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Biomedical subjects

I N Mefford

Publications and source records attributed to I N Mefford.

At least 37 records · Page 2Linked to original sources
PubMed1990

Indomethacin prevents increased catecholamine turnover in rat brain following systemic endotoxin challenge.

1. Key features of the acute phase response to infection are replicated by systemic administrations of lipopolysaccharide and may be mediated via the production of lymphokines and cytokines, including interleukin-1. Inhibition of prostaglandin synthesis may attenuate certain features of the acute phase response. 2. In the present study, the effects of systemic administration of the lipopolysaccharide (LPS, 250 micrograms/rat) and interleukin-1 (IL-1, 10 micrograms/rat) on catecholamine metabolism in different brain regions were compared and the effects of indomethacin, a cyclooxygenase inhibitor was determined. 3. The ratio of metabolite to parent amine was used as an index of turnover of catecholamines. 4. In hypothalamus, both epinephrine and norepinephrine concentrations were decreased and their major metabolite, 3-methoxy,4-hydroxyphenylglycol (MHPG), was elevated at 4, 8 and 24 hr following LPS. The major metabolite of dopamine (homovanillic acid, HVA) was increased at 8 hours in striatum, hypothalamus and medulla. LPS increased dopamine turnover at 8 and 24 hr and norepinephrine turnover at 4, 8 and 24 hr. 5. In all regions examined, IL-1 produced effects similar to LPS on amine and metabolite contents and norepinephrine and dopamine turnover. 6. Significantly, co-administration of a single dose of indomethacin (50 mg/kg) completely blocked LPS-induced changes in hypothalamic catecholamines and metabolites and the increase in turnover at 4 and 8 hr. Furthermore, the effects of IL-1 on hypothalamic MHPG content and norepinephrine turnover were also blocked by indomethacin, although the effects of IL-1 on regional catecholamines and HVA content and turnover were either not modified or partially antagonized by indomethacin. 7. The present results suggest that in the rat, activation of noradrenergic, dopaminergic and epinephrine-containing neurons in hypothalamus, as well as dopaminergic neurons in other regions is associated with the acute phase response to endotoxin and that synthesis of prostaglandins plays a pivotal role in catecholamine responses in all brain regions examined.

Animals↗
PubMed1990

Stimulant drug treatment of hyperactivity: biochemical correlates.

To compare the effects of the stimulant drugs dextroamphetamine and methylphenidate on urinary and plasma monoamines and metabolites within the same clinical sample, thirty-one children with attention-deficit disorder with hyperactivity were treated with dextroamphetamine (up to 1.5 mg/kg/day), methylphenidate (up to 3.0 mg/kg/day), and placebo in an 11-week double-blind crossover trial. As expected, both drugs showed striking clinical efficacy, and within a subsample of the group, earlier findings were confirmed, that dextroamphetamine but not methylphenidate lowered urinary and plasma 3-methoxy-4-hydroxyphenylglycol and whole body norepinephrine turnover, and that urinary and plasma concentration of homovanillic acid was unaltered by either drug. Methylphenidate but not dextroamphetamine increased plasma norepinephrine. Urinary epinephrine and metanephrine were increased with both drugs, but this increase did not correlate significantly with clinical improvement.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1990

Effects of different semipermeable membranes on in vitro and in vivo performance of microdialysis probes.

The in vitro and in vivo performance of three different semipermeable microdialysis membranes was compared: a proprietary polycarbonate-ether membrane made by Carnegie Medecin; cuprophan, a regenerated cellulose membrane; and polyacrylonitrile. When microdialysis probes were tested in a stirred in vitro solution, large and statistically significant differences among the three membranes in extraction of acid metabolites (3,4-dihydroxyphenylacetic acid, 5-hydroxyindoleacetic acid, and homovanillic acid) and acetaminophen were found. Polyacrylonitrile had the highest extractions in vitro. In contrast, when microdialysis probes were implanted in vivo (in rat striatum), extraction of acid metabolites and acetaminophen did not differ significantly among the different membranes. These results are consistent with predictions made by a mathematical model of microdialysis and can be explained by the fact that in vitro the main factor limiting extraction is membrane resistance to diffusion, whereas tissue resistance to diffusion plays a more dominant role in vivo. These findings suggest that (aside from differences in surface area), the choice of semipermeable membrane will generally have little effect on in vivo microdialysis results. Furthermore, in vitro measurements of microdialysis probe extractions are not a reliable way of calibrating in vivo performance.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1990

Antagonism of ethanol intoxication in rats by inhibitors of phenylethanolamine N-methyltransferase.

The probable involvement of brain epinephrine in the expression of the acute sedative and intoxicating effects of ethanol and pentobarbital is demonstrated. Two selective inhibitors of phenylethanolamine N-methyltransferase (PNMT), LY134046 and LY78335, proved to be potent and long-lasting antagonists of ethanol intoxication in rats. Acute antagonism of pentobarbital-induced intoxication was observed with LY134046. The present results are compatible with a role for central epinephrine synthesis in ethanol and pentobarbital-induced sedation and intoxication in rats.

Alcoholic Intoxication↗
PubMed1990

A cerebrospinal fluid study of the pathophysiology of panic disorder associated with alcoholism.

In order to investigate the neurochemistry of panic disorder in alcoholics, we measured various cerebrospinal fluid (CSF) parameters in subjects with both conditions and compared them with an age- and sex-matched population of alcoholics and normal controls. When height, age and weight were covaried, subjects with panic disorder had higher levels of B-endorphin in CSF. There were no differences in other CSF measures between the groups. Alcoholics with panic disorder had higher plasma MHPG concentrations compared with alcoholics without panic disorder but these were not statistically different from controls.

Adult↗
PubMed1990

Biogenic amines distribution in the brain of nervous and normal pointer dogs. A genetic animal model of anxiety.

Nervous pointer dogs have been suggested as an animal model for pathological anxiety. In order to study possible disturbances in neurotransmitter functions in this animal model, we measured brain biogenic amines (norepinephrine, dopamine, and serotonin) and their metabolites in both nervous and normal dogs. Eight nervous and six normal dogs were behaviorally tested and later anesthetized and killed. Brains were removed and dissected while frozen using a punch technique. Samples were assayed using high-performance liquid chromatography (HPLC) with electrochemical detection. The nervous dogs had higher [NE] in the reticular formation and lower serotonin, and its metabolite 5-hydroxyindoleacetic acid, in the septal nuclei, indicating possible important differences in noradrenergic and serotonergic functions in the nervous dogs. There was a trend for lower [HVA] and [DOPAC] levels and a significantly lower [DOPAC]/[DA] ratio in the nervous dogs, suggesting decreased dopaminergic function.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1989

Effects of xylazine on cerebrospinal fluid catecholamines in the rhesus monkey.

The i.v. administration of xylazine, a potent, selective alpha 2-adrenergic receptor agonist, resulted in a 76% decrease in cerebrospinal fluid (CSF) norepinephrine in chair-adapted rhesus monkeys. A significant decrease was observed within 1.5 h of administration and continued through the 3 h course of sampling. Dopamine was maximally decreased by 24% at 1.5 h. Epinephrine was not significantly decreased following xylazine administration. These data suggest that norepinephrine release into monkey CSF, as an index of central or peripheral norepinephrine turnover, is more sensitive to alpha 2-adrenergic agonists than in CSF dopamine or epinephrine.

Adrenergic alpha-Agonists↗
PubMed1989

Effect of single and repeated electroconvulsive shock on the hypothalamic-pituitary-adrenal axis and plasma catecholamines in rats.

The effects of single and repeated electroconvulsive shock (ECS) on the hypothalamic-pituitary-adrenal (HPA) axis and plasma catecholamines were studied. Rats were divided into three groups and each group received sham treatment, single ECS, or ten once-daily ECS. Jugular venous blood samples were obtained immediately before treatment and at 10, 30, 60, and 90 min following sham treatment, a single ECS or following the last of ten ECS. Plasma concentrations of corticosterone (CS), ACTH, immunoreactive beta-endorphin (ir-BE), epinephrine (E) and norepinephrine (NE) were determined. Following the single ECS plasma CS was significantly elevated at 10 and 30 min, ACTH was significantly elevated at 10, 30, and 60 min, whereas ir-BE and E peaked at 10 min and returned to basal concentration by 30 min. The concentration of plasma NE did not significantly vary at any time point. Following the tenth ECS the concentration of plasma CS revealed a significant attenuation of the increase at 10 and 30 min when compared with the CS changes observed following a single ECS. Plasma ACTH following chronic ECS was also significantly decreased in magnitude at 10, 30, and 60 min when compared with plasma ACTH levels following a single ECS. Ir-BE in plasma following ten ECS mirrored the changes following single ECS. In contrast to the attenuation of CS and ACTH following chronic ECS, the increase in peripheral catecholamines was markedly elevated after the last of ten ECS. Compared with single ECS, ten ECS produced significant increases in plasma E at 10, 30, and 60 min and at 10, 30, 60, and at 90 min for NE.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1989

Activation in young rats induced by LY134046, an inhibitor of phenylethanolamine N-methyltransferase.

LY134046, a potent, selective inhibitor of rat brain phenylethanolamine N-methyltransferase, was shown to increase activity in 18- and 19-day-old rats. The effects on day 25 were different, with LY134046 causing a decrease in activity. The effects of yohimbine, a selective antagonist of the alpha-2 adrenergic receptor, were markedly different from LY134046, causing a decrease in activity on day 19. These data suggest that epinephrine synthesis may play an inhibitory role in the regulation of activity in young rats.

Animals↗
PubMed1989

A neuroanatomical and biochemical basis for attention deficit disorder with hyperactivity in children: a defect in tonic adrenaline mediated inhibition of locus coeruleus stimulation.

Attention deficit disorder with hyperactivity (ADDH) is characterized by a high level of inappropriate activity, distractability and impulsivity as well as learning deficits. In mammals, the protective mechanism for acquisition of sensory information, processed for its survival value, can be termed "vigilance". In ADDH, a low threshold for novel or sensory stimuli, results in a "hard wired" mammalian response, orienting, followed by exploratory behavior, the orienting reaction. This behavior is mediated in the brainstem through sensory neurons in the reticular formation regulating the discharge of locus coeruleus noradrenergic neurons. It is proposed that adrenaline acts as a tonic inhibitor of these neurons, modulating the level of sensory stimulation necessary to elicit locus coeruleus excitation. An imbalance in adrenaline formation or alpha-2 adrenergic receptor number (or affinity) leads to the inability to maintain the appropriate threshold for discharge of locus coeruleus neurons. The consequences are inability to maintain focused attention, difficulty in falling asleep or light levels of sleep, inattention to consumptive behavior, and probable inappropriate response for reward as all these behaviors require disruption of processing of sensory stimuli. Cognitive deficits may occur secondarily.

Animals↗
PubMed1989

Evidence for the presence of PNMT-containing cell bodies in the hypothalamus.

The presence of intrinsic neurons in the hypothalamus containing the enzyme phenylethanolamine N-methyltransferase (PNMT), was investigated by selective destruction of the local cell bodies with kainic acid (KA), a potent excitotoxin. The unilateral stereotaxic injection of 2 micrograms of KA into the lateral hypothalamus produced a 30-35% decrease in the hypothalamic PNMT activity in the lesioned side compared with the contralateral uninjected side. The difference was statistically significant for up to 4 days after the lesion. The unilateral lesion did not have a unilateral effect on epinephrine or norepinephrine content as there was a significant reduction on both sides (50% for epinephrine and 30% for norepinephrine compared with saline injected). These data suggest the presence of intrinsic cell bodies in the lateral hypothalamus, containing the epinephrine-forming enzyme but lacking epinephrine storage sites. Our results support the previous hypothesis of the dissociation between epinephrine present in the hypothalamus and hypothalamic PNMT activity.

Animals↗
PubMed1989

Measurement of tryptophan hydroxylase activity in rat pineal glands and pinealocytes using an HPLC assay with electrochemical detection.

A method for measuring tryptophan hydroxylase activity by assaying the product 5-HTP using high-performance liquid chromatography (HPLC) with electrochemical detection is described. A nocturnal elevation (80%) in rat pineal gland tryptophan hydroxylase activity was detected. Experiments on isolated rat pinealocytes with the protein synthesis inhibitor cycloheximide indicate that tryptophan hydroxylase turns over rapidly in these cells. This method will be valuable in studies of the adrenergic mechanisms regulating pineal tryptophan hydroxylase activity.

5-Hydroxytryptophan↗
PubMed1989

Single-dose ethanol administration activates the hypothalamic-pituitary-adrenal axis: exploration of the mechanism of action.

Activation of the hypothalamic-pituitary-adrenal axis (HPAA) by single-dose ethanol administration, which achieved moderately high blood ethanol levels, was explored in naive rats in order to determine the mechanism of ethanol's activation of the stress axis. Adult male rats received a single dose (3.2 g/kg body weight-1 of a 12% solution of ethanol in physiological saline. The plasma concentration of immunoreactive (ir) adrenocorticotropic hormone (ACTH), beta-endorphin (BE) and corticosterone (CS) was determined by radioimmunoassay, whereas, plasma concentrations of epinephrine (E) and norepinephrine (NE) were quantified following reverse-phase liquid chromatographic separation and amperometric detection. Ethanol induced maximal plasma ACTH levels within minutes, which declined toward basal levels by 60 min, whereas, plasma concentration of CS rose rapidly and remained elevated at 60 min. Plasma ACTH and CS levels in saline-treated control animals did not vary significantly at any time point. Consistent with co-release of ACTH from corticotrophs, the plasma concentration of ir-BE increased 5-fold at 15 min and declined towards basal levels at 60 min after-ethanol challenge. Plasma E increased 10- to 20-fold as compared to saline controls or preinjection levels and returned to preinjection levels by 90 min, in a manner similar to ethanol-induced changes in proopiomelanocortin-derived peptides and CS. Removal of the adrenal medulla and thus the source of E prior to ethanol administration, did not attenuate activation of the HPAA. Passive immunoneutralization of arginine vasopressin (AVP), using a high-titer AVP antiserum and a protocol which was found to block ether-induced ACTH secretion by 40% in adult male rats, failed to even partially block ethanol-induced ACTH or CS secretion. The results of this study indicate that neither adrenal medulla-derived E nor AVP are significant regulators or coregulators of corticotroph secretions following a moderately high, single-dose, intragastric administration of ethanol.

Adrenocorticotropic Hormone↗
PubMed1988

Enhancement of dopamine metabolism in rat brain frontal cortex: a common effect of chronically administered antipsychotic drugs.

Administration of 4 antipsychotic drugs, haloperidol, chlorpromazine, thioridazine and clozapine, for 21 days elicited increased dopamine metabolism in frontal cortex of rat brain. Only clozapine failed to decrease the apparent firing rate of dopamine neurons in the striatum, as indexed by [homovanillic acid]/[dopamine]. These data support the hypotheses that frontal cortex dopamine neurons may be a common site for antipsychotic action while decreased release of dopamine in the striatum may be associated with the development of extrapyramidal side effects.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1988

Epinephrine in mammalian brain.

1. Epinephrine is widely distributed in brains of various species throughout phylogeny but maintains its localization to hypothalamus and brainstem/medulla in all species studied. 2. A general decrease in brain epinephrine content is observed phylogenetically beyond fishes with wide variation within species. 3. The cellular localization of epinephrine forming enzyme is dissociated from epinephrine stores in hypothalamus where epinephrine appears to be primarily a hormone. 4. Three proposed functional pools of epinephrine are described. Synthesis of a hormonal pool and a second, perhaps nonfunctional, pool co-stored in noradrenergic terminals in the forebrain occurs extraneuronally and is probably inhibited acutely in the presence of high corticosteroids due to inhibition of uptake 2. Synthesis of epinephrine in the neuronal pool found primarily in the medulla may be enhanced due to increased PNMT activity in the presence of elevated corticosteroids. 5. Phylogenetic and pharmacological data suggest that epinephrine may play an important role in tonic regulation of the level of arousal, reward and sensitivity to environmental stimuli in mammals.

Animals↗
PubMed1988

Acute effect of intragastric ethanol administration on plasma levels of stress hormones.

We have previously demonstrated that single-dose ethanol administration enhanced plasma levels of ACTH, beta-endorphin, corticosterone (CS) and catecholamines. Since the secretion of proopiomelanocortin-derived peptides (e.g., ACTH, beta-endorphin) can be influenced by catecholamines and vasopressin in addition to the primary physiological regulator, corticotrophin-releasing hormone, we have attempted to determine whether or not the ethanol-induced activation of the hypothalamic-pituitary-adrenal axis (HPAA) could in part be mediated via either epinephrine or vasopressin (AVP) secretion. The selective neutralization of AVP through the administration of AVP antiserum failed to block the ethanol-induced secretion of either ACTH or CS. In addition, adrenal demedullation did not significantly attenuate the ethanol-induced increase of ACTH and CS. It would appear that neither adrenal medulla-derived epinephrine nor median eminence-derived AVP mediates ethanol's activation of the HPAA.

Adrenal Medulla↗
PubMed1987

Application of a novel cation-exchange reagent, Igepon T-77 (N-methyl oleoyl taurate), to microbore separations of alumina extracts of catecholamines from cerebrospinal fluid, plasma, urine and brain tissue with amperometric detection.

The use of a novel amide surfactant, N-methyl oleoyl taurate (Igepon T-77), has been examined for the separation of amines on reversed-phase chromatographic material. This reagent was found to partition onto the C18 material in a partially irreversible and concentration independent manner. When the stationary phase is saturated with this surfactant, the loaded column performs as a strong cation exchanger. Novel separations are possible as a result of secondary hydrogen-bonding effects which modify classical retention order for primary, secondary and tertiary amines. Sensitive and selective applications of these separations are demonstrated for catecholamine determinations in blood plasma, cerebrospinal fluid, urine and brain tissue. Additional sensitivity is obtained for epinephrine by taking advantage of the pH-dependent intramolecular cyclization and on-column concentration of large injection volumes.

Aluminum Oxide↗