculus: absence of support for a GABA antagonist action for TRH.

Antagonism of ethanol-induced depression of locomotion was observed after intracisternal injection of thyrotropin releasing hormone (TRH) and bicuculline methiodide (BICM), as well as after microinjection of these drugs into the medial septum. The present investigation compared the behavioral and physiological consequence of administering TRH and BICM into the medial septum, inferior colliculus and substantia nigra to quantitate the similarities between these compounds. BICM produced a major increase in locomotor activity when injected into the medial septum and stereotypies when injected into the substantia nigra, suggesting that GABA-containing neurons have widespread influences on motor function. The wild running and seizure activity observed after BICM injection into the inferior colliculus was also consistent with this latter view. The marked increase in rectal temperature observed when BICM was injected into the medial septum may also implicate GABAergic mechanisms in temperature control at this brain site. TRH produced no such behavioral or physiological changes when administered into these three sites. Thus, this work strongly suggests that TRH does not exert a widespread action as a GABA antagonist because TRH did not produce the same changes induced by BICM. The actions of BICM and TRH to antagonize ethanol-induced depression when microinjected into the medial septum suggests that this brain area may be a critical site for the depressant action of ethanol.

Animals↗
PubMed1984

Attempted antagonism of adenosine analogue induced depression of respiration.

Intracerebroventricular (ICV) administration of the stable adenosine analogue 2-chloroadenosine (2CA) to hyperoxic halothane-anesthetized rats produced a dose-dependent depression of respiration largely as a result of a decrease in tidal volume. Similar changes were noted after another adenosine analogue, phenylisopropyladenosine (PIA). Higher doses shifted the minute ventilation-PaCO2 curve to the right and decreased its slope. Bradycardia and hypotension were produced at doses which altered respiration. Neonatal destruction of brain serotonin or dopamine-containing nerve terminals did not alter the 2CA-induced respiratory depression. Naloxone significantly antagonized the respiratory and circulatory changes produced by 2CA though the changes produced by PIA were not significantly antagonized. Peripherally and intracerebroventricularly administered theophylline were largely ineffective in reversing the 2CA-induced respiratory depression. Thus, these data suggest that a major part of the respiratory depression produced by 2CA is due to indirect activation of opioid receptors. In contrast, very little of the respiratory depression after PIA is via mechanisms antagonized by naloxone. Thus, putative adenosine agonists appear to vary in the extent to which respiratory depression is provoked by interactions with opioid systems.

2-Chloroadenosine↗
PubMed1984

Neonatal-6-hydroxydopamine treatment: model of susceptibility for self-mutilation in the Lesch-Nyhan syndrome.

Neonatal-6-OHDA treated rats given L-DOPA after a decarboxylase inhibitor showed a high incidence of self-mutilation behavior (SMB) and self-biting. These behaviors were not observed in adult-6-OHDA-treated rats or in controls. Since inhibition of dopamine-beta-hydroxylase did not prevent or inhibit the SMB exhibited in neonatal-6-OHDA-treated rats after L-DOPA, norepinephrine is not likely to be contributing to this response. The age dependent effects observed are consistent with the hypothesis that neonatal reduction of dopamine-containing fibers is responsible for the SMB susceptibility observed in Lesch-Nyhan disease, making the neonatal-6-OHDA-treated rat a model of this neurological syndrome.

Age Factors↗
PubMed1984

Behavioral differences between neonatal and adult 6-hydroxydopamine-treated rats to dopamine agonists: relevance to neurological symptoms in clinical syndromes with reduced brain dopamine.

Administration of L-dopa or apomorphine to neonatal and adult 6-hydroxydopamine (6-OHDA)-treated rats resulted in different behavioral responses depending on the age at which dopaminergic fibers were destroyed. When neonatal 6-OHDA-treated rats were tested as adults, they exhibited marked stereotypies, self-biting and self-mutilation behavior (SMB) when given these dopamine agonists. Self-biting as well as the incidence of SMB in neonatal 6-OHDA-treated rats showed dose-related changes between 10 and 100 mg/kg of L-dopa. This SMB and self-biting after L-dopa was observed as early as 22 to 24 days of age. Adult 6-OHDA-treated rats did not exhibit SMB or self-biting to L-dopa (100 mg/kg) or apomorphine (10 mg/kg), but did display paw treading and head nodding--behaviors not observed in neonatal 6-OHDA-treated rats. In addition, the locomotor response to apomorphine (1 mg/kg) was significantly greater in adult 6-OHDA-treated rats than in neonatal 6-OHDA-treated rats. Brain dopamine was reduced markedly in striatum, nucleus accumbens and olfactory tubercles in both 6-OHDA treatment groups with the reduction being slightly greater in rats treated with 6-OHDA neonatally. Serotonin content was elevated in striatum of rats treated neonatally with 6-OHDA, but not in adult 6-OHDA-treated rats. SMB and behaviors observed after L-dopa in rats treated neonatally with 6-OHDA were not apparent after L-dopa in rats with brain serotonin or norepinephrine reduced. Rats with brain dopaminergic fibers destroyed neonatally exhibited self-biting and SMB after L-dopa, suggesting that neonatal reduction of this amine is responsible for the SMB and self-biting in neonatal 6-OHDA-treated rats. 5-Hydroxytryptophan administration to neonatal 6-OHDA-treated rats did not induce SMB, indicating that release of serotonin by L-dopa is not responsible for this behavior. Because inhibition of dopamine-beta-hydroxylase did not alter the SMB response to L-dopa observed in neonatal 6-OHDA-treated rats, norepinephrine synthesized from L-dopa does not appear to contribute to the response. High doses of a decarboxylase inhibitor sufficient to inhibit conversion of dopa to dopamine in brain did not reduce the incidence of SMB. Administration of haloperidol (1 mg/kg) reduced the incidence of SMB, but did not antagonize the self-biting or the taffy pulling exhibited by L-dopa. In contrast, cisflupentixol completely blocked the SMB and self-biting induced by L-dopa.(ABSTRACT TRUNCATED AT 400 WORDS)

Age Factors↗
PubMed1984

Ethanol-induced locomotor stimulation in rats after thyrotropin-releasing hormone.

Ethanol-induced sedation in Sprague-Dawley rats was antagonized by intracisternally administered thyrotropin releasing hormone (TRH) at a dose as low as 1 microgram. Furthermore, when a dose of 25 micrograms or greater of TRH was combined with ethanol doses above 2 g/kg, the locomotor activity was significantly greater than observed for TRH alone. A dose-related increase in activity was observed when varying doses of ethanol were administered with a constant dose of TRH (100 micrograms). This increase in locomotion induced by the TRH-ethanol combination could not be attributed to a change in TRH concentration, ethanol distribution or to a pituitary action of TRH. Inasmuch as tert-butanol in combination with TRH produced the same effects as ethanol, the hyperactivity does not appear to be associated with acetaldehyde formation. TRH acid and His-Pro-diketopiperazine, metabolites of TRH, did not produce hyperactivity when administered with ethanol, whereas MK-771, a TRH analog, produced a significant increase in locomotion in ethanol-treated rats greater than that for MK-771 alone. Three lines of evidence suggested that the hyperactivity induced by the TRH-ethanol combination could not be attributed to an influence of ethanol on the stimulant effects of TRH. First, pentobarbital- and chlordiazepoxide-induced depression of locomotion was antagonized by TRH (100 micrograms) but, unlike ethanol, locomotor stimulation greater than that for TRH was not observed. Second, behavioral observations did not reveal ethanol altering any effects of TRH that would compete with locomotion.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Sodium kinetics and membrane potential in aorta of magnesium-deficient rats.

In light of the important role of magnesium (Mg) in vascular smooth muscle function, this study was undertaken to examine effects of dietary Mg deficiency on membrane potential (Em), sodium (Na) efflux and distribution, and total ion content in rat aorta. Rats were fed either Mg-sufficient or Mg-deficient diets for 30 days. The aortic arch was removed and a segment incubated in 22Na to monitor kinetics of Na efflux. Another segment was used for measurement of Em under control conditions and during ouabain suffusion. Total tissue water and ion content were also determined. Results of this work indicate that, in aorta from Mg-deficient rats, Em was less polarized and Na accumulated intracellularly. Although the Em in Mg-deficient aorta was not affected by ouabain, which suggested Na-K pump inhibition, Na efflux was greater in Mg-deficient aorta, suggesting increased passive permeability changes to Na as the mechanism responsible for these changes.

Animals↗
PubMed1983

Codepletion of serotonin and TRH induces apparent supersensitivity of spinal TRH receptors.

Thyrotropin-releasing hormone (TRH), substance P (SP) and serotonin (5-HT) coexist in raphe efferents to the spinal cord. Lesions of these serotonergic projections by intracisternal injection of 5,7-dihydroxytryptamine (50 micrograms) in rat pups resulted in 93% and 65% decreases in 5-HT and TRH content of adult rat spinal cords, respectively. This codepletion induced a 30-40% increase in binding of [3H][3-Me-His2]TRH [( 3H]MeTRH) to TRH receptors. The affinity and pharmacological specificity of [3H]MeTRH binding to control and DHT-lesioned cords appeared closely similar.

5,7-Dihydroxytryptamine↗
PubMed1983

Pharmacokinetics and pharmacodynamics of local analgesia for laparoscopic tubal ligations.

The pharmacokinetics and pharmacodynamics of lidocaine and bupivacaine, when used for laparoscopic sterilization under local anesthesia, are described in 21 patients. Under direct vision with the use of a laparoscope, local anesthetic solution was sprayed onto the fallopian tubes. Nine patients were administered 12 ml of lidocaine 2% (240 mg), and 12 patients received 20 ml of bupivacaine 0.5% (100 mg). Samples of venous blood were drawn at 0, 5, 10, 15, 20, 30, 60, and 120 minutes after the intraperitoneal placement of local anesthetic. Drug assays were performed by means of gas chromatography. The peak concentration of lidocaine was detected within 30 minutes. The mean concentration was 1.70 +/- 0.34 micrograms/mg (range, 1.19 to 2.07 micrograms/ml; convulsive level, 18 to 26 micrograms/ml). The peak concentration of bupivacaine was not evident until 60 minutes after injection. The mean concentration was 0.44 +/- 0.15 micrograms/ml (range, 0.20 to 0.77 micrograms/ml; convulsive level, 4.5 to 5.5 micrograms/ml). These findings may justify the use of larger volumes of these local anesthetics for more painful diagnostic laparoscopies whenever adhesions and/or extensive manipulation is anticipated.

Anesthesia, Local↗
PubMed1983

Pharmacokinetics of methylphenidate in man, rat and monkey.

The pharmacokinetics and bioavailability of methylphenidate (MPH) and a metabolite, ritalinic acid (RA), were studied in normal adults, children with hyperactivity, monkeys and rats. Adult males received 0.15 or 0.3 mg/kg of MPH orally and MPH and RA were analyzed in plasma samples obtained at various times after treatment. Maximal MPH concentrations in plasma were found to occur 2.2 hr after administration of either dose (range: 1.0-4.0). The mean (+/-S.E.) maximal concentration in plasma for MPH was 3.5 +/- 0.4 ng/ml after 0.15 mg/kg and 7.8 +/- 0.8 ng/ml after 0.3 mg/kg. MPH clearances were high (10.1 liters/hr/kg) and variable (range: 3.6-23.2) for the 0.3 mg/kg dose. Pharmacokinetic parameters for children receiving 0.3 mg/kg were essentially the same as for adults. RA plasma levels were 50 to 100 times greater than MPH levels in normal adults. The clearance of RA is less than that of MPH. The absolute bioavailability of MPH was found to be 0.19 in the rat and 0.22 in the monkey, suggesting substantial presystemic elimination of MPH.

Adult↗
PubMed1983

Effects of anesthetics and electrical stimulation on nigrostriatal dopaminergic neurons.

Induction of anesthesia with pentobarbital (40 mg/kg), urethane (1.8 g/kg), chloral hydrate (400 mg/kg) or ketamine (150 mg/kg) followed by a 20-min sham implantation of a bipolar electrode in substantia nigra fibers caused a marked, ipsilateral increase in caudate dihydroxyphenylacetic acid (DO-PAC). Conversely, no sham stimulation was found after gamma-butyrolactone (500 mg/kg) anesthesia or in a paralyzed, artificially respired preparation. By using gamma-butyrolactone anesthesia, the nigrostriatal fibers were electrically stimulated (25 Hz, 1.5 msec duration) at differing current intensities (40, 80, 100, 120 and 180 microA). The maximum increase in caudate DOPAC occurred at 120 microA. Electrical stimulation (100 microA, 25 Hz, 1.5 msec duration) in the paralyzed preparation yielded similar increases in caudate DOPAC. By using a 50% effective current (100 microA), variation of the frequency (5, 10, 25 and 125 Hz) produced a maximum in caudate DOPAC at 10 Hz. These data reveal an interaction between many anesthetics and physical disruption of dopaminergic neurons, as well as provide an in vivo model of stimulus-dependent dopamine release.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1982

[The 5q syndrome--a chromosome aberration with characteristic hematologic picture: preleukemia? Literature review and description of a personal case].

The case of a 74-year-old woman with macrocytic, refractory anemia, typical changes in the bone marrow and a 5q-chromosome in bone marrow cells is presented and the literature of this newly described hematological disorder is reviewed. The syndrome is characterized by partial deletion of the long arms of a chromosome No. 5 in bone marrow cells. The chromosomal anomaly is acquired and originates most probably from a pluripotent hematologic stem cell. Hematologic changes are (1) macrocytic, refractory anemia, (2) low to normal leukocyte counts, (3) normal to increased platelet number with marked anisocytosis and a high proportion of megathrombocytes, (4) normal to hypoplastic erythropoiesis and generally small megakaryocytes with nonlobulated nuclei in the bone marrow. In most of the reported cases (16 out of 19) with isolated 5q-anomaly, the clinical picture and laboratory findings remained stationary during a follow-up period of up to 6 years. In only 2 out of 19 cases did acute leukemia develop. In the presence of additional chromosomal abnormalities, all the cases developed acute leukemia and especially acute myelogenous leukemia. The diagnosis of 5q-syndrome in patients with refractory anemia is of prognostic significance, since it renders possible early recognition of a potentially malignant disorder and early detection of leukemic transformation.

Aged↗
PubMed1982

Dopamine antagonists do not block testosterone-induced decrease in luteinizing hormone.

These studies were designed to test the hypothesis that testosterone might lower circulating levels of luteinizing hormone (LH) in castrated male rats by activating dopaminergic neuronal systems. Blood samples were drawn from conscious rats through an indwelling cannula during the fourth and eight hours after subcutaneous administration of testosterone (1 or 5 mg/kg, in corn oil). Testosterone caused a dose-dependent decrease in plasma LH levels eight hours after administration. This decrease was not blocked by prior administration of the dopaminergic antagonists haloperidol and flupenthixol. This lack of effect of dopaminergic antagonists indicates that testosterone does not act primarily via dopaminergic activation to lower LH.

Animals↗
PubMed1982

Effects of vagotomy and glossopharyngectomy on respiratory response to dopamine-agonists.

In normal rats lightly anesthetized with halothane apomorphine increased both resting and CO2-dependent minute ventilation (VM) by stimulating respiratory frequency (RF) whereas tidal volume (VT) was slightly decreased. Acute bilateral glossopharyngectomy, which impaired carotid body function, did not change the apomorphine effects in contrast to bilateral vagotomy, which abolished the RF response of the drug, but now increased VT. Intravenous infusion of dopamine increased VM by elevating RF, and this effect was only slightly blunted by bilateral glossopharyngectomy but nearly abolished by vagotomy and totally eliminated by the combined procedures. The respiratory response to dopamine was depressed in rats with chronically destroyed central catecholaminergic neurons. These findings indicate that there may be two different dopaminergic stimulatory mechanisms that modulate RF-one peripheral and one central-and both depend upon afferent vagal activity. With impaired vagal function, however, two other dopaminergic stimulatory mechanisms effecting VT are evident-one central, and one peripheral which involves the carotid body.

Animals↗
PubMed1981

Effect of 5,7-dihydroxytryptamine on serotonergic control of prolactin secretion and behavior in rats.

The intracisternal administration of 5,7-dihydroxytryptamine (5,7-DHT) to rats resulted in a potentiated response to 5-hydroxytryptophan (5-HTP) when the animals were tested 30 days later. The 5-HTP-induced changes include elevation of serum prolactin, decrease in operant responding, and the magnitude of the "serotonin behavioral syndrome" observed after 5-HTP administration. The serotonin concentration in brains of 5,7-DHT-treated animals reached maximum earlier and remained elevated longer than that of controls following administration of 5-HTP. Brain norepinephrine and dopamine concentration were not affected by 5-HTP in either group of animals. The increase in serum prolactin concentration elicited by administration of the serotonergic agonists quipazine or 5-methoxy-N,N-dimethyltryptamine and by the serotonin uptake inhibitor fenfluramine also was potentiated by pretreating rats with 5,7-DHT. These data suggest that both serotonergic receptor supersensitivity and the absence of presynaptic uptake sites contribute to the enhanced responses to 5-HTP occurring in rats previously treated with 5,7-DHT. The findings further demonstrate that both behavioral and hormonal measures can be used to assess the sensitivity of serotonergic receptors and indicate that 5,7-DHT may be useful in evaluating the role of serotonergic neurons in neuroendocrine function.

5,7-Dihydroxytryptamine↗
PubMed1981

Behavioral and biochemical studies of the scopolamine-induced reversal of neuroleptic activity.

Scopolamine reversed the reduction in avoidance responding caused by spiperone and antagonized the inhibitory effects of spiperone on the behavioral actions of d-amphetamine or apomorphine. Scopolamine-induced locomotor activity was greater in 6-hydroxydopamine (6-OHDA)-treated animals than in controls. This increase was prevented by administration of alpha-methyltyrosine, but not by inhibition of dopamine-beta-hydroxylase, indicating that this action of scopolamine was associated with presynaptic dopaminergic fibers. Therefore, the possibility that pre-synaptic dopaminergic function was the locus of the antagonism of spiperone by scopolamine was examined using drug interaction studies in 6-OHDA-treated rats. However, when 6-OHDA-treated rats were given alpha-methyltyrosine, scopolamine still reversed the spiperone blockade of apomorphine-induced locomotion. Although these data provided evidence for a post-synaptic action for this cholinergic blocking agent, scopolamine affected neither dopamine-stimulated adenylate cyclase activity nor 3H-spiperone binding in vitro. Furthermore, scopolamine did not alter the level of specific 3H-spiperone binding found in brain after in vivo administration. This suggests that the post-synaptic mechanism affected by scopolamine is different from the site affected by spiperone. Thus, it is concluded that scopolamine can affect both pre- or post-synaptic events associated with dopaminergic function and that both may contribute to the reversal of the actions of spiperone.

Adenylyl Cyclases↗