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Biomedical subjects

D E Redmond

Publications and source records attributed to D E Redmond.

At least 109 records · Page 6Linked to original sources
PubMed1982

The primate locus coeruleus and effects of clonidine on opiate withdrawal.

Studies of nonhuman primates suggested that the noradrenergic locus coeruleus (LC) may be involved as part of the neural substrate for a brain alarm function which includes attentiveness, arousal, anxiety, fear, terror, and the physiological correlates of these states. The studies compared the effects of electrical activation of tiny electrodes in the locus coeruleus with the effects of other agents and conditions which increased or decreased LC activity. The results suggested that the activation of the LC system is prevented by endogenous morphine-like substances and by opiates and that the opiate withdrawal syndrome is due to activation of this LC-noradrenergic system. Clonidine, which in low doses suppressed noradrenergic and LC activity, was therefore postulated to suppress opiate withdrawal signs and symptoms. The confirmation of this hypothesis in rats, monkeys and human subjects has added to the understanding of the mechanisms of opiate action and withdrawal.

Animals↗
PubMed1982

Clonidine suppression of noradrenergic hyperactivity during morphine withdrawal by clonidine: biochemical studies in rodents and primates.

In rodents, naloxone-precipitated withdrawal of morphine-dependent animals causes an increase in NE turnover and MHPG accumulation in certain regions of the brain. This increase in NE turnover and MHPG accumulation is suppressed by clonidine to a dose-dependent degree via a naloxone-insensitive mechanism. In general, drugs which have been shown by electrophysiological studies to cause changes in the activity of NE neurons in the locus coeruleus also alter the brain levels of MHPG. These studies suggest that the brain levels of MHPG may be used as a biochemical measure of alterations of impulse flow in NE neurons of the locus coeruleus. In morphine-dependent vervet monkeys, administration of naloxone or naltrexone causes an increase in the brain levels of MHPG. The increase in MHPG observed during withdrawal is suppressed by clonidine. Brain levels of MHPG measured in both drug-treated and control monkeys correlate significantly with plasma and CSF measures of MHPG. These observations suggest that under controlled conditions plasma MHPG can provide a reasonable measure of brain NE metabolism in primates. Pilot data from clinical studies taken together with the more direct observations made in non-human primates are consistent with the hypothesis that in humans brain NE systems become hyperactive during opiate withdrawal and that this hyperactivity of NE systems is suppressed by clonidine.

Animals↗
PubMed1981

The clinical use of clonidine in abrupt withdrawal from methadone. Effects on blood pressure and specific signs and symptoms.

Clonidine hydrochloride was found to be effective in the treatment of methadone hydrochloride withdrawal. Under controlled inpatient conditions established to assess dosage guidelines and to examine specific signs and symptoms of withdrawal, 20 of 25 (80%) patients were able to withdraw completely from methadone by the end of a two-week period. In most patients, ten to 11 days of clonidine administration, with a peak mean dose of 16 micro g /kg/day, resulted in a perceived reduction in symptoms compared with previous attempts to become opiate free. At these doses clonidine significantly reduced standing blood pressure without producing clinical problems. The withdrawal symptoms of anxiety, restlessness, insomnia, and muscular aching were most resistant to clonidine treatment and were reported by the majority of patients.

Adult↗
PubMed1981

Presynaptic adrenergic receptor sensitivity in depression. The effect of long-term desipramine treatment.

Stimulation of presynaptic alpha 2-adrenergic receptors located on norepinephrine (NE)-containing cells in the brain decreases the firing rate and turnover of NE in these neurons. To assess whether abnormalities in the regulation of the NE system during desipramine hydrochloride treatment may be present in depressed patients, the effects of an alpha 2-agonist, clonidine hydrochloride, on plasma levels of the NE metabolite 3-methoxy-4-hydroxy/phenethyleneglycol (MHPG) and on blood pressure (BP) were evaluated in ten depressed patients before and during long-term desipramine treatment. Long-term desipramine treatment significantly attenuated the effects of clonidine on plasma MHPG level and BP, indicating that during desipramine treatment alpha 2-adrenergic receptors had become subsensitive. In addition, plasma MHPG levels were significantly reduced during long-term desipramine treatment. These findings are discussed in relation to the hypothesized therapeutic mechanism of action of desipramine and the hypotheses relating noradrenergic function and depression.

Adult↗
PubMed1981

Clonidine and the primate locus coeruleus: evidence suggesting anxiolytic and anti-withdrawal effects.

One may conclude from this series of studies and the data of others reviewed at this symposium that NE systems are involved in fear or anxiety and in mediating the actions of opioids and endorphins. It is rational pharmacotherapy, therefore, to utilize anatomically and neurophysiologically characterized receptors to produce those desired specific effects on NE systems that are expected to reduce anxiety. These same receptor interactions could also be used to antagonize side effects or to reverse withdrawal syndromes via alternative receptor sites. This strategy of using different receptors to produce synergistic or antagonistic effects on a common neuronal pathway has benefited the treatment of pathological anxiety, pain, drug withdrawal symptoms, and other classical psychosomatic conditions. It should be emphasized, of course, that the LC-noradrenergic system has a much broader function than the mediation of fear or anxiety, and that the endorphins, opiates, and clonidine influence many other systems, as do their abstinence syndromes. Anatomical projections of the LC and similar central NE systems also produce the observed effects. Detailed studies are needed to discover precisely how the abnormalities observed in numerous biochemical systems [Eidelberg, 1976] are related to the alterations in NE function we have studied and discussed in this chapter. Finally, careful clinical studies are needed to determine, define, and delimit the potential therapeutic uses of clonidine in the areas suggested by the preliminary studies reviewed here.

Animals↗
PubMed1981

The neuroanatomy and pharmacology of the nucleus locus coeruleus.

Several points are particularly relevant to an understanding of the effects of clonidine in the brain: Clonidine appears to act preferentially at alpha-2 adrenergic receptors and, in systemic doses of less than 50-100 microgram/kg, to exert its effects at autoreceptors, which initially decrease noradrenergic neuronal firing rates, NE release, and NE turnover. This action results in functional decreases of the usual effects of these neurons at their post synaptic alpha-1 and beta-adrenergic receptor-mediated projections, which are widely distributed throughout the limbic system, cerebrum, cerebellum, and spinal cord. Higher doses of clonidine appear to produce agonist effects at alpha-1 adrenergic receptors, counteracting the effects of decreases in firing rates and turnover. However, decreased function at beta receptors would continue after these higher doses owing to continued inhibition of neuronal activity and the lack of direct effects of clonidine on beta receptors. Receptors for GABA, endorphins, substance P, and ACh on LC neurons provide an anatomical and physiological basis for interactions among systems utilizing these substances as neurotransmitters in that they act on a common final noradrenergic pathway. These noradrenergic pathways, in turn, also project to and mediate functional changes in areas utilizing other neurotransmitters. Although these changes affect numerous types of behavior and responses that are measurable by psychopharmacologists, it is the neurons of the locus coeruleus and other noradrenergic neurons with similar receptor combination that provide the entry point to this NE system. Studies of the LC, therefore, may help to determine the nature of these specific effects and to characterize the effects of clonidine and other alpha-2 agonists on the brain.

Animals↗
PubMed1980

Clonidine suppresses the opioid abstinence syndrome without clonidine-withdrawal symptoms: a blind inpatient study.

Nine hospitalized opioid-addicted patients were blindly given clonidine within 36 hours of the abrupt and blind discontinuation of methadone. All nine patients were successfully withdrawn from methadone and were asymptomatic upon discharge. Clonidine-treated patients had significantly fewer symptoms than a comparable group of opioid addicts abruptly withdrawn from methadone. No exacerbation of symptomatology developed after the cessation of clonidine. The clinical implications of clonidine's suppression of opioid withdrawal and the alpha-2 adrenergic mediation of the abstinence syndrome are discussed.

Adult↗
PubMed1980

Biological component of the NIMH clinical research branch collaborative program on the psychobiology of depression: II. Methodology and data analysis.

A preceding paper has reviewed the history, background, and rationale for this collaborative effort exploring the biologic basis of the affective disorders. This paper details the "flow" of a subject through the experimental protocol, the instrumentation used to obtain the clinical and behavioural data, and the biologic methodologies employed in the analysis of the body fluids. Data management and analysis techniques developed for this study are also examined.

Adrenocorticotropic Hormone↗
PubMed1980

Social and nonsocial behaviours of sex- and age-matched enclosed and free-ranging rhesus monkeys (Macaca mulatta).

The behavioural profiles (time budgeting of social and nonsocial activities) and the frequencies of major social interactions of corral-enclosed rhesus monkeys were compared with sex- and age-matched free-ranging rhesus monkeys on La Cueva Island, Puerto Rico. All animals (n = 32) were provisioned ad libitum at specific feeder sites. The occurrence of 14 behaviours around feeders was compared with their occurrence away from the feeders by noting the location of each monkey relative to the feeder at the time of observation. An analysis of variance between free-ranging versus corral-enclosed groups and within groups by location (around or away from the feeder) revealed significant differences in several behavioural categories, including foraging, lookout, inactive, dominant, submissive, allogrooming, social contact, social initiative, active, and passive behaviours. When the effect of limited food distribution sites was analyzed by comparing data recorded away from the feeding sites, there were remarkably few differences between the groups.

Age Factors↗
PubMed1980

Chronic haloperidol or fluphenazine: effects on dopamine metabolism in brain, cerebrospinal fluid and plasma of Cercopithecus aethiops (vervet monkey).

Chronic treatment with haloperidol for 3 to 5 weeks (0.5 mg/kg, daily) resulted in significant increases of homovanillic acid (HVA) content in dorsal and orbital frontal cortex and in cingulate cortex. No change in HVA was seen in the olfactory cortex, basal ganglia, cisternal cerebrospinal fluid or plasma of animals chronically treated with haloperidol. Treatment with a single weekly dose of fluphenazine decanoate (5 mg/kg) for 3 weeks resulted in increased HVA levels in all the above brain regions, cisternal cerebrospinal fluid and plasma. Moreover, the fluphenazine-treated group had a significantly higher incidence of extrapyramidal side effects than the haloperidol-treated group. It is concluded that chronically increased dopamine metabolite production in the basal ganglia but not in cortex is reflected by increases in the HVA level of cerebrospinal fluid and plasma and is accompanied by severe extrapyramidal side effects.

Animals↗