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Biomedical subjects

C W Simpson

Publications and source records attributed to C W Simpson.

34 records · Page 2Linked to original sources

Neurochemical coding for feeding in sheep and steers.

Feeding responses of sheep and steers were compared following intraventricular injection of alpha-adrenergic agonists and antagonists in 2-hr. tests. In sheep, injection of the alpha-agonist 1-norepinephrine (1-NE) (140-1,120 nmoles) increased feed intakes 288% and 388% compared with intakes following synthetic cerebrospinal fluid. This response was blocked by the alpha-antagonist phenoxybenzamine, whereas the antagonist alone decreased feed intake. The beta-adrenergic antagonist propranolol did not modify the 1-NE response. A purer but weaker alpha-agonist, 1-phenylephrine, also resulted in increased feed intake that was blocked by phenoxybenzamine. In contrast to the feeding responses of sheep, 1-NE caused hypophagia in steers, reducing intakes as much as 58% in 2-hr. tests over doses ranging 42-27,800 nmoles. Phenoxybenzamine blocked the 1-NE-induced hypophagia in steers; when injected alone, it increased feed intakes 181% of control values. Changes in feeding following 1-NE injections are probably not attributable to changes in temperature, fat mobilization, or stupor. The data support the hypothesis of an alpha-adrenergic-coded system for feeding in sheep and for satiety in steers.

Animals↗

Dopamine-B-hydroxylase activity in rat hypothalamus during the estrus cycle.

This experiment provides a direct test of our previous suggestion that estradiol regulates dopamine-B-hydroxylase (DBH) activity in hypothalamic loci. Anterior, medial and posterior hypothalamic slices from triplets of rats were taken during estrus and diestus and assayed for DBH activity using the technique of Molinoff et al. [15]. DBH activity was measured in hypothalamic slices on three different occasions from three triplets during the estrous phase of the cycle and also from separate triplets during the diestrous stage of the cycle. Results showed a significant increase in DBH activity during the estrous phase of the cycle. Increased activity did not appear to be anatomically localized within the tissue slices. Explanation of the results has been discussed in terms of possible mechanisms of action.

Animals↗

Effects of central alpha-MSH injections on performance in a cued discrimination task.

Alpha-MSH has been implicated in changing attention behavior following peripheral injections, but no brain sites were studied. In the present report, alpha-MSH was injected directly into specific sites in the medial anterior hypothalamic/preoptic area (MAHPOA) while measuring performance in a visually cued discrimination task. Alpha-MSH injections resulted in reduced errors, indicated by decreased responding during noncued intervals, but no change in responding to correct cues. The improved error rate was consistent with attentional changes in a variety of paradigms. Attentional and motivational parameters were differentiated. The injected alpha-MSH appears to act on an inhibitory component of an attentional mechanism.

Animals↗

Hypothalamic Na+ and Ca++ ions and temperature set-point: new mechanisms of action of a central or peripheral thermal challenge and intrahypothalamic 5-HT, NE, PGEi and pyrogen.

The effects of changes in ambient and central temperature, amines, PGEu and pyrogen were investigated with respect to the mechanism of Na+-Ca++ ratio in the posterior hypothalamus of the unrestrained cat. Guide tubes were implanted bilaterally above the posterior hypothalamic area of 23 cats so as to accommodate push-pull cannulae. After a Na+ or Ca++ sensitive site was identified by perfusion at 50 mul/min of an artificial CSF containing 10.4 mM excess Ca++ ions or 13.6 mM excess Na+ ions, several types of experiments were undertaken with the results summarized as follows: if the cat was exposed to a cold or warm environmental temperature as the posterior hypothalamus was perfused with excess cation, the typical hypothermia was produced by Ca++ and hyperthermia by Na+ ions. However, if the cat was exposed to peripheral cooling or warming 30 min prior to the perfusion, the fall or rise produced by Ca++ or Na+ was attenuated or prevented. In other experiments, 1.0 muCi 45Ca++ was injected in the ion sensitive site in the posterior hypothalamus to label stores of the cation. Raising of ambient temperature caused a retention of 45Ca++ in this hypothalmic area, whereas a cold environmental temperature enhanced the efflux of 45Ca++ at the same perfusion site. The magnitude of change in 45Ca++ efflux depended upon the intensity of the thermal challenge. Similarly, warming of the anterior hypothalmic, preoptic area by means of implanted thermodes caused an immediate diminution in 45Ca++ efflux in the posterior hypothalamus, whereas cooling of this anterior region augmented the extrusion of 45Ca++ ions from the posterior area. When substances which produce a temperature change were applied to the same thermosensitive zone, the direction of shift in 45Ca++ flux in the posterior area corresponded to the signal for heat production or heat loss. That is, the microinjection of 5-HT, PGE1 or Salmonella typhosa into the anterior hypothalamus enhanced the efflux of 45Ca++ in the posterior hypothalamus as hyperthermia developed, whereas a similar microinjection of norepinephrine reduced the 45Ca++ output from the same sites. Finally, locally anesthetizing the cells of the anterior hypothalamus by the nerve blocker, procaine, prevented the cold and heat-induced 45Ca++ eflux and retention, respectively. These results suggest that if the Na+-Ca++ ratio in the posterior hypothalamus establishes and maintains the set-point for body temperature of 37 degrees -38 degrees C, the mechanism of lability of Ca++ through changes in binding characteristics, transport, or metabolism of the cation serves two purposes: (1) the active defense of the set-point temperature through gradations in ion shifts; and (2) the upward or downward change in set-point value, pathological or normal, triggered by virtue of impulses relayed from the anterior hypothalamus.

Animals↗

Dopamine release within forebrain sites perfused with tetrahydroisoquinolines or tryptoline in the rat.

The localized effect of amine-aldehyde condensation products on the endogenous release of dopamine (DA) was examined in dopaminergic-rich areas of the brain. In the unanesthetized rat, dopaminergic stores were labeled by 14C-dopamine (1.0 microCi) microinjected in a volume of 1.0 microliters into the caudate nucleus, tuberculum olfactorium, nucleus accumbens or other contiguous sites within the ventral forebrain. Subsequently, each labeled site was locally perfused with an artificial CSF, by means of push-pull cannulae, at a rate of 25.0 microliters per min. Two tetrahydroisoquinolines, tetrahydropapaveroline and 4,6,7-TH-tetrahydroisoquinoline, as well as the tetrahydro-beta-carboline, tryptoline, significantly enhanced the release of 14C-DA when each alkaloid metabolite was perfused in a concentration of 250 nanograms per min. Tetrahydroisoquinoline was without effect on the local kinetics of 14C-DA, whereas salsolinol had an intermediary action on DA release. These findings suggest that an alkaloid conjugate when given in the cerebral ventricle could exert its central effects by way of a dopaminergic mechanism in the telencephalon.

Animals↗

Disulfiram alters dopamine metabolism at sites in rat's forebrain as detected by push-pull perfusions.

The effect of tetraethylthiuramdisulfide (disulfiram) on the catabolism of dopamine within discrete regions of the brain was investigated in the unrestrained rat. After a guide cannula had been implanted stereotaxically, a given subcortical site was radiolabeled with 14C-dopamine (DA) by microinjecting 2.0 mu Ci in 2.0 microliters. Successive push-pull perfusates collected from each tissue were assayed by paper electrophoresis for the separation of DA metabolites. When disulfiram, a potent aldehyde dehydrogenase (ALDH) inhibitor, was given intragastrically in a clinically efficacious dose of 200 mg, the formation of the acids DOPAC and HVA was inhibited within perfusates of the caudate nucleus and nucleus accumbens. However, following disulfiram treatment, the proportion of alcohol metabolites did not differ from the control level in the untreated rat. The level of ALDH decreased by approximately 50% in these subcortical nuclei following the inhibition of the enzyme by disulfiram. Conversely, in samples of perfusate obtained from 14C-labeled sites within inferofrontal cortex, periform cortex, diagonal band of Broca, lateral-posterior caudate nucleus, tuberculum olfactorium, lateral olfactory tract or the olfactory nuclear complex, the proportion of DA metabolites remained stable. Generally, a low rate of deamination of the exogenously injected DA occurred within perfusion sites in the ventrobasal forebrain, whereas an intermediate rate of deamination was noted in samples collected at more dorsal loci. Thus, clearcut regional differences in DA catabolism occur in the brain of the living animal, which may depend upon the characteristics of the dopaminergic-rich area of the rat's brain.

Alcohols↗

Serum thyroxin levels during hyperthermia evoked in the monkey by intrahypothalamic injection of PGE1, 5-HT or pyrogen.

Serotonin (5-HT), prostaglandin E1 (PGE1) or a bacterial pyrogen (E. coli or S. typhosa) was microinjected in a volume of 1.0--1.5 microliter into the hypothalamus of the unanesthetized monkey to evoke a long-term hyperthermia. Samples of venous blood collected every 15 min, before, during and after each fever were analyzed by radioimmunoassay for plasma thyroxin levels. There was no statistically significant correlation between plasma thyroxin values and a given phase of the hyperthermic episode induced by the microinjections of 5--HT, PGE1 or bacteria. The possibility that an enhanced release of the thyroid hormone serves to sustain a long-term elevation in temperature evoked by a centrally acting pyrogenic substance is not supported.

Animals↗

Anatomical distribution of brainstem sites where PGE1 induces hyperthermia in macaque species.

The neuroanatomical distribution of sites in the diencephalon and mesencephalon within which a prostaglandin (PG) of the E series elicits hyperthermia was characterized in Macaca mulatta and Macaca nemestrina. In 420 experiments undertaken in 13 animals, 225 loci were examined for their reactivity to PGE1 microinjected in a dose of 30 or 100 ng given in a volume of 1.0-1.5 microL. The regions of the brainstem for injection extended rostrally from the thermosensitive cells of the anterior hypothalamic, preoptic area (AH/POA) to the caudal border of the mesencephalon. Colonic and skin temperatures of the monkeys were measured continuously by thermistor probes. A hyperthermic response of > or = 0.5 degrees C and a latency of < or = 45 min was evoked by PGE1 within sites located primarily in the AH/POA. When PGE1 was microinjected at loci located caudal to the AH/POA, the elevation in body temperature (Tb) not only was less intense but rose at a slower rate. A higher concentration of PGE1 in these caudal regions was required to induce hyperthermia comparable with that elicited at loci within the AH/POA. In a second series of experiments either 1.0-5.0 micrograms 5-hydroxytryptamine (serotonin) or a concentration of 10(8) organisms/mL of Escherichia coli was microinjected at PGE1-reactive sites. A close anatomical concordance within the AH/POA of the animal was found in terms of the temporal characteristics and magnitude of the hyperthermia evoked by the indoleamine or lipopolysaccharide. The present results coincide with the reported neuroanatomical distribution of sites in the diencephalon and mesencephalon of other species in which PGE1 causes hyperthermia. Furthermore, these findings support the concept that the local neuronal mechanism of action of a pyrogen in the brainstem of the primate may involve phasic changes in the endogenous activity of both the serotonergic pathway and cyclo-oxygenase system in the AH/POA. In turn, their commonality of action suggests a functional similarity in their effect of shifting the set point for Tb.

Alprostadil↗