Chronic high dose L-dopa treatment does not alter the levels of dopamine D-1, D-2 or D-3 receptor in the striatum of normal monkeys: an autoradiographic study.

To assess the role of dopamine receptors in the genesis of dyskinesia, we have used quantitative autoradiography to determine the effect of chronic L-dopa administration on dopamine D-1 (using [3H]SCH 23390), D-2 (using [3H]spiperone) and D-3 (using [3H]7-OH-DPAT) receptor binding levels in the striatum of dyskinetic or non-dyskinetic monkeys. Total and subregional striatal analysis showed no difference in D-1, D-2 or D-3 receptor binding in the caudate and putamen between monkeys receiving high dose L-dopa treatment with marked dyskinesia and those without dyskinesia compared to untreated animals. It thus appears unlikely that changes in dopamine receptor expression are a primary cause of L-dopa induced dyskinesia. Rather, a functional dissociation of D-2 receptor coupling to co-expressed enkephalin/adenosine-2a receptor activity in the striato-GPe indirect pathway may be more important in the development or expression of L-dopa-induced involuntary movements.

Osteoporosis. Recommended guidelines and New Jersey legislation.

More than 28 million Americans aged 50 and over have osteoporosis or low bone density. While 80% of those affected are women, one in eight men also suffer from the disease. This number is expected to increase as men live longer. Commonly called the "silent disease," osteoporosis exhibits no symptoms or pain until a fracture occurs. The most common fractures involve the wrist, vertebra, and hip. Half of all women and 20% of men will have at least one osteoporosis fracture in their lifetime. This article describes statewide efforts to prevent and manage osteoporosis and the recommended practice guidelines for the diagnosis and treatment of the disease.

Alterations in preproenkephalin and adenosine-2a receptor mRNA, but not preprotachykinin mRNA correlate with occurrence of dyskinesia in normal monkeys chronically treated with L-DOPA.

Chronic treatment with L-DOPA induces dyskinesia in patients with Parkinson's disease (PD) and 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP)-treated monkeys, but is not thought to do so in normal humans or primates. However, we have shown that chronic oral high dose L-DOPA administration, with the peripheral decarboxylase inhibitor, carbidopa and with or without the peripherally acting catechol-O-methyl transferase (COMT) inhibitor, entacapone, to normal macaque monkeys for 13 weeks induced dyskinesia in a proportion of animals. In the present study, in situ hybridization histochemistry was used to investigate the effect of chronic L-DOPA administration on the activity of the direct and indirect striatal output pathways by measuring striatal preprotachykinin (PPT), preproenkephalin-A (PPE-A) and adenosine-2a (A2a) receptor gene expression in these monkeys. Overall there was no significant difference in striatal PPT, PPE-A and A2a receptor mRNA levels between normal animals and all L-DOPA (plus carbidopa and/or entacapone)-treated animals irrespective of whether or not dyskinesia occurred. However, when the level of PPE-A and A2a receptor mRNA was analysed in eight monkeys displaying marked dyskinesias as a result of L-DOPA (plus carbidopa with or without entacapone) treatment, there was a significant increase in PPE-A and A2a receptor mRNA message levels in the striatum compared with animals receiving identical treatment, but displaying few or no involuntary movements, and compared with normal controls. There was no difference in striatal PPT mRNA levels in monkeys exhibiting severe dyskinesia compared with those showing little or no dyskinesia after L-DOPA treatment or to normal controls. These results suggest that prolonged L-DOPA treatment alone has no consistent effect on either the direct or indirect pathways, as judged by striatal PPT, PPE-A or A2a receptor mRNA levels in normal monkeys. However, in monkeys exhibiting marked dyskinesia resulting from chronic L-DOPA treatment, abnormal activity is detected in the indirect striato-pallidal output pathway, as judged by striatal PPE-A and A2a receptor mRNA levels, indicating an imbalance between the direct and indirect striatal pathway which may explain the emergence of dyskinesia in these animals.

Nitric oxide synthase inhibition and MPTP-induced toxicity in the common marmoset.

Nitric oxide, produced following activation of N-methyl-D-aspartate (NMDA) receptors, may be involved in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity since NMDA receptor antagonists have been shown to prevent MPTP induced nigral cell loss in primates. Common marmosets were treated with either saline or MPTP or L-NGnitro arginine methyl ester (L-NAME) or MPTP and L-NAME. MPTP-treated common marmosets showed motor deficits including bradykinesia, rigidity, and tremor accompanied by a marked loss of tyrosine hydroxylase-immunoreactive neurones in the substantia nigra pars compacta and of [3H]-mazindol binding in the caudate-putamen. MPTP treatment also caused an increase in glial fibrillary acidic protein (GFAP) staining in the substantia nigra compared to controls. However, MPTP treatment did not alter the number of constitutive nitric oxide synthase-immunoreactive neurones in the caudate-putamen. Furthermore, neurones or glial cells immunoreactive for inducible nitric oxide synthase were not observed in the substantia nigra pars compacta following MPTP treatment. L-NAME treatment alone did not produce any behavioural changes in marmosets and did not alter the number of tyrosine hydroxylase-immunoreactive cells in the substantia nigra pars compacta, the number of constitutive nitric oxide synthase-immunoreactive neurones or [3H]-mazindol binding in the caudate-putamen compared to saline-treated control animals. Furthermore, L-NAME did not affect the motor deficits, loss of tyrosine hydroxylase-immunoreactive neurones in the substantia nigra pars compacta, loss of [3H]-mazindol binding in the caudate-putamen, or the increase in GFAP staining in the substantia nigra induced by MPTP treatment of common marmosets. The failure of L-NAME to protect against MPTP-induced toxicity in the marmoset suggests that nitric oxide does not play a major role in such toxicity and casts doubt over the involvement of the NMDA:nitric oxide system in neurodegeneration in MPTP-treated primates.

Morphology and electrophysiology of guinea-pig paratracheal neurones.

BACKGROUND: Although guinea-pig tracheal preparations are used as models of asthma, the morphological and electrophysiological characteristics of its associated ganglion neurones (paratracheal neurones) have not been characterized. METHODS: Intracellular staining and electrophysiological recording techniques have been applied to guinea-pig paratracheal neurones in isolated preparations. RESULTS: Most (32/35) neurones were multipolar, with many short (< 70 microns), finely tapering processes and one or more long processes; the latter, which were traced for up to 400 microns, travelled along the interconnecting nerve trunks, often in pairs, or over smooth muscle bundles. About 20% (6/32) of neurones had conspicuous somal extensions that gave rise to 3-8 processes. The soma morphology of neurones of the intrinsic ganglionated plexus close to the trachealis muscle were usually more complex than those in or associated with recurrent or vagal nerve trunks. Two types of neurone were identified electrophysiologically; neurones with fast excitatory synaptic potentials were found only in ganglia located very close to the smooth muscle, whereas > 90% of neurones lacking synaptic inputs were associated with recurrent nerve trunks. Transmural or focal electrical stimulation failed to evoke either slow inhibitory or slow excitatory (cholinergic or non-cholinergic) synaptic potentials in either electrophysiological type. CONCLUSIONS: It is tentatively concluded that the neurones of the intrinsic ganglionated plexus receiving synaptic input probably provided the para-sympathetic innervation to effector cells (such as trachealis muscle). Both these and the spiking neurones located in or near nerve trunks showed little potential for synaptic modulation of their excitability.

Effect of 7-nitro indazole on quinolinic acid-induced striatal toxicity in the rat.

Nitric oxide (NO) is implicated as a mediator of cell death in models of neurodegenerative disease. However, the precise role of NO in neuronal degeneration remains controversial. In the present study we employed 7-nitro indazole (7-NI), reportedly a selective inhibitor of neuronal nitric oxide synthase (nNOS) in vivo, to investigate the possible involvement of NO in quinolinic acid (QA)-induced striatal toxicity in the rat. Intrastriatal injection of QA (30 nmol) caused loss of NADPH diaphorase (48%), NOS (48%) and acetylcholinesterase (AChE; 22%) positive neurones and a loss of NOS activity (78%) in striatal homogenates. 7-NI (30 mg kg-1, i.p. every 4 h for 20 h) did not affect the loss of NADPH diaphorase (52%), NOS (52%) and AChE (16%) positive neurones or the loss of NOS activity (66%) in striatal homogenates. The present study does not support a role for NO in QA-induced striatal toxicity.

The effect of nitric oxide synthase inhibition on quinolinic acid toxicity in the rat striatum.

Neurons containing reduced nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase and acetylcholinesterase in the striatum are spared in Huntington's disease. It has been claimed that these neurons are also spared after intrastriatal injection of the N-methyl-D-aspartate receptor agonist, quinolinic acid. In the present study the effects of intrastriatal injection of quinolinic acid (15, 30 and 60 nmol) on neurons containing NADPH diaphorase and acetylcholinesterase were examined in rats. Neurons identified histochemically were counted in whole striatal sections at the level of the injection site and at 400 microns intervals anterior and posterior to the injection site. There was a dose-related reduction in the total number of NADPH diaphorase-containing neurons counted in these levels, but only a mild loss of acetylcholinesterase-containing neurons. Acetylcholinesterase-positive neurons were observed near the injection site following administration of all doses. The effects of the nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (50 mg/kg, i.p. twice daily for seven days), on quinolinic acid (30 nmol. day 5)-induced toxicity were also investigated. Striatal sections were stained for NADPH diaphorase-, nitric oxide synthase- and acetylcholinesterase-containing neurons and cells were counted in whole striatal sections at the level of the injection site and at four levels posterior to the injection site. Nitric oxide synthase activity was measured in striatal homogenates. NG-Nitro-L-arginine methyl ester did not protect against or potentiate the loss of NADPH diaphorase-, nitric oxide synthase- or acetylcholinesterase-containing neurons or the loss in nitric oxide synthase activity. Acute intrastriatal injection of quinolinic acid may not be a suitable model for Huntington's disease and a role for nitric oxide in quinolinic acid-induced toxicity is not supported in this model.

Time course of inhibition of brain nitric oxide synthase by 7-nitro indazole.

7-Nitro indazole (7-NI) inhibits rat striatal, cerebellar, hippocampal, cerebral cortex and olfactory bulb nitric oxide synthase (NOS) in vitro with IC50 values of 0.68 +/- 0.01 microM, 0.64 +/- 0.03 microM, 1.53 +/- 0.05 microM, 0.93 +/- 0.04 microM and 1.05 +/- 0.02 microM respectively (n = 6). Intraperitoneal (i.p.) or oral administration of 7-NI (30 mg kg-1) to rats inhibited NOS enzyme activity measured ex vivo in all five brain regions (n = 5-6). NOS inhibition (maximal effect, 0.5 h post-injection) was transient with complete recovery at either 4 h (oral administration) or 24 h (i.p. administration). Repeated i.p. injection of 7-NI (30 mg kg-1, every 4 h for 20 h) inhibited NOS enzyme activity at 24 h by 51-61% in all brain regions. The relatively transient NOS inhibitory effect of 7-NI following parenteral administration should be taken into account when using this drug to evaluate the central effects of nitric oxide.

Complex correlations between the morphology, electrophysiology and peptide immunohistochemistry of guinea-pig enteric neurones.

Neuroanatomical, electrophysiological and immunohistochemical techniques were used to describe correlations between soma morphology and electrophysiological properties in two groups of guinea-pig enteric neurones posing particular challenges. Lucifer Yellow-staining of 542 myenteric plexus neurones of duodenum revealed a great diversity of neuronal morphology. The distribution was: Dogiel Type I 27%, Dogiel Type II 54%, Stach Type IV 9%; 10% were unclassified. Correlations were sought in 59 of these cells between morphology and electrophysiological properties but no particular association was recognised. Dynorphin A(1-8)-like immunoreactivity (Dyn A(1-8)-IR) was found in up to 90% of identified submucous neurones of guinea-pig ileum. Of 62 S-neurones, 41 showed 'weak' and 19 had 'intense' Dyn A (1-8)-IR. There was no evidence of Dyn A(1-8)-IR in 2 S-neurones, nor in 8/8 AH-neurones. As for 11/16 vasoactive intestinal peptide- (VIP-) IR neurones, there was a strong correlation between the presence of 'weak' Dyn A(1-8)-IR and the occurrence of inhibitory (IPSPs) and slow excitatory synaptic potentials (EPSPs) (13/16 cells tested), which were never observed in neurones with 'intense' Dyn A(1-8)-IR (16/16) or neuropeptide Y (NPY)-IR (8/8). Similarly, 7/7 neurones with 'weak' Dyn A(1-8)-IR, but not those (7/7) with 'intense' Dyn A(1-8)-IR, hyperpolarised or showed a conductance change to noradrenaline. It was concluded that dynorphin A(1-8)-like-IR was contained in two populations of submucous neurone that are anatomically, immunohistochemically, electrophysiologically and pharmacologically distinct and closely related to those containing VIP and NPY. Furthermore, as in the myenteric plexus throughout the small intestine, opioid peptides are not expressed in Dogiel Type II cells.

Monocytosis in experimental zinc deficiency of domestic birds.

Differential and total white cell counts on the peripheral blood of chickens, turkeys and quails maintained from hatching on an experimental zinc-deficient diet, revealed a severe monocytosis. In chickens the increase in monocytes was first detected on the 3rd day after hatching and was maintained until 18 days of age. The relationship of this monocytosis to the zinc-associated factors which affect mammalian leucocytes and to the damaged epithelium in zinc-deficient birds is discussed.

The adrenal cortico-medullary ratio in the fowl.

1. A new integrating method of assessing the proportions of cortical and medullary tissue in the avian adrenal gland is described and statistically evaluated. 2. It is shown that a single "central" section of the adrenal gland will suffice to obtain accurate results. 3. Each section was projected on to a grid of about 2500 intersection points and the ratio of points falling on cortical or medullary tissue was determined. 4. Applications of this method to normal fowls showed that there were significant breed, sex and, particularly, age differences in the cortico-medullary ratio of the fowl's adrenal glands.