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J F Lorden

Publications and source records attributed to J F Lorden.

At least 37 records · Page 2Linked to original sources
PubMed1991

A behavioral augmentation of natural immunity: odor specificity supports a Pavlovian conditioning model.

BALB/c mice were conditioned by pairing an odor to an injection of poly-inosinic:poly-cytidylic acid (poly I:C), a strong inducer of natural killer (NK) cell activity as the unconditioned stimulus (US). When later reexposed to the odor conditioning stimulus (CS), these mice showed a conditioned augmentation of the NK cell response to a suboptimal dose of 1 microgram poly I:C. The two stimuli used in these studies were camphor (Ca) and citronella oil (Cr) odors, two chemically-related but distinct odor stimuli. The conditioned mice demonstrated the ability to discriminate between Ca and Cr, such that the conditioned response (CR) was only elicited by the odor CS used in the formation of the conditioned association. Exposure of conditioned mice to the non-associated odor stimulus on the test day did not elicit a change in the NK cell response to the suboptimal dose of poly I:C when compared to mice in the US group that had been given the US on day 0 without pairing to either odor stimulus. This specificity of the CR for the odor CS and not the unassociated odor stimulus supports the interpretation that the elevation of NK cell activity in this paradigm is due to Pavlovian conditioning and therefore dependent on central nervous system (CNS) associative processes.

Animals↗
PubMed1990

Enhanced sensitivity to quipazine in the genetically dystonic rat (dt).

Both normal and genetically dystonic (dt) rats show a high-frequency forepaw tremor in response to systemic administration of the serotonin (5-HT) agonist quipazine at 8 days of age. The response declines with age in normal, but not dystonic, rats. By 16 days of age and after the development of a generalized movement disorder, the dystonic rat exhibits enhanced sensitivity to the tremorogenic effects of the drug in comparison with normal rats. Tremor was blocked by pretreatment with ketanserin, suggesting that it is mediated by 5-HT2 receptors. The dystonic rat has previously been shown to be insensitive to the tremorogenic effects of harmaline, a drug presumed to act indirectly through serotonergic neurons. This finding, coupled with the increased sensitivity to quipazine, suggests the presence of an abnormality in serotonergic systems in the mutants. Since there is evidence of abnormality in the olivo-cerebellar system in the dystonic rat, the alternative hypothesis that a nonserotonergic defect in the olivo-cerebellar system accounts for both the failure of behavioral response to harmaline and the persistent expression of a response to quipazine is also discussed.

Aging↗
PubMed1990

Quantitative autoradiography reveals selective changes in cerebellar GABA receptors of the rat mutant dystonic.

In the rat mutant dystonic (dt), glutamic acid decarboxylase (GAD) activity in the deep cerebellar nuclei (DCN) is elevated compared to normal littermates. The distribution of this increase within the DCN, and the effect upon GABA receptor density, was assessed in 25-d-old animals. GAD activity was increased 45, 41, and 74% in the medial, interpositus, and lateral divisions of the DCN, respectively. Autoradiographic analysis of GABAA receptor density, using the ligand 3H-muscimol (MUSC), revealed a significant decrease in MUSC binding in the DCN of the mutant. No changes in the binding of the benzodiazepine ligand 3H-flunitrazepam (FLU) were found in the DCN. At 18 other sites, including motor areas in the brain stem, midbrain, and forebrain, no significant changes were found in either MUSC or FLU binding. There also was a failure to find any significant changes in dt animals in the binding of ligands which label the muscarinic cholinergic receptor, dopamine D2 receptor, or serotonin 5-HT2 receptor. The results support earlier findings that GABAergic activity is increased in Purkinje cell terminals of the dt mutant and suggest that in response to this enhanced activity, GABA receptors in the DCN are down-regulated. At other levels of the neuraxis no consistent changes were found in any of the variables studied, suggesting that cerebellar dysfunction may be a primary component of the dystonic syndrome.

Animals↗
PubMed1989

Forebrain monoamines and associative learning: III. The US pre-exposure effect.

This experiment evaluated the effects of forebrain norepinephrine (NE) and serotonin depletion on the unconditioned stimulus (US) pre-exposure phenomenon. Rats with either dorsal bundle lesions, raphe lesions, or which served as vehicle controls were assigned to one of two training conditions. One-half of the animals in the 3 lesion groups received 30 episodes of a stimulus which later served as the US. The remaining rats experienced standard conditioning of CS-US pairing without US pre-exposure. The results indicate that while raphe-lesioned and vehicular rats exhibited the US pre-exposure effect, conditioning was unimpaired in NE-depleted rats following pre-exposure. These findings are consistent with a contextual blocking interpretation of the US pre-exposure effect.

Animals↗
PubMed1989

Regional cerebral glucose utilization reveals widespread abnormalities in the motor system of the rat mutant dystonic.

Rats with an inherited movement disorder (dystonic, dt), their phenotypically normal littermates, and normal unrelated controls were studied using a metabolic mapping technique, 2-deoxyglucose autoradiography. This approach was used to identify potential sites of abnormality underlying the movement disorder, as no morphological abnormalities using light and electron microscopic techniques have been identified in this mutation. There was a significant overall glucose utilization (GU) reduction in the dt rats and their littermate controls when they were at rest and not displaying abnormal movements. Conversion of GU values to standard scores showed abnormalities in dt compared with both control groups in the following areas: deep cerebellar nuclei, locus coeruleus, pontine gray, ventrolateral-ventromedial thalamic complex, nucleus of the third nerve, lateral habenula, and basolateral amygdala. Littermates were different from nonlittermates in several regions, including the dentate and red nuclei. A study of relative GU performed in animals displaying dystonic movements also showed abnormalities in the deep cerebellar nuclei and locus coeruleus, and in the red nucleus, external cuneate, and medial septum. Correlations computed for GU in pairs of regions with known anatomical connections suggested that cerebellar, substantia nigra, and basal ganglia efferents may be abnormal. These studies complement existing biochemical and neuropharmacological data which show abnormalities in the cerebellum of the dt rat. Additionally, the function of brain stem and even basal ganglia nuclei is affected in this mutant, perhaps as a consequence of abnormal cerebellar activity. The partial effects in the littermates suggest that abnormalities in only a few regions are not sufficient to produce the movement disorder, and a gene dose effect may exist.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Tolerance to the tremorogenic effects of harmaline: evidence for altered olivo-cerebellar function.

Administration of the beta-carboline alkaloid, harmaline, causes the neurons of the inferior olive to fire synchronously and to act as a pacemaker for the generation of tremor. Rats treated daily with harmaline showed a progressive loss of drug-induced tremor. This tolerance was long-lasting and specific. No cross-tolerance was noted to the drug oxotremorine. Prevention or attenuation of tremor by pretreatment with diazepam or morphine preserved the tremorogenic capacity of harmaline when administered alone. These results suggest a relatively permanent change in the olivo-cerebello-bulbar pathway that underlies the generation of tremor induced by harmaline. Treatment with harmaline also increased cyclic 3',5'-guanosine monophosphate (cGMP) in the cerebellum, presumably through activation of the climbing fiber pathway from the inferior olive to the cerebellar cortex. These increases were attenuated after repeated treatment. These results suggest that the site of tolerance to the tremogenic effects of harmaline lies within the olivo-cerebellar system.

Alkaloids↗
PubMed1988

Purkinje cell activity in rats following chronic treatment with harmaline.

Harmaline and related alkaloids produce a fine, generalized motor tremor with a frequency of 8-14 Hz in many mammalian species. The tremor is though to be initiated by the synchronous activation of cells in the inferior olive. Repeated administration of the drug at tremorogenic doses results in the rapid development of tolerance in the rat. Since the generation of cerebellar cyclic 3',5'-guanosine monophosphate by harmaline or apomorphine is reduced in harmaline-tolerant rats, it is possible that the site of tolerance is the olivocerebellar system. The present study used extracellular single unit recording techniques to determine whether harmaline tolerance was associated with changes in the firing patterns of Purkinje cells in the cerebellar vermis of the rat. In non-tolerant animals, the majority (8/13) of Purkinje cells recorded in the vermis responded to harmaline with a rhythmic increase in complex spike rate and a prolonged suppression of simple spikes. In harmaline-tolerant animals, only one cell in 14 could be identified that showed this response. In these animals, a variety of responses not encountered in experimentally naive animals were observed. Since the complex spike activity of Purkinje cells is presumed to reflect the activity of climbing fibers originating in the cells of the inferior olive, the results of the studies reported here support the conclusion that a reduction in the synchronous activation of cells at the olivocerebellar level blocks the appearance of tremor in harmaline-tolerant animals.

Action Potentials↗
PubMed1988

Neuropharmacological correlates of the motor syndrome of the genetically dystonic (dt) rat.

The research program described here has focused primarily on identifying sites of dysfunction in the central nervous system of rat mutants described as dystonic. The evidence strongly favors the position that there is a defect in the cerebellum of the dt rat. At present it seems reasonable to propose as a working hypothesis that there is a defect in the Purkinje cells that renders these neurons less sensitive to the excitatory neurotransmitters released by the climbing and parallel fibers. The finding that an abnormality in GAD activity in the deep cerebellar nuclei is relatively localized when first detected but spreads over time as the motor syndrome intensifies may indicate that there is a progressive decline in the function of the Purkinje cells. The fact that electrophysiological techniques detect a mixture of relatively normal and abnormal Purkinje cell activity in animals with advanced symptoms is consistent with such a proposal. Finding significant abnormalities in the cerebellum of the dt rat does not necessarily mean that this is the site of the primary defect responsible for the motor syndrome seen in these animals. We have failed to detect any signs of dysfunction in the basal ganglia, the presumed locus of a defect in human torsion dystonia. However, our investigations have been limited almost exclusively to the striatum. Thus, the possibility of defects at other sites, such as the globus pallidus or thalamus must be considered. Although we have not yet demonstrated that the abnormalities detected in the cerebellum are causally related to the behavior of the dt rat, the behavioral syndrome is consistent with a cerebellar defect. It has been suggested that the cerebellum is important for the continuing calibration of coordinated motor behavior. Important observations on the effects of cerebellar lesions have come from the study of the oculomotor system. Lesions in the cerebellum have been shown to eliminate the ability to recalibrate the saccadic eye movement system and to destroy the adaptive plasticity of the vestibulo-ocular reflex A cerebellar defect could result in a failure in motor learning or in the calibration of motor systems that must take place as the rat pup masters adult patterns of locomotion. We note that lesions of the climbing fiber system with 3-AP lead to some of the same biochemical effects seen in dt rats but do not produce an identical behavioral syndrome.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetylcholine↗
PubMed1988

Spontaneous and harmaline-stimulated Purkinje cell activity in rats with a genetic movement disorder.

The genetically dystonic rat (dt) displays a complex movement disorder in the absence of morphological defects in the nervous system. This mutant is also insensitive to the tremorogenic effects of harmaline. Because harmaline is known to act on the cells of the inferior olive to induce activity at the tremor frequency in the olivocerebellobulbar pathway, this pathway has been investigated as a possible site of a defect in the dt rat. Biochemical studies suggested the presence of abnormalities at the level of the Purkinje cell or its afferent input. Thus, the present study investigated the harmaline response of Purkinje cells in dt rats and unaffected littermate controls with extracellular single-unit recording techniques. The spontaneous, simple spike and complex spike firing rates of dt rats were significantly lower than those of normal littermate controls. In normal rats, 2 responses to systemic harmaline injection were seen. Simple spikes were either completely suppressed for periods of 30-180 min, or were intermittently suppressed, pausing repeatedly for periods of 1-18 sec. Cells that showed complete suppression of simple spike activity also showed increased frequency and rhythmicity of complex spikes. In dt rats, intermittent simple spike responses were seen in a proportion (41%) similar to that in normal rats (53%). However, the proportion of cells showing high-frequency, rhythmic, complex spikes and complete suppression of simple spikes was low in the dt rats in comparison with littermate controls (18 versus 47%). In addition, 41% of the cells from dt rats displayed no change, or an anomalous change, in firing patterns in response to harmaline. Since the rhythmic activation of olivary neurons that results in the rhythmic, complex spike discharge of Purkinje cells is assumed to be responsible for the appearance of harmaline tremor, the failure of the dt rat to display tremor is most likely due to a failure at the olivocerebellar level, rather than at a site efferent to the cerebellum.

Action Potentials↗
PubMed1987

Acute and chronic effects of climbing fiber lesions on cerebellar cyclic guanosine monophosphate.

The neurotoxin 3-acetylpyridine was administered to 20-day-old rats to produce lesions of the inferior olive-climbing fiber projection to the cerebellum. Cerebellar cGMP levels were determined 6 h, 24 h, 48 h, 7 days, 14 days and 20 days postlesion. A significant effect on cGMP was found only at 48 h (-28%) and 7 days (-45%) postlesion. The results are discussed with respect to the cellular localization of cGMP and the hypothesized relationship of cGMP to cerebellar Purkinje cell activity.

Action Potentials↗
PubMed1987

Temporal sequence of motor disturbances and increased cerebellar glutamic acid decarboxylase activity following 3-acetylpyridine lesions in adult rats.

Adult male rats were administered 75 mg/kg of the neurotoxin 3-acetylpyridine to produce lesions of the inferior olive-climbing fiber projection to the cerebellum. At selected times ranging from 6 h to 43 days postlesion, rats were evaluated for motor dysfunction, and glutamic acid decarboxylase (GAD) activity was determined in the deep cerebellar nuclei and cerebellar vermis. In the deep nuclei non-monotonic changes in GAD activity were found following climbing fiber destruction. Initially, there was a steady increase in GAD activity which peaked at 38% above control values 14 days postlesion. GAD activity then slowly declined, although it remained significantly above control levels at 43 days postlesion, the latest time point examined. In the vermis, GAD activity was significantly increased at 4 days postlesion (+8%) and remained at approximately this level throughout the experiment. The initial behavioral effects of climbing fiber loss included hypotonia and ataxia with severely reduced mobility. With time, the ataxia and hypotonia decreased and movements such as mud-walking and pivoting developed. As these behaviors diminished, other novel conditions such as movement-associated tremor and hopping appeared. These results are discussed in the context of the previously reported effects of climbing fiber lesions on the firing rates of Purkinje cells and deep nuclei cells.

Action Potentials↗
PubMed1987

Monosodium L-glutamate lesions reduce susceptibility to hypoglycemic feeding and convulsions.

Lesions of the circumventricular regions of the brain induced by neonatal administration of monosodium L-glutamate (MSG) are associated with chronic hypophagia and deficits in response to a variety of feeding challenges. These deficits occur despite the fact that, at least at high doses, MSG can produce obesity. The cause of the feeding deficits in MSG-treated animals is unknown. However, the circumventricular regions that are damaged by MSG contain high concentrations of insulin binding sites. In order to determine whether the MSG lesion alters responsiveness to circulating insulin, we have investigated the response of non-obese MSG-treated mice to doses of exogenous insulin designed either to stimulate feeding or to induce hypoglycemic convulsions. We report that MSG produces a dose-related decrease in hypoglycemic convulsions and glucoprivic feeding, suggesting that a loss in sensitivity to insulin may contribute to the MSG syndrome.

Animals↗
PubMed1986

Glutamic acid decarboxylase activity in micropunches of the deep cerebellar nuclei of the genetically dystonic (dt) rat.

Glutamic acid decarboxylase (GAD) activity was measured in specific divisions of the deep cerebellar nuclei of rats with an inherited dystonia. In 16-day-old dystonic rats there was a significant increase in GAD activity only in the nucleus interpositus (+26%). In 20-day-old dystonic rats GAD activity in all 3 cerebellar nuclei (fastigial, interpositus, dentate) was significantly increased compared to normal controls. The results indicate a spread of the anatomical locus of the neurochemical abnormality with time. During this period (postnatal days 16-20) there is a progressive worsening of the motor disorder in the affected animals.

Animals↗
PubMed1986

Alterations in the noradrenergic projection to the cerebellum of the dystonic (dt) rat.

The genetically dystonic rat (dt) has elevated resting levels of cerebellar norepinephrine (NE) in comparison with phenotypically normal littermates. This difference is not secondary to cerebellar hypoplasia. Increased NE is observed as early as postnatal day 12, when clinical symptoms have become evident. The elevation in cerebellar NE levels in the dt rat involves all cerebellar areas, but is not generalized to all terminal fields of the locus coeruleus. Elevations in cerebellar NE are followed developmentally by a reduction in sensitivity to the NE-depleting effects of reserpine, a change which is also confined to the cerebellum. The effects of amphetamine and the tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine were similar in normal and dt rats. Levels of the major cerebellar metabolite of NE, 3-methoxy-4-hydroxyphenylglycol, did not differ between mutant and normal animals. Nor were any changes noted in the number or affinity of beta-adrenergic receptors. These data indicate that there is a regional alteration in NE storage. Cerebellar morphology appears normal in the dt rat, except for a decrease in Purkinje cell size. This change and other evidence of biochemical abnormalities in the Purkinje cells suggest that the alterations in cerebellar NE in the dt mutant may be a secondary response to a functional change in the target neuron for this system, the Purkinje cell.

Amphetamine↗
PubMed1986

Effect of paraventricular nucleus lesions on body weight, food intake and insulin levels.

Lesions of the paraventricular nucleus of the hypothalamus (PVN) produce obesity and hyperphagia. However, the underlying mechanism is unknown. The connections of the PVN with brainstem centers for autonomic control suggest that a change in autonomic function could mediate the PVN obesity syndrome. We examined this hypothesis in a series of 3 experiments, searching specifically for changes in insulin secretion. Rats with PVN lesions were hyperphagic and hyperinsulinemic, when obese. However, hyperinsulinemia could not be detected prior to the onset of obesity or following weight reduction. Subdiaphragmatic vagotomy reversed the PVN obesity and lowered insulin levels below those of sham-vagotomized rats. Since noradrenergic innervation of the hypothalamus is implicated in feeding, hypothalamic norepinephrine (NE) was depleted by injection of 6-hydroxydopamine into the central tegmental tract, posterior to the hypothalamus. The effects of NE depletion was compared with those of PVN lesions. Loss of hypothalamic NE resulted in hyperphagia with no increase in body weight and no change in insulin. Histological analyses indicated that the posterior PVN was the most effective lesion focus for producing disturbances in body weight and food intake. Although the results of these experiments implicate the autonomic nervous system in PVN obesity, basal hyperinsulinemia does not appear to be a primary feature of the syndrome.

Animals↗
PubMed1986

Dietary obesity: brown fat denervation fails to alter development or recovery.

We assessed the effect of scapular brown adipose tissue (BAT) denervation on dietary obesity in adult female Sprague-Dawley rats. In rats maintained for 32 days on an obesity-inducing regimen, BAT denervation produced significant reductions in food intake (83.4 vs. 94.4 kcal/day), weight gain (66.0 vs. 103.5 g), and carcass fat (19.3 vs. 27.6%). A subgroup of denervates consuming as many calories as controls (94.1 kcal/day) failed to gain more weight (92.2 g) or accumulate more fat (25.4%) than controls. In rats developing obesity for 32 days followed by 8 days on laboratory chow, weight change was unaffected by denervation during either weight gain (89.4 vs. 87.1 g for controls) or weight loss (21.2 vs. 22.1 g) phases, as was carcass fat (21.0 vs. 20.4%). BAT norepinephrine utilization was unchanged in nondenervated obese rats and those recovering from obesity. We did not, therefore, find evidence that under these experimental conditions sympathetic activation of BAT countered obesity during overconsumption or contributed to recovery from obesity.

Adipose Tissue↗
PubMed1985

Lesions of the inferior olive increase glutamic acid decarboxylase activity in the deep cerebellar nuclei of the rat.

Inferior olive-climbing fiber lesions were made by administering 3-acetylpyridine to 16-day-old rats. This treatment produced multiple motor abnormalities which gradually improved over the subsequent 28 days. A significant increase in glutamic acid decarboxylase (GAD) activity was found in the deep cerebellar nuclei 24 h after treatment. This elevation increased with time, reaching 134% of control values 28 days after treatment. GAD activity in the cerebellar vermis also increased but did so more slowly and to a lesser degree than in the deep nuclei, reaching 114% of control values 28 days after treatment. The results suggest the operation of different mechanisms in producing the increased GAD activity in the different areas.

Animals↗