Gout and hyperuricemia: diagnosis and management.
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Adult↗
Biomedical subjects
D C German
Publications and source records attributed to D C German.
Evidence for a functional role of dopamine type-1 (D-1) receptors in the substantia nigra of rats.
The microiontophoretic application of dopamine onto neurons in the substantia nigra of rats increased the spontaneous activity of zona reticulata (ZR) neurons but decreased the activity of zone compacta (ZC) neurons. The systemic administration of the dopamine antagonists, haloperidol and cis-flupentixol, blocked the dopamine effects. However, haloperidol was more potent on ZC neurons that on ZR neurons whereas cis-flupentixol was of comparable potency on ZC and ZR neurons. In addition, microiontophoretic application of a cyclic adenosine monophosphate analog was found to mimic the effects of dopamine on ZR neurons, but not on ZC neurons. Taken together with receptor binding studies on the relative affinities of haloperidol and cis-flupentixol for various dopamine receptor subtypes, these data suggest that the excitatory effect of dopamine on ZR neurons is mediated by a D-1 type receptor whereas its inhibitory effect on the ZC dopaminergic neuron is mediated by a D-2 type receptor.
8-Bromo Cyclic Adenosine Monophosphate↗
Activation of specific central dopamine pathways: locomotion and footshock.
The present study examined whether neostriatal monoamine biochemistry was activated in a bilaterally symmetrical fashion during a non-lateralized forward locomotor task, and whether specific midbrain dopamine (DA) neuronal systems were influenced selectively by specific behavioral tasks. Monoamine concentrations (DA, serotonin and their metabolites) were measured, using high pressure liquid chromatography, in the neostriatum, nucleus accumbens, and medial prefrontal cortex in rats that were either induced to walk forward in a motorized rotating wheel (two speeds) or were exposed to footshock stress (two shock intensities). Our results demonstrate that during locomotor behavior there is an increase in neostriatal DA metabolism, but not in serotonin metabolism. Furthermore, the increase in DA metabolism was found: (a) in both right and left neostriatal nuclei, but with significantly less asymmetry than occurred in non-locomoting control rats; and (b) within the neostriatum at both speeds and also in the nucleus accumbens at the higher speed. Locomotion had no effect on DA metabolism in the prefrontal cortex. With both shock intensities there was increased DA metabolism in the prefrontal cortex, whereas during the low shock intensity there was also an increased DA metabolism in the nucleus accumbens. At the high level of footshock, which evoked jumping and running escape behavior, there was also an increase in neostriatal DA metabolism. These data indicate that a non-lateralized forward locomotor task activates DA metabolism primarily in the less metabolically active hemisphere. Secondly, we found that specific subgroups of midbrain DA neurons can be selectively activated by specific behavioral tasks.
3,4-Dihydroxyphenylacetic Acid↗
Hyperuricemia and gout.
Gout is a clinical syndrome encompassing a group of metabolic diseases that are all characterized by abnormal uric acid metabolism. In its fullest form, gout is defined by: an increase in the serum urate concentration; characteristic, recurrent, acute arthritic attacks, with monosodium urate monohydrate crystals demonstrable in synovial fluid leukocytes; tophi, usually in and around joints of the extremities, composed of monosodium urate monohydrate deposits; renal disease, often accompanied by hypertension with glomerular, tubular, interstitial, and vascular involvement; and uric acid nephrolithiasis. Any combination of these manifestations may occur, although tophi and urate nephropathy rarely antedate gouty arthritis.
Acute Disease↗
Immunohistochemical staining of cholinergic neurons in the human brain using a polyclonal antibody to human choline acetyltransferase.
Antibodies against human placental choline acetyltransferase (ChAT) were used to immunohistochemically stain cholinergic neurons in the neostriatum and nucleus basalis of Meynert in human brain. Cells in both regions were intensely stained as were nerve fibers. Comparable cells were stained in these same brain regions in the rat. This anti-human ChAT antibody will enable the further detailed characterization of cholinergic neurons in the human brain in both health and disease.
Animals↗
Neuronal pathology in the nucleus basalis and associated cell groups in senile dementia of the Alzheimer's type: possible role in cell loss.
The loss of cortical cholinergic innervation in senile dementia of the Alzheimer's type (SDAT) is associated with cell loss in the nucleus basalis and related cell groups (magnocellular basal nucleus, MBN). We examined MBN in Nissl-, acetylcholinesterase- and thioflavin S-stained sections in two cases of SDAT and in four control brains. Using these sensitive methods, senile plaques were easily demonstrated in MBN, and most MBN neurons showed neurofibrillary degeneration as an early change. Cell loss appeared to be due to maturation of neurofibrillary tangles, displacing normal cellular contents. In contrast to theories that the cell loss in MBN represents retrograde degeneration due to axonal injury in the cerebral cortex, MBN neuronal perikarya may be involved by the same primary processes as cortical neurons.
Acetylcholinesterase↗
A radioenzymatic assay for plasma adenosine.
A method for analysis of plasma adenosine which combines the principles of radioisotope dilution and enzymatic catalysis is presented. Plasma from venous heparinized blood containing the adenosine deaminase inhibitor 2'-deoxycoformycin is mixed with a small amount of [3H]adenosine and extracted with perchloric acid. Using highly purified enzyme and [gamma-32P]GTP as the phosphate donor, the neutralized extract then serves as substrate for adenosine kinase, and the AMP product is purified by high-performance liquid chromatography. Adenosine concentrations in plasma are linearly proportional to 32P/3H ratios in the enzymatically synthesized AMP and are calculated from a standard curve. The advantages of the method are: ease of sample preparation; sensitivity of 20 nM in as little as 0.3 ml plasma; 20 samples per day can be analyzed by a single operator. Care must be used when obtaining plasma since cellular contamination will affect results. Using this assay, human plasma adenosine levels are 0.121 +/- 0.054 microM for males and 0.101 +/- 0.067 microM for females.
Adenosine↗
Naloxone antagonism of stress-induced augmentation of frontal cortex dopamine metabolism.
Foot shock stress selectively elevates dopamine metabolism in the medial frontal cortex but not nucleus accumbens or caudate nucleus. Pretreatment with a low dose of naloxone, an opiate antagonist, reversed the elevation in medial frontal cortex dopamine metabolism observed after foot shock. These data support the hypothesis that the stress-induced release of endogenous opioids cause an excitation of mesocortical dopamine neurons.
Animals↗
A subpopulation of mesocortical dopamine neurons possesses autoreceptors.
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Action Potentials↗
Electrophysiological evidence for excitation of rat ventral tegmental area dopamine neurons by morphine.
A considerable body of evidence indicates that opiates have an important influence on midbrain dopaminergic neurons. However, little data exist concerning the effects of opiates on the activity of single dopaminergic neurons, particularly the dopaminergic neurons of the ventral tegmental area. Firing rates of mesencephalic dopaminergic neurons were recorded extracellularly, and the effects of morphine, administered systemically or applied locally onto dopaminergic cells, were tested in paralyzed, unanesthetized or chloral hydrate anesthetized rats. In general, dopaminergic neurons were excited by both systemically and locally applied morphine. When mesencephalic dopaminergic neurons were subdivided into substantia nigra zona compacta (A9) and ventral tegmental area (A10) neurons, A10 neurons were excited 2-3 times more than A9 neurons by systemic morphine. Systemic administration of the specific opiate antagonist, naloxone, in large part reversed the effects of morphine. Microiontophoretic or micropressure ejection of morphine caused an apparent depolarization-induced excitation of both A10 and A9 dopaminergic neurons. These results provide direct evidence that morphine increases impulse flow of A10 dopaminergic neurons, which are known to be involved in locomotor stimulant and positive reinforcement effects of opiates.
Animals↗
Electrophysiological properties of mouse dopamine neurons: in vivo and in vitro studies.
The present experiments were conducted to determine the electrophysiological and pharmacological properties of substantia nigra neurons in the mouse. These cells were studied using extracellular single unit recording and microiontophoretic techniques in both chloral hydrate anesthetized mice and in vitro mouse slices. In the in vivo preparation the substantia nigra zona compacta neurons had long duration action potentials (greater than 4 ms), fired from 1 to 7 impulses/s, and the cells discharged with either a decremental burst pattern or with a regular pattern. The dopamine agonists apomorphine and d-amphetamine, given systemically, decreased the firing rate of these neurons and the dopamine receptor blocker, haloperidol, reversed these effects. The zona compacta neurons were inhibited by the micro-iontophoretic application of dopamine and gamma-aminobutyric acid, and systemic haloperidol selectively attenuated the effects of dopamine. In vitro recordings from substantia nigra zona compacta and zona reticulata neurons were generally similar to those found in vivo, both in terms of the electrophysiological and pharmacological properties. However, the zona compacta cells fired faster in vitro than in vivo, and the firing pattern in vitro tended to be pacemaker-like, especially when recordings were made in an incubation medium which blocks synaptic transmission (e.g. low Ca2+/high Mg2+). Our data indicate that: (a) in vivo mouse zona compacta neurons exhibit the same electrophysiological and pharmacological properties as rat dopamine-containing neurons; (b) in vitro mouse dopaminergic neurons fire with pacemaker regularity when in a low Ca2+/high Mg2+ environment; and (c) in vitro studies offer an approach to examine the basic properties of dopaminergic neurons exclusive of feedback pathways and other afferent inputs.
Animals↗
Effects of zoxazolamine and related centrally acting muscle relaxants on nigrostriatal dopaminergic neurons.
The effects of zoxazolamine (ZOX) and related centrally acting muscle relaxants on striatal dopamine (DA) metabolism and turnover, and substantia nigra zona compacta DA neuronal impulse flow were studied in rats. ZOX, chlorzoxazone and mephenesin, but not meprobamate, chloral hydrate, diazepam, pentobarbital, ethanol or dantrolene, decreased striatal DA metabolism without affecting striatal DA concentrations. More specifically, ZOX, as a representative muscle relaxant, was shown to decrease striatal DA turnover without directly affecting DA synthesis, catabolism, reuptake, or release. ZOX decreased nigral DA neuronal firing rates and dramatically decreased firing rate variability (normally many of the cells fire with bursting firing patterns but after ZOX the cells often fired with a very regular pacemaker-like firing pattern). ZOX and related centrally acting muscle relaxants appear to decrease striatal DA turnover by decreasing both neuronal firing rate and firing rate variability. The possible relationships between DA neuronal activity and muscle tone are discussed.
Animals↗
Measurements of S-adenosylmethionine and L-homocysteine metabolism in cultured human lymphoid cells.
The intracellular content and turnover of S-adenosyl-L-methionine (AdoMet) were measured in cultured human lymphoid cells. AdoMet levels were found to be 59 nmol/ml cell volume in exponentially growing WI-L2 lymphoblasts, 3.3-8.1 nmol/ml cell volume in unstimulated peripheral blood mononuclear cells, and 25-33 nmol/ml cell volume 24-48 h after the latter were stimulated with phytohemagglutinin. Increases in the AdoMet content of stimulated cells occurred within 2 h after addition of lectin. First order, pool turnover rates were of the same order of magnitude (0.029-0.091/min) for all three types of cultured cells, but owing to the differences in AdoMet content, absolute utilization rates differed markedly and were 4.5, 0.12-0.40, and 1.41-1.57 nmol/min/ml cell volume in WI-L2, unstimulated peripheral mononuclear cells, and lectin-stimulated peripheral mononuclear cells, respectively. Measurements of homocysteine accumulation in growth medium and of transsulfuration to cysteine indicate that a minimum of 82% of the AdoMet synthesized by WI-L2 is used for transmethylation. Remethylation of homocysteine by these cells could not be detected. AdoMet synthesis accounts for 20-23% of methionine utilization by WI-L2. Judging from the accumulation of homocysteine in the medium of phytohemagglutinin-stimulated peripheral mononuclear cells, a minimum of 38% of AdoMet synthesized must be used for transmethylation. Even though AdoMet utilization by unstimulated peripheral mononuclear cells is relatively small compared to that of stimulated cells and WI-L2, our data indicate that AdoMet turnover in such "resting" cells is three to five times that estimated for nonhepatic tissues. These findings may be relevant to the hypothesis that lymphoid cells are unusually sensitive to inhibition of transmethylation reactions.
Cells, Cultured↗
Activity of mesencephalic dopamine and non-dopamine neurons across stages of sleep and walking in the rat.
Single unit activity of dopamine and non-dopamine neurons in the substantia nigra and ventral tegmental area was recorded across stages of sleep and waking in the rat. These stages consisted of slow wave sleep (SWS), rapid eye movement (REM) sleep, awake-quiet (AQ) and awake-moving (AM). The dopamine neurons showed no change in mean firing rate across the stages of sleep or waking. During REM sleep, however, the dopamine cells fired with a more variable interspike interval than during SWS. In contrast, non-dopamine neurons in the substantia nigra and ventral tegmental area showed large increases in firing rate in REM compared to SWS, and in AM compared to AQ, without showing changes in interspike interval variability. In conclusion, whereas other monoaminergic neurons and various cortical and subcortical neurons exhibit marked changes in firing rate across the stages of sleep and waking, the dopamine neurons are unique in their lack of change in firing rate across stages.
Action Potentials↗
Three-dimensional computer reconstruction of midbrain dopaminergic neuronal populations: from mouse to man.
A technique is described which has been used to quantitate the 3-dimensional configuration of the midbrain dopamine (DA) nuclei (cell groups A8, A9, and A10). This technique provides cell counting information, for example, the BALB/c mouse has approximately 25,000 midbrain DA neurons, the albino rat has about 40,000 neurons, and man (33 year old) has approximately 450,000 neurons. Furthermore, cell density topography maps were constructed which enable quantitation of the 3-dimensional cellular distribution. These topography maps revealed both similarities and differences across the three species examined. The number of midbrain DA neurons is known to be genetically determined and to decrease with aging. DA cell number is also related to motoric behavior and neurologic and perhaps psychiatric disease. The ability to quantitate DA regional cell densities represents a new technique which can be used to study the neurobiology of DA neurons and relate DA cell number to both normal and abnormal behaviors.
Adult↗
The effects of benzodiazepine and non-benzodiazepine anxiolytics on locus coeruleus unit activity.
Two theories have been put forth concerning the anxiolytic actions of the anti-anxiety drugs. One theory maintains that these drugs decrease locus coeruleus output, and the other maintains that they facilitate gamma-aminobutyric acid (GABA) neurotransmission at benzodiazepine (BZ)-linked GABA receptors. The BZ-anxiolytic diazepam does decrease locus coeruleus neuronal impulse flow. However, this decrease is not due to effects on BZ-linked GABA receptors in the locus coeruleus. Furthermore, the non-BZ anxiolytic buspirone, its metabolite and its analog all slightly increase locus coeruleus neuronal impulse flow. This increase, in the case of the metabolite, appears to be due, in part, to blockade of alpha 2-adrenoceptors. Finally, buspirone, unlike diazepam, did not potentiate GABA inhibition at BZ-linked GABA receptor sites (i.e. cerebellar Purkinje cells). These data suggest that the non-BZ anxiolytic buspirone produces its anti-anxiety effects by unconventional mechanisms.
Action Potentials↗
Dopamine receptor antagonism by the novel antianxiety drug, buspirone.
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Animals↗
Buspirone, a non-benzodiazepine anxiolytic, increases locus coeruleus noradrenergic neuronal activity.
It has been hypothesized that treatments which increase locus coeruleus (LC) noradrenergic neuronal activity produce anxiety, whereas treatments which decrease LC neuronal activity are anxiety-reducing. Although the benzodiazepine anxiolytic diazepam decreases LC neuronal impulse flow and norepinephrine metabolism, the non-benzodiazepine anxiolytic buspirone does the opposite. These data suggest that a reduction in LC output is not a necessary prerequisite for anxiolytic activity.
Animals↗