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Biomedical subjects

C W Callaway

Publications and source records attributed to C W Callaway.

At least 19 recordsLinked to original sources

Electron spin resonance measure of brain antioxidant activity during ischemia/reperfusion.

An electron spin resonance technique was used to measure cerebral antioxidant activity during asphyxial cardiac arrest and reperfusion. There were significant decreases in ascorbate (48%), glutathione (44%), total thiols (42%), protein thiols (38%) and alpha-tocopherol (26%) in the hippocampus 10 min after reperfusion (p < 0.05 vs respective baselines) but not during asphyxial cardiac arrest. The levels of antioxidants returned to baseline values by 120 min after reperfusion. The results support the hypothesis that reperfusion from asphyxial cardiac arrest, but not arrest alone, produced a significant oxidative stress as reflected by a depletion of both water and lipid soluble antioxidants. Furthermore, antioxidant depletion was transient, with normal antioxidant levels observed 120 min, 24 h and 72 h after reperfusion.

Analysis of Variance

Noninvasive cerebral cooling in a swine model of cardiac arrest.

OBJECTIVE: Mild cerebral hypothermia improves neurologic outcome in animals resuscitated from cardiac arrest. This study examined whether one practical external cooling method, i.e., local application of ice to the heads and necks of swine, during resuscitation induces cerebral cooling. METHODS: Local external cerebral cooling was examined in a prospective laboratory investigation using 24 female swine in a model of cardiac arrest. The swine were randomized into hypothermia and normothermia groups. Intracerebral temperature was measured in the parietal cortex. Eight minutes after induction of ventricular fibrillation, chest compressions and mechanical ventilation were initiated. The hypothermia group was treated with 1,500 mL of ice in plastic bags applied to the head and neck, while the normothermia group received no extra interventions. Data were analyzed using repeated-measures ANOVA. RESULTS: In the normothermia group, there was no significant change in nasopharyngeal (-0.8 +/- 0.6 degree C), intracerebral (-0.6 +/- 0.8 degree C), or esophageal (-0.2 +/- 0.6 degree C) temperatures during 20 minutes of resuscitation. However, in the hypothermia group, application of ice during resuscitation significantly reduced nasopharyngeal (-2.9 +/- 1.4 degrees C), intracerebral (-2.1 +/- 0.6 degrees C), and esophageal (-1.4 +/- 0.8 degrees C) temperatures. CONCLUSIONS: External application of ice packs during resuscitation effectively reduced intracerebral temperatures in swine by an amount that improved neurologic outcomes in previous large animal studies. These data suggest that clinically significant cerebral cooling could be accomplished with a noninvasive, inexpensive, and universally available intervention. Further studies are required to assess the clinical feasibility and therapeutic efficacy of this intervention.

Analysis of Variance

Dietary guidelines for Americans: an historical perspective.

Since 1980, Dietary Guidelines for Americans have been published jointly, every 5 years, by the U.S. Department of Agriculture (USDA) and the Department of Health and Human Services (DHHS). They benefit from the recommendations of a formally appointed Dietary Guidelines Advisory Committee. The Guidelines are an example of public health recommendations that are based upon published original research and analysis of that data by expert panels. The Guidelines are intended for healthy adults, so they might reduce their risks for certain diet-related chronic conditions. They are suggestions; they do not serve-and should not be used-as regulations. Greater individualization of dietary recommendations, for both major subgroups of the population and for individual patients, can improve our effectiveness in preventing and treating specific diet-related chronic conditions. To accomplish this objective, we need to move beyond the use of "indicators" (e.g., body mass index or blood cholesterol levels) as if they were "diagnostic," and focus on dietary and pharmacologic interventions (or, in some cases, no intervention) based on more specific diagnostic criteria (e.g., lipid patterns, fat distribution patterns, evidence of insulin resistance, and family history). Better targeting of dietary recommendations should improve their effectiveness, while reducing costs.

Diet

Hyperthermia in psychostimulant overdose.

Psychostimulant drugs such as amphetamines, amphetamine derivatives, and cocaine produce a variety of potentially lethal effects, and an understanding of these toxic effects is important for emergency physicians. While some effects of psychostimulant poisonings such as cardiovascular compromise and seizures have been discussed extensively, other metabolic derangements such as hyperthermia are less well characterized. In fact, hyperthermia is a common feature of severe-to-lethal poisonings and may be the primary mode of demise in some patients. Animal studies confirm that drug-induced hyperthermia alone can be lethal in some species, although other toxic effects may predominate at different drug doses or rates of administration. In non-lethal poisonings, hyperthermia can produce rhabdomyolysis, leading to further morbidity. Clinical reports and animal studies indicate that hyperthermia is a primary effect of psychostimulant drugs and can occur independently of seizures or increased motor activity. Furthermore, activation of particular dopamine receptors in the central nervous system appears to mediate psychostimulant-induced hyperthermia. The literature suggests cooling and tranquilization of psychostimulant-poisoned patients after cardiovascular stabilization. Paralysis and mechanical ventilation may be required. The involvement of dopamine receptor activation in psychostimulant toxicity suggests that dopamine-blocking neuroleptic drugs may be a useful adjunct to current treatment regimens. However, further studies are required to assess this approach. In summary, hyperthermia is a potentially lethal but treatable manifestation of severe psychostimulant poisoning.

Amphetamines

Suppression of behavioral activity by norfenfluramine and related drugs in rats is not mediated by serotonin release.

Fenfluramine, a phenalkylamine with serotonin (5-HT) releasing properties, decreases motor activity in rats. The following studies assessed the contribution of 5-HT release to the behavioral effects of fenfluramine and norfenfluramine using a behavioral pattern monitor that simultaneously assesses locomotor and investigatory behavior. First, both fenfluramine and its active metabolite d-norfenfluramine dose-dependently reduced locomotor and investigatory activity. The norfenfluramine-induced reduction in activity was not antagonized by pretreatment with the 5-HT uptake inhibitor fluoxetine or the 5-HT synthesis inhibitor p-chlorophenylalanine, drugs that reduce drug-induced 5-HT release. Second, the d- and l-enantiomers of norfenfluramine were nearly equipotent at reducing behavioral activity, although d-norfenfluramine is more potent as a 5-HT releasing agent. Third, p-chloroamphetamine, a drug that shares the 5-HT releasing properties of fenfluramine produced locomotor hyperactivity in the same paradigm. Previous studies indicate that other 5-HT releasing phenalkylamines have behavioral effects resembling those of p-chloroamphetamine rather than those of fenfluramine. Finally, a structurally related drug, 4-methoxy-5-methyl-aminoindan (MMAI), produced dose-dependent reductions in behavioral activity that are similar to the effects of fenfluramine. The behavioral effects of MMAI were not antagonized by fluoxetine or by the 5-HT receptor antagonist methiothepin. These data suggest that the decrease in activity induced by fenfluramine, norfenfluramine and the related drug MMAI is not related to 5-HT release.

Animals

Quantitative assessment of the microstructure of rat behavior: II. Distinctive effects of dopamine releasers and uptake inhibitors.

The effects of four indirect dopamine agonists, d-amphetamine (0.25-4.0 mg/kg), cocaine (2.5-40.0 mg/kg), GBR 12909 (10.0-30.0 mg/kg), and nomifensine (5.0-20.0 mg/kg), on the behavioral organization of movements in an unconditioned motor paradigm were investigated in rats. The extended scaling hypothesis using the fluctuation spectrum of local spatial scaling exponents was used to quantify the geometrical characteristics of movements. The results reveal a qualitatively similar disruption of behavioral organization by lower doses of these drugs. Specifically, rats treated with d-amphetamine (< 2.0 mg/kg), cocaine (< 20.0 mg/kg), GBR 12909 (< 20.0 mg/kg), or nomifensine (< 10.0 mg/kg) exhibited a reduced range in the fluctuation spectrum, reflecting a predominance of meandering movements with local spatial scaling exponents between 1.3 and 1.7. This reduction was accompanied dynamically by a reduced predictability of movement sequences as measured by the dynamical entropy, h. By contrast, higher doses of these drugs produced distinctly different changes in behavioral organization. In particular, 4.0 mg/kg d-amphetamine and 40.0 mg/kg cocaine increased the fluctuation range, reflecting relative increases in both straight and circumscribed movements that are interpreted as a combination of spatially extended and local perseveration. In contrast, high doses of 30.0 mg/kg GBR 12909 and 20.0 mg/kg nomifensine induced only local perseveration. High doses of d-amphetamine, cocaine, GBR 12909 and nomifensine reduced the dynamical entropy, h, indicating an increased predictability of the movement sequences. These results suggest that the generic behavioral change induced by low doses of dopamine agonists is characterized by a reduced variety of path patterns coupled with an increased variability in sequential movement sequences. The differential effects of higher doses of these drugs may be due to their influences on other neurotransmitter systems or differential affinities for different dopamine subsystems.

Animals

Serotonin1B receptor activation mimics behavioral effects of presynaptic serotonin release.

The locomotor hyperactivity induced by 3,4-methylene-dioxymethamphetamine (MDMA) and related drugs in rats appears to be due to the drug-induced release of presynaptic serotonin (5-HT). Thus, these drugs increase locomotor activity by acting as indirect 5-HT agonists. The subtype of 5-HT receptor upon which this released 5-HT acts postsynaptically to produce the activating effect of MDMA-like drugs is not known. When tested under conditions in which MDMA increases locomotion, direct agonists at both 5-HT1A and 5-HT1C/2 receptors consistently decrease locomotion. Hence, the present experiments tested the hypothesis that the hyperactivity produced by the release of endogenous 5-HT is due to the activation of 5-HT1B receptors. Using the Behavioral Pattern Monitor (BPM), the profile of behavioral effects of a 5-HT1B agonist, 5-methoxy-3(1,2,3,6)tetrahydropyridin-4yl)-1H-indole (RU 24969), was compared to that previously described for MDMA and related indirect 5-HT agonists. The BPM provided detailed information regarding the amount and qualitative patterning of locomotor activity and investigatory responses in rats. Various doses of RU 24969 (1.25 to 5 mg/kg) were administered to naive male rats 10 minutes prior to placement in the test chambers. As previously reported for MDMA, locomotor activity increased with dose, and investigatory rearings and holepokes decreased. The hyperactivity was characterized by repetitive spatial patterns of locomotion that were qualitatively similar to those produced by indirect 5-HT agonists such as MDMA and dissimilar to those produced by indirect dopamine (DA) agonists such as amphetamine. Pretreatment with racemic propranolol but not (+)propranolol antagonized the hyperactivity induced by RU 24959. Fluoxetine, a 5-HT reuptake inhibitor, failed to block the locomotor activating effects of RU 24969. These findings confirm the similarity between the behavioral effects of RU 24969 and indirect 5-HT agonists and suggest that the locomotor hyperactivity produced by both RU 24969 and MDMA is mediated by the activation of 5-HT1B receptors. Although the effects of MDMA on 5-HT1B receptors are secondary to its ability to release presynaptic 5-HT, the activation produced by RU 24969 appears to be a consequence of its direct agonist effects.

3,4-Methylenedioxyamphetamine

Stimulant effects of 3,4-methylenedioxymethamphetamine in the nucleus accumbens of rat.

This study examined the behavioral effects in rats of intracerebral administration of S(+)-3,4-methylenedioxymethamphetamine (S-MDMA) using an automated holeboard and open-field apparatus. Administration of S-MDMA into the nucleus accumbens septi produced locomotor hyperactivity. Although the stimulant effects of S-MDMA administered systemically are antagonized by fluoxetine pretreatment, the activating effects of S-MDMA administered into the nucleus accumbens were not antagonized by fluoxetine. A similar increase in locomotor activity was observed after S-amphetamine administration into the nucleus accumbens. In contrast, the selective 5-HT-releasing drug and S-MDMA congener N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine (MBDB) produces MDMA-like locomotor hyperactivity when administered systemically but did not alter locomotor activity when injected into the nucleus accumbens. These data indicate that S-MDMA actions in the nucleus accumbens are pharmacologically distinct from the primary effects of systemically administered S-MDMA. Behavioral effects of S-MDMA in the nucleus accumbens may result from the catecholamine-releasing properties that S-MDMA shares with S-amphetamine and not via the 5-HT-releasing properties that it shares with MBDB.

3,4-Methylenedioxyamphetamine

Neuronal firing in the nucleus accumbens is associated with the level of cortical arousal.

Because of evidence that the nucleus accumbens mediates the activating effects of many drugs, this study examined the hypothesis that the firing rates of individual nucleus accumbens neurons are positively correlated with spontaneous changes in behavioral arousal that occur during the sleep-wake cycle. The present report examined the firing patterns of 80 neurons in the nucleus accumbens of unanesthetized, unrestrained rats during various electrographically determined levels of arousal. Synaptic responses to stimulation of hippocampal and pallidal nucleus accumbens afferents indicated that the present sample of neurons was similar to a large population of nucleus accumbens neurons previously recorded in anesthetized rats. Confirming the participation of the nucleus accumbens in behavioral arousal, the firing rates of nucleus accumbens neurons were greatest during wakefulness and rapid eye movement sleep and lowest during non-rapid eye movement sleep. Furthermore, the induction of halothane anesthesia decreased behavioral and electrocorticographic arousal concurrent with a suppression of the spontaneous nucleus accumbens unit discharge. These data support the hypothesis that the firing of nucleus accumbens neurons is closely related to arousal.

Action Potentials

Tolerance and cross-tolerance to the activating effects of 3,4-methylenedioxymethamphetamine and a 5-hydroxytryptamine1B agonist.

Previous studies indicate that 3,4-methylenedioxymethamphetamine (MDMA) produces locomotor hyperactivity in rats by increasing the presynaptic release of serotonin (5-HT). Interactions between MDMA and 5-HT receptor antagonists suggest that the activating effects of MDMA are mediated via 5-HT1-like receptors. In order to assess the contribution of particular 5-HT receptor subtypes to the behavioral effects of MDMA, the present studies examined the development of tolerance and cross-tolerance to the behavioral effects of MDMA and selective 5-HT receptor agonists. In the first study, rats were pretreated with saline, a 5-HT1A receptor agonist (8-hydroxy-2-(di-n-propylamino)tetralin, 1.0 mg/kg), a 5-HT1B receptor agonist [5-methoyx-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole butane dioate (RU24969), 2.5 mg/kg] or a 5-HT1C/5-HT2 receptor agonist (2,5-dimethoxy-4-iodoamphetamine, 1.0 mg/kg) twice daily for 3 days. The behavioral response to S-MDMA (3.0 mg/kg) was assessed 36 hr after the last pretreatment injection. Pretreatment with RU24969 antagonized the activating effects of S-MDMA. In contrast, pretreatment with 2,5-dimethoxy-4-iodoamphetamine did not alter the response to S-MDMA, and pretreatment with 8-hydroxy-2-(di-n-propylamino)tetralin reduced the activity of both control and S-MDMA-treated animals. In the second study, rats were pretreated with saline or RS-MDMA (10 mg/kg), twice daily for 4 days. The behavioral response to saline, S-MDMA (3.0 mg/kg), RU24969 (2.5 mg/kg) or S-amphetamine (1.0 mg/kg) was assessed 36 hr after the last pretreatment injection.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Methylenedioxyamphetamine

Serotonin 5-HT1-like receptors mediate hyperactivity in rats induced by 3,4-methylenedioxymethamphetamine.

This study was designed to evaluate the role of different serotonin (5-HT) receptor subtypes in mediating the effects of 3,4-methylenedioxymethamphetamine (MDMA) on rat exploration of a novel environment. The active enantiomer of MDMA, S-MDMA increases forward locomotion and suppresses investigatory behaviors and local movements. Previous studies indicate that S-MDMA-induced hyperactivity depends upon drug-induced 5-HT release. Propranolol and pindolol, beta-noradrenergic antagonists with affinity for 5-HT1 receptors, antagonized the S-MDMA-induced locomotor hyperactivity. The antagonism by propranolol was stereoselective. In contrast, a beta-noradrenergic antagonist that is a weaker antagonist of 5-HT receptors, betaxolol, was much less effective at blocking the behavioral response to S-MDMA. Among nonselective 5-HT antagonists, methiothepin was effective and methysergide and cyproheptadine were ineffective as antagonists of S-MDMA-induced hypermotility. In other systems, methiothepin has been found to be a good antagonist at 5-HT1B receptors where methysergide and cyproheptadine are ineffective. The 5-HT2 antagonist ritanserin was ineffective in blocking S-MDMA-induced hypermotility. However, ritanserin, methysergide, and cyproheptadine partially reversed the S-MDMA-induced suppression of investigatory responding, suggesting a contribution of 5-HT2 receptor activation to this component of the behavioral response to S-MDMA. This study indicates that S-MDMA produces a characteristic form of locomotor hyperactivity in rats that depends upon activation of 5-HT1-like receptors, possibly of the 5-HT1B subtype.

3,4-Methylenedioxyamphetamine

Distribution of amygdala input to the nucleus accumbens septi: an electrophysiological investigation.

The nucleus accumbens septi (NAS) receives afferent input from the amygdala via the stria terminalis and from the hippocampus via the fimbria. Extracellular recordings from 196 NAS neurons in halothane-anesthetized rats revealed heterogeneous response patterns following stimulation of the amygdala. The observation that 30% of anterior NAS units but only 16% of posterior NAS units were responsive to amygdala stimulation suggested a topographical arrangement of amygdala efferents. Comparing the effects of amygdala and fimbria stimulation revealed that the two afferent pathways converge onto individual NAS neurons, but that the two sites of stimulation can differentially influence other neurons. The present results clarify the topographical distribution of amygdala input to the NAS, confirm that inputs from two limbic structures are integrated within the NAS, and further illustrate the electrophysiological heterogeneity of NAS neurons.

Action Potentials

Amphetamine derivatives induce locomotor hyperactivity by acting as indirect serotonin agonists.

Derivatives of amphetamine are potent releasers of both dopamine (DA) and serotonin (5-HT), but the relative contributions of DA and 5-HT release to the behavioral effects of these drugs have not been established. Previously, S-(+)3,4-methylenedioxymethamphetamine (S-(+)MDMA) was found to produce locomotor hyperactivity in rats which was dependent on 5-HT release. The present study found that MBDB (1.25, 2.5, 5.0 or 10.0 mg/kg), the alpha-ethyl derivative of MDMA that produces little or no direct DA release, also induced locomotor hyperactivity that lasted for greater than 60 min after the 5.0 and 10.0 mg/kg doses. MBDB produced spatial patterns of locomotor hyperactivity and suppression of exploratory activity (holepokes and rearings) very similar to the behavioral syndrome produced by MDMA. MBDB-induced hyperactivity was blocked by pretreatment with the selective 5-HT uptake inhibitor fluoxetine (2.5 or 10 mg/kg), suggesting that MBDB produced behavioral effects via uptake-carrier mediated release of 5-HT. Similarly, fluoxetine pretreatment blocked the locomotor hyperactivity produced by S-(+)3,4-methylenedioxyamphetamine (3.0 mg/kg) or p-chloroamphetamine (2.5 mg/kg), supporting a serotonergic basis for the action of these drugs. Tissue levels of 5-HT and its metabolite 5-HIAA were decreased 40 min after administration of S-(+)MDMA (3.0 mg/kg) or MBDB (5.0 mg/kg), and these decreases were prevented by fluoxetine pretreatment. S-(+)MDMA also produced a fluoxetine-sensitive increase of tissue DA levels, suggesting that 5-HT release may indirectly result in increased DA release, although MBDB did not significantly increase DA levels.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Methylenedioxyamphetamine

Serotonin release contributes to the locomotor stimulant effects of 3,4-methylenedioxymethamphetamine in rats.

Methylenedioxymethamphetamine (MDMA) is a phenylethylamine with novel mood-altering properties in humans. MDMA shares the dopamine-releasing properties of amphetamine but has been found to be a more potent releaser of serotonin (5-HT). The present study undertook to determine the relative roles of dopamine and 5-HT release in MDMA-induced locomotor hyperactivity. S-(+)MDMA produced dose-dependent increases of rat locomotion. Investigatory behaviors such as holepokes and rearings were suppressed by (+)MDMA. Pretreatment with the selective 5-HT uptake inhibitors fluoxetine, sertraline and zimelidine inhibited (+)MDMA-induced locomotor hyperactivity but failed to antagonize the reduction of holepokes and rearings. Because 5-HT uptake inhibitors have been found previously to block the MDMA-induced release of 5-HT in vitro, and because fluoxetine was found to have no effect on (+)amphetamine-induced hyperactivity, the present results suggest that (+) MDMA-induced locomotor hyperactivity is dependent on release of endogenous 5-HT. Additionally, prior depletion of central 5-HT with p-chlorophenylalanine partially antagonized the (+)MDMA-induced hyperactivity, although catecholamine synthesis inhibition with alpha-methyl-p-tyrosine did not block the effects of (+)MDMA. Taken together, these studies suggest that (+)MDMA increases locomotor activity via mechanisms that are dependent on the release of central 5-HT and that are qualitatively different from the mechanism of action of (+)amphetamine.

3,4-Methylenedioxyamphetamine

Reserpine enhances amphetamine stereotypies without increasing amphetamine-induced changes in striatal dialysate dopamine.

Indirect evidence suggests that amphetamine (AMPH) releases dopamine (DA) from an extravesicular, cytoplasmic pool. Disruption of vesicular DA storage by reserpine has been hypothesized to increase the concentration of extravesicular DA available for release by AMPH, which is consistent with the observation that reserpine does not prevent but augments the behavioral response to AMPH. In order to more directly test this hypothesis, the in vivo microdialysis technique was used to concurrently examine the behavioral and striatal dopaminergic response to AMPH (1.25 or 2.5 mg/kg) 24 h following reserpine pretreatment (2.5 mg/kg). Reserpine decreased tissue levels of DA by approximately 90% and reduced baseline dialysate DA concentrations by approximately 80%. Reserpine augmented the behavioural effects of AMPH, particularly increasing the occurrence and intensity of stereotypies. In contrast, reserpine did not alter the amount or duration of AMPH-induced DA release. This observation confirms that DA release by AMPH does not depend on vesicular stores but is inconsistent with the hypothesis that augmentation or behaviour by reserpine results from increased striatal DA release.

Amphetamines

The carbachol-induced enhancement of desynchronized sleep signs is dose dependent and antagonized by centrally administered atropine.

Considerable data show that microinjection of carbachol into the pontine reticular formation produces a desynchronized (D) sleep-like state. The present study examined the hypothesis that this carbachol-induced enhancement of D sleep signs is mediated by muscarinic, cholinergic receptors. This hypothesis was tested by quantifying the dose-dependent effects of centrally administered carbachol on the D sleep-like state and by pretreating the animals with centrally administered atropine. Six dosages of carbachol were microinjected into the pontine reticular formation of conscious cats and polygraphic measures of behavioral state were recorded. The percentage, latency, duration, frequency, and time course of the carbachol-induced D sleep-like state were dose dependent. Centrally administered atropine competitively antagonized the ability of carbachol to induce the D sleep-like state, whereas pontine administration of L-glutamate did not significantly alter D sleep. These data demonstrate that muscarinic, cholinergic receptors within the pontine reticular formation mediate the phenomenon of cholinoceptive D sleep sign enhancement.

Animals

Nutritional assessment of intensive-care unit patients.

The decision about whether to institute aggressive nutritional support, with its attendant expense and potential morbidity, in critically ill patients remains controversial. We studied numerous commonly used variables for assessment of nutrition to identify critically ill patients at increased risk for the development of infection, for becoming ventilator dependent, and for mortality. We enrolled 111 patients in this study on their third day in the intensive-care unit (ICU). No attempt was made to influence nutritional support, nor was adequacy of such support studied. Although several measurements correlated with outcome, the serum albumin correlated with number of ICU days (r = -0.38; P less than 0.001), with the number of days on a ventilator, and with the number of hospital days. It was the only measurement that correlated with the development of both a new infection (P less than 0.05) and ventilator dependency (P = 0.002). Although the use of the serum albumin concentration in this setting has limitations, it is still the best, most commonly used measurement of nutrition available.

Adult