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Biomedical subjects

J W Chambers

Publications and source records attributed to J W Chambers.

At least 19 recordsLinked to original sources
PubMed1999

Depletion of brain serotonin following intra-raphe injections of 5,7-dihydroxytryptamine does not alter d-amphetamine self-administration across different schedule and access conditions.

OBJECTIVES: These experiments investigated the effects of selective serotonin (5-HT) depletion on intravenous self-administration of d-amphetamine. METHODS: Depletion of brain 5-HT levels was induced by injecting the serotonergic neurotoxin 5,7-dihydroxytryptamine (5, 7-DHT) into the dorsal and median raphe nuclei. Rats were then trained to self-administer d-amphetamine according to various schedule and access conditions via chronically indwelling intravenous catheters. RESULTS: Large reductions of brain 5-HT did not alter responding for a training dose of 120 microgram/kg d-amphetamine delivered according to a fixed ratio 1 schedule during 3-h sessions. When the dose of d-amphetamine was altered (0, 3.75, 7. 5, 15, 30, 60 microgram/kg per infusion) a characteristic inverted U-shaped dose response function was obtained. The 5-HT depleted rats showed increased responding for the lower doses of d-amphetamine, with a large significant increase in responding for the 7.5 microgram/kg dose. In these same rats, the suppressive effect of 10 mg/kg fluoxetine on d-amphetamine (60 microgram/kg) self-administration was prevented. The 5,7-DHT lesion also did not alter responding for d-amphetamine (120 microgram/kg) in longer (8 h) daily access sessions. Responding for d-amphetamine delivered on a progressive ratio schedule, in which response requirements increased for each successive infusion of d-amphetamine, was also determined in 5-HT depleted rats. The number of d-amphetamine infusions was not different from the number of infusions earned by sham-lesioned rats across a range of doses of d-amphetamine (7.5-60 microgram/kg). In a final experiment, spontaneous acquisition of self-administration of low doses of d-amphetamine (10 and 30 microgram/kg) was measured in 5-HT depleted and control rats. Again, self-administration behaviour in the 5-HT depleted rats did not differ from controls. CONCLUSIONS: These results provide no evidence that reducing 5-HT function alters the primary reinforcing effects of self-administered amphetamine. The increase in self-administration of a low dose of amphetamine observed in experiment 1 probably involves some other process such as increased resistance to extinction.

5,7-Dihydroxytryptamine↗
PubMed1996

Direct in vivo effects of nitric oxide on the coronary circulation.

To determine the direct in vivo effects of nitric oxide (NO) on the coronary circulation, we infused NO-saturated saline (1.0 +/- 0.1 mmol/l) into the coronary arteries of anesthetized dogs and measured changes in coronary blood flow velocity (CBFV) with a Doppler catheter, changes in coronary artery size with quantitative angiography, and transmural myocardial perfusion with radioactive microspheres. Boluses of NO (1-8 micromol) caused a stepwise increase in CBFV (3.1 +/- 0.3 x basal CBFV at 8 micromol) similar to that caused by adenosine (2.6 +/- 0.3 x basal CBFV, maximal dose). Continuous subselective infusions (0.1, 1.0, and 4.0 micromol/min) caused dose-dependent increases in CBFV (2.2 +/- 0.3 x basal CBFV at 4.0 micromol/min) and in epicardial artery diameter (+ 15 +/- 6% diam). Left main infusions (8 micromol/min) caused a stepwise increase in CBFV and in the endocardial-to-epicardial flow ratio without affecting systemic hemodynamics. Brief infusion of NO (2 min) did not significantly reduce acetylcholine-mediated endothelial NO release. Therefore, despite rapid metabolism, direct intra-arterial infusion of NO can be given at a rate sufficient to overwhelm metabolic elimination, providing direct evidence that NO is a potent in vivo coronary vasodilator. Moreover, the enhanced subendocardial vasodilator response to direct NO infusion suggests increased regional sensitivity to NO.

Animals↗
PubMed1995

Serotonin depletion by 5,7-dihydroxytryptamine does not affect G protein subunit levels in rat cortex.

To investigate the role of G proteins in denervation supersensitivity of the CNS serotonergic system, we examined the effect of lesioning serotonergic neurons on the abundance of cerebral cortical membrane G protein subunits in rats. Three weeks after intracisternal injection of 5,7-dihydroxytryptamine (5,7-DHT), which significantly reduced cortical 5-hydroxytryptamine (5-HT; -90%) and 5-hydroxyindoleacetic acid (approximately 98%) levels, no statistically significant differences were observed for G alpha s-1, G alpha s-s, G alpha i1, G alpha i2, G alpha q/11, G alpha 0, G beta 1 and G beta 2 immunoreactivity levels between sham-lesioned and 5,7-DHT lesioned rats. These data suggest that the functional supersensitivity of 5-HT neuronal system often observed following lesions of 5-HT fibers may not involve changes at the level of G proteins but may instead encompass other downstream elements of the 5-HT receptor signaling cascade.

Animals↗
PubMed1995

Familial sudden death syndrome with an abnormal signal-averaged electrocardiogram as a potential marker.

Most familial sudden cardiac death syndromes are associated with structural heart disease or 12-lead electrocardiographic abnormalities. Additionally, the utility of signal-averaged electrocardiograms in patients with familial sudden death syndromes has not been examined. We studied a kindred with sudden death to determine whether they could be classified into any of the previously described syndromes and whether an abnormal signal-averaged electrocardiogram is a marker for this trait. Surviving family members had normal 12-lead electrocardiograms and echocardiograms. Two of the patients who died from ventricular arrhythmias had normal hearts on autopsy. Two surviving family members had a clinical history of arrhythmic events; both had abnormal signal-averaged electrocardiograms and inducible ventricular arrhythmias during electrophysiologic studies. The other family members had normal signal-averaged electrocardiograms. This familial sudden death syndrome appears to be unique because the patients have anatomically normal hearts and normal 12-lead electrocardiograms. An abnormal signal-averaged electrocardiogram may be a marker for the sudden death trait.

Adult↗
PubMed1994

Corticosterone-responsive and -unresponsive metabolic characteristics of adrenalectomized rats.

Glucocorticoids are important in influencing substrate flux through the metabolic pathways. This study was designed to answer the question "Does adrenalectomy (ADX) cause a shift toward fat metabolism as measured by a decrease in respiratory quotient (RQ)?" Male Sprague-Dawley rats were divided into four groups, ADX, ADX + 20% corticosterone (Cort) (ADX-20%), ADX + 40% Cort (ADX-40%), or sham-operated controls (Sham). ADX-20% received 50 mg and ADX-40% 100 mg Cort dissolved in 250-mg cholesterol pellets and placed subcutaneously. Each rat was monitored for 90 min four times both during a preoperative period and again after a 1-wk postsurgical recovery period in an indirect calorimeter. Cort prevented ADX-induced suppression of weight gain and food intake. ADX decreased motoric activity in both the light and dark periods. Cort restored activity to Sham levels. ADX decreased RQ only in the dark (0.858 ADX vs. 0.891 Sham) and was reversed only in the ADX-40% group. Energy expenditure (EE) was depressed in both the light and dark by ADX; Cort partially restored EE to Sham values in the light period.

Adrenalectomy↗
PubMed1994

Pectus excavatum: abnormal exercise scintigraphy with normal coronary arteries.

Pectus excavatum is the most common congenital abnormality of the chest wall, and is frequently associated with chest pain. The invasive, as well as the ECG and echocardiographic assessment of possible coronary artery disease (CAD) in adults with moderate to severe forms of this deformity, is often complicated by the associated displacement of the heart in the chest cavity in these patients. We present findings in a 67-yr-old male that demonstrate that the predictive accuracy of positive stress radionuclide ventriculogram (RVG) and SPECT scintigraphic studies may be significantly reduced in patients with moderate to severe forms of this abnormality. Our findings also suggest, however, that either lateral or even a shallow left posterior oblique detector positioning during RVG, a significantly revised SPECT acquisition orbit, or planar imaging may provide a more accurate means to assess possible CAD in these patients. Like-wise, physician input would appear to be invaluable in determining the optimal mode of imaging and the acquisition protocol for patients with pectus excavatum.

Adult↗
PubMed1993

Radiofrequency lesions of the PVN fail to modify the effects of serotonergic drugs on food intake.

Past research has suggested that the paraventricular nucleus (PVN) of the hypothalamus is an important brain site mediating changes in feeding induced by drugs that modify 5-hydroxytryptamine (5-HT; serotonin) neurotransmission. To test this possibility, several experiments examined the impact of lesions of the PVN on both decreases and increases in feeding following treatment with 5-HT-acting drugs. Rats with free access to standard lab chow were given access also to a wet mash diet for 1 h each day. When intakes of this diet had stabilised, rats were divided into two groups: one group received bilateral radiofrequency lesions of the PVN, the other served as a sham-operated control group. The PVN-lesioned group consumed more lab chow and gained significantly more weight over a 10-week period than the control group. Clonidine stimulated feeding in the sham-operated group, but did not do so in the lesioned group. These findings confirmed that the PVN lesions disrupted the control of food intake, as well as body weight regulation. The indirect 5-HT agonists D-fenfluramine (0.63, 1.25 and 2.5 mg/kg) and fluoxetine (2.5, 5 and 10 mg/kg), and the 5-HT1 agonist 1-(m-trifluoromethylphenyl)piperazine (TFMPP, 0.63, 1.25 and 2.5 mg/kg) dose dependently reduced the intake of the wet mash diet in sham-operated animals. This action was not modified by the PVN lesions. The highest doses of D-fenfluramine and fluoxetine also suppressed intake of chow over the 23-h period subsequent to the wet mash presentations, but the magnitude of this effect was similar in sham-operated and PVN-lesioned animals.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1991

Serotonin-depleting midbrain lesions do not prevent ovariectomy-induced weight gain.

Past research has shown that subdiaphragmatic vagotomy and midbrain raphe lesions are each effective in impeding the development of hypothalamic obesity while neither affects the development of genetic obesity in Zucker rats. To further test the parallels that may exist between these two manipulations on another putative obesity model, we studied the effects of midbrain raphe lesions on the development of ovariectomy-induced weight gain, previously shown to be unaffected by vagotomy. Ten adult female rats received thermal lesions of the dorsal and median raphe nuclei (RAPHE) while 7 served as sham controls (SHAM). Following a 26-day recovery period during which body weight, food intake and water intake were periodically monitored, bilateral ovariectomy (OVX) was performed on 7 RAPHEs and 4 SHAMs, with laparotomy (LAP) being performed on 3 RAPHEs and 3 SHAMs. Body weights and intake variables were monitored for an additional 58 days, then animals were sacrificed for brain histological and biochemical assessments. RAPHEs weighed less despite eating and drinking more than SHAMs throughout this study. Nevertheless, OVX rats gained more weight regardless of lesion (mean +/- SEM weight gain = 73.9 +/- 5.5 g for RAPHE + OVX and 67.0 +/- 6.6 g for SHAM + OVX vs. 30.7 +/- 3.0 g for RAPHE + LAP and 39.7 +/- 5.5 g for SHAM + LAP). This occurred without reliable changes in the food or water intakes of either OVX subgroup. Histology confirmed that RAPHE lesions were largely localized to the dorsal and median raphe nuclei, as planned.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Intake of greasy diets in hypothalamic obesity: a re-assessment.

Rats with medial hypothalamic lesions are known to prefer greasy diets. Past research has suggested that this is based on the oily texture rather than caloric content of these foods. We have re-examined this appetite in rats with bilateral parasagittal knife-cuts between the medial and lateral hypothalamus. Following knife cuts vs. sham surgery, the body weight and food consumption of adult female rats were monitored during four experimental phases. During the first month post-surgery rats were fed powdered Chow (3.61 kcal/g) and showed the usual hyperphagia and obesity. Each group was then subdivided and fed either a high-fat diet (5.5 kcal/g) or a similarly greasy mineral-oil diet (3.61 kcal/g) for a second month. The knife-cut group fed high-fat showed significantly higher intake than both sham-cut controls and knife-cut rats fed the mineral-oil diet. The latter group showed only a non-significant feeding increase over controls. Following a third month when all groups again received Chow, animals were given the opposite greasy diet for a final month. Knife-cut rats previously fed the high-fat diet showed significant overeating of the mineral-oil diet and defended their obesity, while those fed the mineral-oil free diet first now showed significant hyperphagia and obesity on the high-fat diet. Across both target phases (months 2 and 4) knife-cut rats always ate significantly more of the high-fat diet than of the mineral-oil diet. The latter only elicited hyperphagia in animals that had been previously exposed to the high-fat diet. These findings suggest that the hyperphagic response to greasy foods relatively low in calories and digestible fats by rats with hypothalamic injury is a function of prior experience with the sensory and/or metabolic consequences of having first eaten highly caloric fatty foods. If that is true, it may be that such animals are capable of learning positive food-associated cues in addition to negative ones (i.e. enhanced taste aversions) documented earlier by other investigators.

Animals↗
PubMed1989

Synthesis and pharmacology of a series of 3- and 4-(phosphonoalkyl)pyridine- and -piperidine-2-carboxylic acids. Potent N-methyl-D-aspartate receptor antagonists.

We recently prepared a series of 3- and 4-(phosphonoalkyl)pyridine- and -piperidine-2-carboxylic acids as antagonists of neurotransmission at N-methyl-D-aspartate (NMDA) preferring receptors. NMDA antagonists may prove to be useful therapeutic agents, for instance, as anticonvulsants, in the treatment of neurodegenerative disorders such as Alzheimer's disease and in the prevention of neuronal damage that occurs during cerebral ischemia. The compounds prepared were evaluated for their ability to displace [3H]CPP binding (an assay shown to be selective for compounds that bind at the NMDA receptor) and for their ability to block NMDA-induced lethality in mice (an assay that is also specific for competitive and noncompetitive NMDA antagonists). Two of the compounds, cis-4-(phosphonomethyl)piperidine-2-carboxylic acid (11a) and cis-4-(3-phosphonoprop-1-yl)piperidine-2-carboxylic acid (11c) proved to be potent NMDA antagonists. 11a and 11c displaced [3H]CPP binding with IC50's of 95 and 120 nM, respectively, and both protected mice from NMDA-induced lethality, with MEDs (minimum effective dose, the dose at which three of the five animals tested survived) of 10 and 40 mg/kg ip, respectively. The rest of the compounds prepared were weakly active or inactive in these assays. The pattern of activity observed for this series parallels that observed for the acyclic series of omega-phosphono-alpha-amino acids, where AP5 and AP7 possessed NMDA antagonist activity while AP6 and AP8 were inactive. Reduction of conformational mobility by incorporation of the piperidine ring led to enhanced potency relative to the acyclic analogues.

Animals↗
PubMed1985

Impaired diet-induced thermogenesis in brown adipose tissue from rats made obese with parasagittal hypothalamic knife-cuts.

Two experiments were performed to determine if bilateral parasagittal hypothalamic knife-cuts (KCs), which produce long-term overeating and obesity, after biochemical indices of brown adipose tissue (BAT) reactivity to thermogenic stimuli. In the first study, responses to environmental cold were tested. Four weeks after surgery, KC rats had gained 4-5 times more weight than controls and were obese (increased Lee Obesity Index and weight of gonadal white fat). Before being sacrificed, groups of KC and control rats were exposed to 4 degrees C for 21 hr or remained at 28 degrees C. Interscapular BAT weighed 300% more in KC rats, due largely to increased white fat content. Functional indices of BAT thermogenic capacity (protein content, DNA content, cytochrome oxidase activity and mitochondrial guanosine diphosphate (GDP) binding) were normal at 28 degrees C. Exposure to 4 degrees C produced greatly enhanced responses but these were equivalent for both groups. This suggested an intact capacity for non-shivering thermogenesis in obese KC rats. In the second study, the same BAT responses were examined in other rats fed a palatable "cafeteria" diet (CAFE). One week after surgery, KC and control rats were subdivided into groups that received chow alone or chow plus four different palatable foods daily. Before sacrificing 4-5 weeks later, KC rats had gained 3-4 times more weight than controls and were obese. Interscapular BAT weighed 200-300% more in KC rats. CAFE feeding produced larger increments in all variables for KC vs. control rats. Most importantly, GDP binding was reduced in both KC groups, and significantly more so after CAFE feeding.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue, Brown↗
PubMed1984

Effects of P-chlorophenylalanine on pineal and endocrine function in the rat.

This study attempted to determine whether brain serotonin (5-HT), which is altered by melatonin administration, is involved in mediating the effects of melatonin on basal endocrine function. Pineal melatonin levels, serum N-acetylserotonin (NAS) levels, adrenocortical activity, and other endocrine parameters were measured following 5-HT depletion by p-chlorophenylalanine (p-CPA) together with either pineal stimulation by blinding or blinding plus pinealectomy. Blinding increased pineal melatonin levels in both saline and p-CPA treated animals. P-CPA treatment increased adrenal weights and morning plasma corticosterone levels in both blinded and blinded-pinealectomized animals. Conversely, p-CPA depressed pineal melatonin levels and serum NAS but elevated morning plasma corticosterone levels in sighted controls. P-CPA also decreased plasma prolactin and growth hormone levels in intact animals. These findings suggest that 5-HT inhibits morning corticosterone secretion and stimulates prolactin and growth hormone release. In addition, melatonin and serotonin may function independently in regulating adrenocortical function, while melatonin's effect is superceded by that of serotonin.

Adrenal Glands↗
PubMed1983

Catecholamine histofluorescence in the paraventricular hypothalamus of rats made hyperphagic by parasagittal knife cuts.

Histochemical fluorescence microscopy has been used to study changes over a 15-week period in the density of catecholaminergic (CA) varicosities in medial hypothalamic nuclei of rats made hyperphagic by bilateral perifornical parasagittal knife cuts. The average daily intake of food was highest when measured two days after the knife cuts. By the 7th post-cut day, daily food intake was comparable to that measured during the 10th and 11th weeks after the cuts. The number of fluorescent varicosities in the paraventricular and periventricular hypothalamic nuclei diminished steadily after the knife cuts until they were virtually absent by the end of the fourth week. This process then reversed itself so that by the end of the 15th week the varicosities in these nuclei numbered just over 50% of presurgical values. Thus, there was an apparent lack of correspondence between increases in ingestive behavior or body weight and the nature of the CA innervation of the medial hypothalamus. This finding supports previously published work which indicates that the noradrenergic control of feeding behavior in the medial hypothalamus is mediated by a neural system that acts independently of the system responsible for the knife cut-induced hyperphagic response.

Animals↗
PubMed1983

A simpler retractable wire knife.

A detailed description is presented for the construction of a simple and inexpensive retractable wire knife and holder/adjuster for stereotaxically placed transections of neural pathways. The accuracy and reliability of the knife are supported by experimental data demonstrating the ability of bilateral parasagittal hypothalamic knife cuts to induce excessive food intake and body weight gain in female rats.

Animals↗
PubMed1977

Determination of N-acetylserotonin and melatonin activities in the pineal gland, retina, harderian gland, brain and serum of rats and chickens.

An N-acetylserotonin/melatonin radioimmunoassay (NAS/Mel RIA) and a Mel RIA were developed to measure NAS and Mel contents in tissues of rats and chickens. Anti-NAS and anti-Mel sera were produced by immunization of rabbits with NAS-M-bovine serum albumin (BSA) and Mel-M-BSA, respectively. Anti-NAS serum used in the NAS/Mel RIA reacts equally well with NAS and Mel, while anti-Mel serum used in the Mel/RIA reacts specifically with Mel. The NAS and Mel levels in the pineal and Harderian gland, the retina and the brain of rats and chickens and Mel levels in chicken serum were determined using these RIAs. Levels of NAS and Mel in the rat pineal demonstrated diurnal rhythms with high levels during the dark period and low levels during the light period. The indole levels determined in this study correlate well with those obtained by other methods.

Animals↗