Biomedical subjects
Publications and source records attributed to L J Holmes.
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There is evidence for reciprocal interactions between the brain monoamine neurotransmitters serotonin and noradrenaline which may play a critical role in homeostasis. The aim of the present study was to establish the effect of drug-induced damage to the serotoninergic system on noradrenergic activity in the hypothalamus. Bilateral intracerebroventricular injections of p-chlorophenylalanine (PCPA; 3 mg/kg in 2 x 6 microliters) were made to induce destruction in the serotoninergic system. Relative to saline-injected controls, PCPA-injected rats began overeating by 3 days postinjection. On day 10, when the experimental rats were consuming approximately 120% that of controls, animals were 4-h food deprived, sacrificed and the medial basal hypothalamus was removed for later analysis (by gas chromatography/mass spectrometry) of noradrenaline (NA), serotonin (5-HT) and dopamine (DA) and their principal metabolites dihydroxyphenylethyleneglycol (DHPG), 5-hydroxyindoleacetic acid (5-HIAA) and 3,4-dihydroxyphenylacetic acid (DOPAC), respectively. The ratio of metabolite to monoamine provided an index of functional activity. Trunk blood was collected for analysis of serum insulin and glucose. PCPA-injected animals had higher levels of DHPG (P less than 0.05), an increase in the DHPG/NA ratio (P less than 0.02), lower serum insulin (P less than 0.05) and increased serum glucose (P less than 0.05). There were significant correlations between noradrenergic activity (DHPG/NA ratio) and: (1) food intake (day 9 and 10 average; r = 0.62, P less than 0.05); and (2) serum glucose (r = 0.59, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
The present study examined monoaminergic activity at the level of the lateral hypothalamus (LH), ventromedial hypothalamus (VMH) and ventral striatum associated with the conditioned cephalic phase insulin release. Partially food-deprived male Wistar rats were divided into 3 groups. Two of the groups were conditioned to drink a 50% glucose solution each morning for 3 weeks; the control group received an amount of glucose equal to the amount drunk by the experimental animals with their afternoon meal. On test day, conditioned animals were sacrificed either just prior to glucose presentation or 2 min following consumption of the solution; control animals were sacrificed at the same time. Gas chromatography/mass spectrometry was used to determine the levels of the monoamines noradrenaline (NA), dopamine (DA) and serotonin (5-HT), as well as their principal metabolites dihydroxyphenylethyleneglycol, 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindoleacetic acid (5-HIAA) in the LH and VMH. DA and DOPAC levels were assayed in the striatum. Although serum glucose levels were unchanged, animals conditioned to drink glucose had significantly higher serum insulin levels. This increased insulin was associated with increased content of 5-HT and 5-HIAA at the level of the LH and VMH, increased NA content in the LH, increased DOPAC levels in the VMH as well as increases in the ratio of DOPAC to DA in the striatum. A regression analysis showed that 5-HIAA at the level of the LH related closely to serum insulin levels.(ABSTRACT TRUNCATED AT 250 WORDS)
This study elucidated the hypothalamic monoamine systems associated with the cephalic phase insulin release. Male Wistar rats conditioned to drink a glucose solution were killed 2 min after the onset of their scheduled feeding; control rats were killed at the same time. The ventromedial (VMH) and lateral (LH) portions of the hypothalamus were analyzed for the monoamines and their principal metabolites. Serum was assayed for insulin and glucose. The results showed that the experimental animals had significantly higher serum insulin levels than did the control animals, although glucose levels were unchanged. In the LH, there were increased levels of norepinephrine, its metabolite dihydroxyphenylethylene glycol (DHPG), and serotonin [(5-hydroxytryptamine (5-HT)]. In the VMH, 5-HT, its metabolite 5-hydroxyindoleacetic acid, and the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) were all higher in the conditioned animals. 5-HT levels in the LH and DOPAC levels in the VMH were closely associated with serum insulin (r = 0.80 and 0.71, respectively). This study has defined, in the normal animal, changes in monoamines in specific areas of the hypothalamus associated with the cephalic phase insulin release.
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The metabolic effects of electrical stimulation of the hypothalamus were investigated using indirect calorimetry. Stimulation of either the ventromedial hypothalamic nucleus (VMH) or the lateral hypothalamic area (LH) increased both respiratory quotient (RQ) and energy expenditure (EE) in 23 lightly anesthetized rats. The use of a muscle relaxant to reduce motor activity and a regression analysis on the residual activity showed that the metabolic changes were independent of motor activity following LH stimulation. The increased RQ indicates that stimulation increased the dependence on carbohydrates as an energy substrate. The increased EE indicates that the LH modulates EE by mediating thermogenesis. The interpretation of the metabolic changes in RQ and EE following VMH stimulation is complicated by the fact that there were significant relationships between residual activity and metabolic changes in the sedated rats with VMH electrodes. Together, these data suggest that the hypothalamus regulates body weight by controlling energy expenditure, as well as energy intake. At the same time, hypothalamic activity influences which substrate the rat uses for energy.
Standard small, superficial freezing lesions placed along the anterior-posterior plane of the left cortex produced behavioral changes in rats. One to 3 days following the lesion, rats showed asymmetries in somatosensory responsiveness, decreases in running wheel activity and difficulty with limb coordination. No changes in spontaneous circling were seen. At the completion of the behavioral testing on day 3 the [14C]2-deoxyglucose method confirmed the presence of widespread depression in local cerebral glucose utilization with cortical areas ipsilateral to the lesion being most affected. At this time the degree of the somatosensory deficit was significantly correlated with the extent of the depression of glucose utilization in the cortical areas of the lesioned hemisphere. At 6 days following the lesion only deficits in limb coordination remained, while local cerebral glucose utilization had returned to within normal limits. It is concluded that the demonstrated behavioral changes were a manifestation of widespread functional depression, as reflected by decreased cortical glucose utilization throughout the lesioned hemisphere.
Crystalline morphine was applied unilaterally to the ventral tegmental area of rats. Contralateral circling was observed in traditional test chambers and inside the walls of an elevated square enclosure. When tested outside the walls of the same enclosure, the animals turned in the opposite direction, maintaining the same flank in the position nearest the wall. This dopamine-dependent circling thus reflects a more complex interaction between the side of activation and the direction of circling than is implied in current views of dopamine function.
Unilateral morphine application to sites in the ventral tegmentum caused contralateral circling. Positive sites were restricted to the region of the dopamine-containing cells in the ventral tegmental area and substantia nigra; rates were highest with ventral tegmental application. The opiate receptor antagonists naltrexone and naloxone blocked morphine-induced circling whether given before or during the sessions. Pimozide pretreatment also blocked morphine-induced circling at doses that spared muscimol-induced circling. Morphine induced little postural asymmetry and induced forward locomotion in all 4 limbs. The radius of morphine-induced circling was large or small depending on the size of the test environment; thus the behavior was controlled by environmental (sensory) and not central (motor) constraints. These studies suggest that morphine-induced circling results from activation of dopaminergic circuitry involved in sensory-motor integration, particularly that involved in forward locomotion.
Unilateral application of neurotensin (5, 10, and 15 micrograms) to the ventral tegmental area in rats caused contralateral circling. Pretreatment with pimozide (0.5 mg/kg) blocked the behavior. As is the case with circling elicited by unilateral ventral tegmental morphine, the diameter of the circles made by the animals was determined by environmental factors rather than by internal motor programming.
Crystalline morphine applied unilaterally to the ventral tegmental area in rats caused circling away from the side of application. This circling was reversed by naloxone (3 mg/kg) and blocked by pretreatment with pimozide (0.5 mg/kg). When tested in an open field the animals followed the perimeter of the enclosure; thus the radius of the circles described was determined by environmental rather than central factors. Morphine induced forward locomotion in all four limbs; there were no major signs of postural asymmetry noted in the longitudinal axis of the animal's body. This study suggests that morphine activates a population of A-10 dopamine cells known to be involved in locomotion.
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The acute effects of ethanol and tertiary-butanol, an alcohol which is not metabolized via the alcohol dehydrogenase pathway, on whole body metabolism were studied using indirect calorimetry. Ethanol, but not t-butanol, increased energy expenditure in food-deprived rats. Both ethanol and t-butanol reduced respiratory quotient (RQ), an index of overall body energy substrate utilization. The lowered RQ indicates an increased dependence upon lipids as an energy source. Taken together, these data suggest that ethanol, probably within a narrow dose range, can enhance energy expenditure in the rat, either via a metabolite (e.g., acetaldehyde) or through a consequence of its oxidation. The increase in lipid mobilization seen after acute treatment with ethanol, on the other hand, appears to be independent of its oxidation.