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Biomedical subjects

R A Mueller

Publications and source records attributed to R A Mueller.

At least 127 records · Page 7Linked to original sources
PubMed1981

Drug alterations of punished responding after chlordiazepoxide: possible screen for agents useful in minimal brain dysfunction.

In the present study, the effect of various stimulant drugs on the action of chlordiazepoxide to increase punished responding was studied. Drugs such as d-amphetamine, methylphenidate and imipramine that are effective in attentional deficit disorder (MBD) were found to reverse this benzodiazepine-induced increase in responding. Phenobarbital which worsens this condition enhanced the benzodiazepine effect. Since the impairment caused by chlordiazepoxide may be analogous to the lack of impulse control noted in MBD, the bupropion antagonism of this action of chlordiazepoxide suggests that bupropion may be useful in MBD.

Animals↗
PubMed1981

Antagonism of ethanol-induced decrease in LH by para-chlorophenylalanine: lack of correlation with altered serotonergic mechanisms.

Acute administration of ethanol lowers plasma levels of luteinizing hormone (LH) in several species. Since ethanol may interact with central serotonergic (5HT) neurons, and since 5HT systems have been found to play a role in modulating LH release, we examined the possible role of central serotonergic neurons in the ethanol-induced depression of LH. Acute PCPA (400 mg/kg, 20 hr before 2.0 g/kg ethanol) was effective in preventing the ethanol-induced depression of LH, suggesting that ethanol activates 5HT systems to lower LH. In support of this, the central 5HT agonist 5-methoxy-N, N-dimethyltryptamine (5MDMT) depressed LH in a dose-dependent manner. However, while the effects of a sub-maximal dose of 5MDMT were blocked by prior administration of methysergide, this 5HT receptor antagonist was unable to prevent the post-ethanol fall in LH. Additionally, because other doses of PCPA (250 mg/kg 20 hr prior to ethanol, and 100 mg/kg P.O. x 3 days before ethanol) produced similar reductions in hypothalamic 5HT but did not block the ethanol effect, and because electrolytic lesions of the median raphe nucleus were also ineffective in preventing the post-ethanol depression of LH, we conclude that activation of serotonergic systems does not play a major role in the ethanol induced depression of LH.

5,7-Dihydroxytryptamine↗
PubMed1981

Differential effects of TRH, amphetamine, naloxone, and fenmetozole on ethanol actions: attenuation of the effects of punishment and impairment of aerial righting reflex.

The effects of four putative ethanol antagonists [thyrotropin releasing hormone (TRH), naloxone, d-amphetamine, and fenmetozole] on two distinct behavioral actions of ethanol were compared. TRH (20-40 mg/kg) reduced ethanol-induced impairment of the aerial righting reflex (ARR) but enhanced the ethanol-induced increase in punished drinking (anticonflict effect). Naloxone antagonized both actions of ethanol but only at high doses (20-60 mg/kg). Amphetamine (1-4 mg/kg) abolished the ethanol effect on punished drinking but did not alter its impairment of the ARR (1-8 mg/kg). Conversely, fenmetozole antagonized the ethanol impairment of the ARR (15-30 mg/kg) but not ethanol's anticonflict action. The inconsistent pattern of "antagonist" interactions of these drugs with the behavioral actions of ethanol suggests that ethanol alters several neurochemical systems to produce its behavioral effects.

Amphetamine↗
PubMed1981

Brain neurotransmitter and high-energy phosphate concentration after combined hypoxia and hypotension.

Previous work by the authors has established decreased brain ATP concentration after a combined hypoxic-hypotensive episode. This study was undertaken to determine what changes, if any, occur in brain norepinephrine (NE), dopamine (DA), and serotonin (5HT) concentration in association with hypoxia and hypotension, and to correlate any observed changes with simultaneously measured ATP concentrations. Rats were subjected to a 30-minute period of hypoxia (F102 = 0.075) and hemorrhagic hypotension (MAP = 30 mm Hg) and then resuscitated. Significant increases (P less than .05) in cortical 5HT were observed at a time when ATP concentration was significantly (P less than .005) reduced. Additional experiments were conducted on rats depleted of 5HT by prior treatment with 5,7-dihydroxytryptamine. Equal decreases in ATP concentration were measured, and the cardiovascular response to hypoxic hypotension in 5HT-depleted rats was similar to that in 5HT-intact rats. We conclude that the increased 5HT after hypoxic hypotension does not cause the decreased ATP concentration, nor does 5HT play a major role in cardiovascular homeostasis under the conditions of this experiment.

Adenosine Triphosphate↗
PubMed1981

Effects of TRH on central nervous system function.

Evidence has been reviewed which strongly suggests that TRH functions as a neurotransmitter or neuromodulator in the mammalian central nervous system. Both the peptide and its receptor sites are located in the brain. Furthermore, it has protein actions to modify the effects of many neuropharmacological agents and can itself cause alterations in functions mediated by the CNS. Data clearly indicate that many of these actions. of TRH are not dependent on the pituitary- thyroid axis. Various studies of neurotransmitter interactions with TRH have provided evidence that noradrenergic, serotonergic, GABAergic, and cholinergic systems may be influenced by TRH or mediate some of its actions. More than likely, other transmitters will be implicated as the complex actions of TRH are more thoroughly investigated and understood. One set of experiments suggested that TRH may be localized serotonergic fibers. Such findings provide strong support for the view that TRH has a role in the physiology of the CNS. In spite of the progress that has been made, there are several questions to be answered about mechanisms of synthesis, storage, release, and inactivation of TRH. Furthermore, physiological studies would be greatly facilitated if a specific antagonist of TRH actions were available. Controversy still exists about active forms of TRH in situ and the methods by which TRH can be measured in tissue. Future investigations which resolve these difficulties and questions should facilitate our understanding of the role of TRH in brain function and its complex interactions with other neural mechanisms.

Animals↗
PubMed1981

Serotonergic activity in man as a function of pain, pain mechanisms, and depression.

Lumbar cerebrospinal fluid levels of 5-hydroxyindoleacetic acid, which are used as indicators of central nervous system serotonergic neuronal activity, were significantly higher in 67 patients with chronic pain and in 32 patients with acute pain (23.6 +/- 3.3 and 23.1 +/- 3.8, respectively) than in 30 patients (8.8 +/- 1.7) who had no pain. However, there was no correlation between levels of 5-hydroxyindoleacetic acid in patients with chronic or acute pain, nor between groups of patients with chronic pain whose pain mechanisms were of psychogenic, sympathetic, somatic, or central origin, based on their responses to differential spinal block; there was also no correlation between levels of depression, as evaluated by the Zung scale, in patients with different types of chronic pain, even though all of these patients were depressed. The elevated levels of 5-hydroxyindoleacetic acid in the depressed patients with chronic pain are not consistent with previous studies on the etiology and types of chronic pain. As recent research indicates that the perception of pain may be modulated by endogenous analgesic systems involving enkephalin and serotonin (5-HT), this study was undertaken to clarify the association between 5-HT activity and nociception. Our findings did show a link between acute noxious stimulation and central increases in serotonergic activity. However, we could not differentiate between pain mechanisms and degree of depression. Our studies did indicate that, because of both the persistence of pain complaints and the increased levels of brain 5-HT activity, the endogenous analgesic systems are not totally effective as natural inhibitors of pain. Furthermore, the increased depression and continued pain in the presence of elevated 5-HT activity in patients with chronic pain may represent a tolerance or decreased responsiveness to 5-HT.

Adult↗
PubMed1981

Aminophylline may stimulate respiration in rats by activation of dopaminergic receptors.

In intact young rats anesthetized with halothane, aminophylline produces an increase in respiratory minute ventilation due primarily to an increase in respiratory frequency. Although the simulation of respiration by inhalation of 10% CO2 is augmented only at high doses of aminophylline, the response to CO2 is increased at doses as low as 3 mg/kg of aminophylline. Division of the ninth cranial nerve together with removal of the carotid body did not alter the response, whereas vagotomy changed the response from one of increased frequency to an increase in tidal volume. Both awake and anesthetized rats evidence a decrease in PaCO2; after aminophylline administration and in awake animals, a decrease in brain stem dopamine content was observed. Since haloperidol, a dopamine antagonist, blocked the response to aminophylline, it seems likely that aminophylline may stimulate respiration by altering dopamine receptor activation in the brain.

Aminophylline↗
PubMed1981

Effects of acute and chronic 1,3-butanediol treatment on central nervous system function: a comparison with ethanol.

In the present investigation, the neuropharmacology of 1,3 butanediol (1,3-BD) was compared with that of ethanol. Acute i.p. administration of equimolar doses of 1,3-BD or ethanol to rats impaired the aerial righting reflex, attenuated the suppressive effect of punishment on drinking behavior, lowered blood pressure, caused a concomitant reduction in the content of guanosine 3',5'-monophosphate in the cerebellum and reduced ethanol withdrawal reactions. Although these data suggested that ethanol and 2,3-BD were of similar potency, the brain content of 1,3-BD was only 33% of that of ethanol after treatment with equimolar doses, suggesting a greater central nervous system (CNS) potency for 1,3-BD. In rats treated chronically with ethanol to produce physical dependence, 1,3-BD was more potent than ethanol in inhibiting the hyperexcitability observed upon ethanol withdrawal. Furthermore, chronic administration and withdrawal of 1,3-BD caused CNS hyperexcitability in rats that was characteristic of physical dependence. Despite these similarities, there were clear differences in the actions of ethanol and 1,3-BD. In mice, locomotor stimulation caused by ethanol was not observed after 1,3-BD. Furthermore, while 1,3-BD did not alter the concentration of luteinizing hormone in plasma, equivalent doses of ethanol markedly reduced the concentration of this hormone. These data indicate that like ethanol, 1,3-BD depresses CNS activity and induces physical dependence, but has less effect on plasma luteinizing hormone concentration than ethanol.

Animals↗
PubMed1981

Alteration of aminophylline-induced respiratory stimulation by perturbation of biogenic amine systems.

Aminophylline-induced stimulation of respiration in halothane-anesthetized rats was abolished in rats given 6-hydroxydopamine and desmethylimipramine neonatally to selectively destroy central nervous system dopamine nerve terminals. The respiratory stimulation was also prevented by prior administration of dopamine receptor antagonists haloperidol and cisflupenthixol. The combination of apomorphine and aminophylline produced an additive stimulatory effect on respiration to values greater than those observed with either drug alone. Animals which received pargyline and 5,7-dihydroxytryptamine neonatally to selectively destroy central nervous system serotonin nerve terminals appeared to be more sensitive to the stimulatory effects of aminophylline on respiration when tested as adults. The depressant effect of 5-methoxy-N, N-dimethyl-tryptamine on respiration was slightly enhanced in the presence of aminophylline. These data suggest that the respiratory response to aminophylline is the summation of the effects of this drug on central nervous system dopamine on serotonin neuronal systems.

5,7-Dihydroxytryptamine↗
PubMed1980

Erythrosine (Red No. 3) and its nonspecific biochemical actions: what relation to behavioral changes?

Biochemical studies have shown that the ability of erythrosine to inhibit dopamine uptake into brain synaptosomal preparations is dependent on the concentration of tissue present in the assay mixture. Thus, the finding that erythrosine inhibits dopamine uptake (which, if true, would provide a plausible explanation of the Feingold hypothesis of childhood hyperactivity) may simply be an artifact that results from nonspecific interactions with brain membranes. In addition, although erythrosine given parenterally (50 milligrams per kilogram) did not alter locomotor activity of control of 6-hydroxydopamine-treated rats, erythrosine (50 to 300 milligrams per kilogram) attenuated the effect of punishment in a "conflict" paradigm.

Animals↗
PubMed1980

An evaluation of the selectivity of fenmetozole (DH-524) reversal of ethanol-induced changes in central nervous system function.

The selectivity and specificity of fenmetozole (DH-524) [2(3,4-dichlorophenoxy-methyl)2-imidazole HCl] as an antagonist of the actions of ethanol were examined. Fenmetozole (15--30 g/kg) reduced ethanol-induced impairment of the aerial righting reflex without changing blood or brain ethanol content, indicating that the antagonistic actions of fenmetozole were not de to change in the pharmacokinetics of ethanol. Since fenmetozole also reduced aerial righting reflex impairment due to phenobarbital, chlordiazepoxide, and halothane, this action of fenmetozole was not specific to ethanol. In mice, both the ethanol-induced increase in locomotor activity at 2.0 g/kg and the decrease caused by 4.0 g/kg were antagonized by fenmetozole. In addition, fenmetozole attenuated the ethanol-induced reduction in cerebellar cyclic guanosine monophosphate (cGMP) content, but the drug also significantly elevated cGMP levels in this tissue when given alone. Fenmetozole did not alter ethanol-induced increases in punished drinking in a conflict test, except at a high dose which alone decreased both punished and unpunished responding. Fenmetozole also failed to precipitate ethanol withdrawal-like reactions when given to physically-dependent, intoxicated rats. Thus, the antagonistic action of fenmetozole against ethanol would not seem to be related to a specific receptor interaction but rather may be the result of a physiological antagonism.

Acoustic Stimulation↗
PubMed1980

Importance of the Locus coeruleus and involvement of alpha-adrenergic receptors in the post-decapitation reflex in the rat.

The latency, duration, hindlimb kick frequency, and total activity components of the post-decapitation reflex (PDR) were measured in the rat using a movement-sensitive transducer. Reduction of brain and spinal cord norepinephrine (NE) caused by neonatal administration of 6-hydroxydopamine (6-OHDA) or 5,7-dihydroxytryptamine, which also reduced brain serotonin, decreased all components of the PDR. Depletion of serotonin or dopamine alone reduced the vigor of the reflex, suggesting that these pathways can influence the PDR but are not essential for the response. Lesions of neurons in the Locus coeruleus, made electrolytically or with 6-OHDA, decreased the intensity of the PDR, with the 6-OHDA-induced lesion being more effective. Depletion of forebrain NE terminals with 6-OHDA did not alter the PDR, consistent with a critical involvement of spinal noradrenergic fibers. The PDR was also decreased by phentolamine and prazosin, but not by propanolol, suggesting an involvement of alpha-adrenergic receptors in the response. This hypothesis was further supported by the finding that the efficacy of a variety of drugs (such as tricyclic antidepressants, phenothiazines, and anti-hypertensive compounds) for blocking the reflex was apparently related to their affinity for alpha-adrenergic receptors. Thus, the PDR is dependent on noradrenergic fibers in the spinal cord and may provide a simple screen for drugs with suspected alpha-adrenergic blocking properties or for agents that disrupt the function of central noradrenergic fibers.

5,7-Dihydroxytryptamine↗
PubMed1980

Attenuation of the effects of punishment by ethanol: comparisons with chlordiazepoxide.

Ethanol (ETOH), like chlordiazepoxide (CDZ), significantly attenuated the suppressive effect of punishment on licking behavior in water-deprived rats and mice. In rats, the greatest effects of ETOH (1.5 g/kg) were observed between 30 and 60 min following IP administration. tert-Butanol also attenuated the effects of punishment, suggesting that acetaldehyde was not contributing to this effect of ETOH. Since a dose of ETOH that increased punished drinking did not increase unpunished drinking, alteration in thirst motivation would not appear to be responsible for its antipunishment action. However, doses of ETOH or CDZ that significantly increased punished responding increased jump thresholds to aversive shock, suggesting that decreased sensitivity to aversive stimulation may contribute to the anti-punishment action of both agents. In addition to these similarities between ethanol and CDZ, several differences were noted in their effects. For example, CDZ decreased serum corticosterone concentration, whereas ETOH did not. Further, ETOH impaired aerial righting reflex and reduced rectal temperature, whereas CDZ had no effect on these parameters at doses that had anti-punishment activity. Finally, specific binding of [3H]flunitrazepam to crude brain cortical membranes was decreased by CDZ, but not ETOH. Although ETOH and CDZ similarly alter punished behavior, results suggest that ETOH does not act through a direct interaction with a benzodiazepine binding site.

Animals↗
PubMed1980

Evidence that respiratory depression by serotonin agonists may be exerted in the central nervous system.

Resting with CO2 stimulated respiration were measured by means of a whole body plethysmograph in rats lightly anesthetized with halothane. The respiratory effects of different doses of the serotonin precursor 5-HTP, and the serotonin agonist 5-methoxy-N,N-dimethyltryptamine were studied as well as the effects of a serotonin antagonist methysergide and p-chlorophenylalanine, an inhibitor of serotonin synthesis. The serotonergic agonists decreased tidal volume and minute volume in a dose dependent manner and produced a respiratory acidosis. The respiratory depressant effect was antagonized by methysergide, and the serotonergic antagonist and synthesis inhibitor alone stimulated respiration. Rats given intraventricular 5-methoxy-N,N-dimethyltryptamine also evidenced a decrease in tidal volume, and this response was greater in animals given 5,7-dihydroxytryptamine. It seems likely that CNS serotonin receptors are involved in the control of both basal and CO2 stimulated respiration.

5-Hydroxytryptophan↗
PubMed1980

Effects of different monoamine oxidase inhibitors on respiratory activity in rats with chronically impaired central serotonergic function.

Resting and CO2 stimulated respiration were measured by means of a whole-body plethysmograph in rats lightly anaesthetized with halothane. Rats pretreated neonatally with intracisternal 5,7-dihydroxytryptamine (5,7-DHT) to destruct permanently central serotonergic neurones had significantly lower resting and CO2 stimulated respiratory frequency (RF) and minute volume (VM) than naive rats. In the 5,7-DHT pretreated rats, but not in naive rats, the monoamine oxidase inhibitors clorgyline and pargyline further reduced both resting and CO2 stimulated RF and VM, whereas 1-deprenyl stimulated respiration. The results provide additional evidence that monoaminergic mechanisms are involved in central modulation of respiration in which activation of a serotonergic neuronal system depresses, and dopaminergic activation stimulates respiration.

5,7-Dihydroxytryptamine↗
PubMed1980

An evaluation of the mechanism by which serotonergic activation depresses respiration.

The present investigation attempted to determine if the previously reported depression of respiration by serotonergic agonists was a result of peripheral or central nervous system drug effects. Systemic administration of 5-hydroxytryptophan (5-HTP) to pargyline-treated animals and 5-methoxy-N,N-di-methyltryptophan (5-MDMT) probably depress respiration secondary to central penetration of these drugs, since: 1) adult rats with biochemical evidence of partial destruction of central serotonergic neurons after neonatal intracisternal 5,7-dihydroxytryptamine were supersensitive to the respiratory depressing effect of 5-HTP and 5-MDMT; 2) the ventilatory effect of the serotonergic agonists was not reduced by surgical deafferentiation induced by bilateral transection of the glossopharyngeal nerves; 3) after sectioning of the vagus nerve, the absolute change produced by serotonergic agonists was less; however, the relative change was unaltered; and 4) inhibition of peripheral aromatic amino acid decarboxylase by RO-4-4602 significantly blunted the respiratory depressant activity of 5-HTP observed at 15 min but not that present 30 min after 5-HTP. The present fidings thus suggest that the cenvel by the activity of central serotonergic neurons.

5,7-Dihydroxytryptamine↗