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Biomedical subjects

J F Lorden

Publications and source records attributed to J F Lorden.

At least 55 records · Page 3Linked to original sources
PubMed1985

Decreased cerebellar 3',5'-cyclic guanosine monophosphate levels and insensitivity to harmaline in the genetically dystonic rat (dt).

The dystonic rat (dt) is an autosomal recessive mutant displaying a complex motor syndrome that includes sustained axial twisting movements. The syndrome is correlated with increased glutamic acid decarboxylase activity in the deep cerebellar nuclei and increased cerebellar norepinephrine levels in comparison with phenotypically normal littermates. Biochemical, behavioral, and anatomical techniques were used to investigate the possibility that the abnormalities noted in the cerebellum of the dt rat were indicative of altered function of the major projection neurons of the cerebellar cortex, the Purkinje cells. Phenotypically normal rats showed tremor in response to harmaline, a drug that acts on the inferior olive to produce bursting in the climbing fiber pathway. Dystonic rats were insensitive to the effects of harmaline but did respond to oxotremorine. Levels of the cyclic nucleotide 3',5'-cyclic guanosine monophosphate, a biochemical marker for Purkinje cells, increased in response to harmaline in normal rats but were significantly lower in dystonic rats under both basal and harmaline-stimulated conditions. Purkinje cell soma size was reduced in the dystonic rats but no other morphological correlates of the behavioral or biochemical deficits were noted. Taken together with other observations on this mutant, the results suggest an impairment in the cerebellum or in its connections with lower brainstem and spinal cord sites.

Alkaloids↗
PubMed1984

Decreased catalepsy response to haloperidol in the genetically dystonic (dt) rat.

The rat mutant dystonic displays an autosomal recessive neurological disease characterized by slow, twisting movements of the limbs and trunk. Rats displaying clinical signs also show a decreased behavioral response to the dopaminergic blocker, haloperidol. Investigation of the development of the cataleptic response to haloperidol in the dystonic (dt) rat indicated that the response of the dt rat in the bar test is similar to that of normal littermates until after the appearance of clinical symptoms in the mutants on postnatal day 10. Mutant rats did not differ from their normal littermates in response to another cataleptic agent, morphine. Assessment of the integrity of the nigrostriatal dopamine (DA) system did not indicate the presence of any degenerative process or of any alterations in DA metabolism. No reliable differences were found between normal and dt rats in striatal DA levels or turnover rates; in DA levels in response to gamma-hydroxybutyrolactone; or in the number and affinity of striatal DA muscarinic acetylcholine receptors. Nor did qualitative light microscopic examination of Golgi-impregnated tissue from dt rats indicate the presence of any morphological abnormalities in the striatum. These findings suggest that dystonic symptoms can occur in the absence of an alteration in striatal DA metabolism and that the dt rat may have a defect in a pathway efferent to the striatum.

4-Butyrolactone↗
PubMed1984

Alterations in cerebellar glutamic acid decarboxylase (GAD) activity in a genetic model of torsion dystonia (rat).

Glutamic acid decarboxylase (GAD) activity was studied in specific brain regions of a newly identified genetic (rat) model of human torsion dystonia. GAD activity was found to be significantly increased in the deep cerebellar nuclei of dystonic rats at 16, 20, and 24 days of age. GAD activity in the other regions examined (vermis, cerebellar hemispheres, caudate nucleus, and globus pallidus) did not differ from that of age-matched normal littermate controls. Diazepam treatment significantly reduced the frequency of dystonic movements in the mutant.

Animals↗
PubMed1984

Characterization of the rat mutant dystonic (dt): a new animal model of dystonia musculorum deformans.

An inherited neurological disorder characterized by sustained twisting movements during waking has been discovered in Sprague-Dawley rats. The mutation follows an autosomal recessive pattern of inheritance and has been named dystonic (dt). The rat mutants are indistinguishable from normal littermates in open field behavior and climbing activity prior to postnatal days 9 to 10. Clinical signs begin to appear on day 10 and include twisting of the axial musculature, hyperflexion of the trunk, self-clasping of forelimbs and hindlimbs, and poor placement of the limbs during locomotion. No morphological lesions of neural or non-neural tissues have been observed with routine light microscopy. Dystonic rats demonstrate significantly elevated cerebellar norepinephrine levels, although levels in other terminal fields of the locus ceruleus are similar to those of normal littermates. No differences in the pattern or density of noradrenergic innervation were apparent in cerebellar tissue from dt rats examined with histochemical fluorescence techniques. These mutants were less sensitive than unaffected littermates to the akinesic effects of the dopamine blocker haloperidol. However, striatal dopamine levels were not reliably different from normal in dt rats, and their response to the movement-stimulating effects of apomorphine appeared normal. These findings suggest the presence of biochemical disturbances in the extrapyramidal system of dt rats. The dt rat may provide a useful model for human dystonia musculorum deformans.

Aging↗
PubMed1983

Forebrain monoamines and associative learning: I. Latent inhibition and conditioned inhibition.

Two experiments evaluated the effects of depletion of forebrain norepinephrine (NE) or serotonin (5-HT) on two forms of internal inhibition. Experiment 1 examined the role of NE and 5-HT depletion on latent inhibition: rats with dorsal bundle or raphe lesions or vehicle control rats were trained to one of two pre-exposure conditions (single vs multiple stimuli) or to a non-pre-exposure control prior to conditioning. The results of this experiment showed that latent inhibition was attenuated under either condition of pre-exposure following depletion of 5-HT but that attenuation was present in NE depleted rats only when pre-exposed to multiple stimuli. Experiment 2 assessed the rate at which a conditioned inhibitor was established following NE or 5-HT depletion. The results of Experiment 2 indicated that the formation of a conditioned inhibitor was unimpaired following depletion of either NE or 5-HT. The results of Experiment 1 demonstrate that 5-HT and NE have different effects on associative processes: 5-HT apparently affects a habituation-like process, whereas NE is an important influence on more complex mechanisms involving the comparison of new with previously acquired information. The findings of Experiment 2 are consistent with behavioral investigations which show that conditioned inhibition affects output processes rather than the salience of stimuli.

Animals↗
PubMed1983

Forebrain monoamines and associative learning: II. Superconditioning/unblocking.

The roles of norepinephrine (NE) and serotonin (5-HT) were assessed by comparing the effect of their depletion on the associability of stimuli. NE and 5-HT depleted rats and vehicle controls were assigned to two training conditions and to a control condition. In each of the training conditions rats were pre-exposed to a single stimulus prior to conditioning to a compound stimulus formed from the pre-exposed cue and a new stimulus. The training conditions differed only in the order of testing of each of the stimuli following training. Rats assigned to the control condition received only compound conditioning before the associability of each cue was assessed. The findings show that: (a) vehicle rats in the training tasks evidence superconditioning: the associative strength of the new element exceeds that of the pre-exposed cue; (b) equivalent associative strength was found with either cue regardless of their testing order for NE depleted rats; and (c) 5-HT depleted rats did not show superconditioning: the pre-exposed cue competes with the new cue for available associative strength.

Animals↗
PubMed1983

Feeding, activity, and body temperature following 6-hydroxydopamine lesions in diabetes (db/db) mice.

Reductions in central catecholamines produced by intraventricular injections of 6-hydroxydopamine (6-OHDA) cause weight loss and decreased plasma glucose in diabetes (db/db) mice. The effects of this treatment were examined in short-term (64-day) and long-term (120-day) survival groups. Diabetes mice treated with 6-OHDA decreased food intake, lost weight, and maintained a lower weight than vehicle-treated controls until vehicle-treated animals began to enter the terminal stages of the syndrome, indicated by a loss of body weight. Diabetes mice given 6-OHDA lost weight despite reduced body temperatures and activity levels. Blood glucose levels were always lower in 6-OHDA than in ad lib fed vehicle-treated db/db mice. The 6-OHDA treatment also improved pancreatic islet granulation. Pair feeding vehicle-treated with 6-OHDA-treated db/db mice did not halt weight gain in the vehicle-treated group. However, measurement of carcass fat indicated similar losses in db/db-6-OHDA mice and vehicle-treated mice when the vehicle group was pair-fed with lean controls. Treatment with 6-OHDA produced long-term improvement in the diabetes syndrome, but the decreased body weight of the 6-OHDA-treated diabetes mice could not be completely accounted for by changes in food intake or measured indices of energy expenditure.

Animals↗
PubMed1982

Effects of central and peripheral pretreatment with fluoxetine in gustatory conditioning.

The administration of fluoxetine, a relatively specific serotonin uptake inhibitor, an hour prior to a taste-drug pairing was shown to attenuate the acquisition of taste aversions in a dose-dependent manner. Desipramine which is less effective than fluoxetine in blocking the reuptake of serotonin was also less potent in reducing the magnitude of taste aversions. Depletion of forebrain serotonin by lesions of the dorsal and median raphe nuclei or of norepinephrine by lesions of the dorsal noradrenergic bundle failed to prevent the pretreatment effect produced by either fluoxetine or desipramine. Rats with raphe lesions consistently consumed less of the taste paired with lithium than did control animals; however, this decreased intake occurred under both drug and saline pretreatment conditions, suggesting an increased sensitivity to the taste-lithium pairing rather than a diminution of the pretreatment effect. Rats with dorsal bundle lesions failed to differentiate between drug and saline pretreatment, consuming similar amounts under both conditions. These findings as well as the observation that intraventricular administration of fluoxetine did not produce a pretreatment effect suggest that forebrain serotonergic systems are not the critical site of action for the production of pretreatment effects by monoamine uptake inhibitors. Instead, the hypothesis that the peripheral effects of fluoxetine have a stimulus value that acts by way of an associative mechanism to attenuate gustatory conditioning must be considered.

5-Hydroxytryptophan↗
PubMed1981

Increases in alpha-adrenergic receptors in the hypothalamus of the genetically obese mouse (ob/ob).

Despite significantly elevated hypothalamic norepinephrine levels, genetically obese mice (ob/ob) had more hypothalamic alpha-adrenergic receptors than their lean littermates. This receptor increase appeared to be specific to the alpha-receptors in the hypothalamus since no change was found in the number of alpha-receptors in the cortex or in the dopamine and muscarinic receptors in the cortex and striatum.

Adrenergic alpha-Antagonists↗
PubMed1981

Behavioral and neurochemical effects of neonatal administration of monosodium L-glutamate in mice.

Feeding behavior, activity level, and thermoregulatory ability of mice made obese by neonatal administration of monosodium L-glutamate (MSG) were studied. The degree of obesity and other characteristics of the syndrome were found to depend on age, diet, and housing condition. Carcass fat determinations demonstrated the presence of obesity in all MSG animals; however, body weight was elevated over control levels only in adult mice caged in groups. Group-housed MSG animals also failed to increase food intake in response to food deprivation and were both hypoactive and hypothermic. INdividually caged MSG mice showed normal activity levels and body temperature, an attenuated response to food deprivation, and an enhanced response to a high-fat diet. Since MSG obesity may be the consequence of damage to the dopamine-rich arcuate nucleus of the hypothalamus, a second goal of the study was to measure central catecholamines and examined any changes in the MSG animal's behavioral responses to catecholaminergic drugs. Animals treated with MSG sustained some loss of hypothalamic dopamine, but no systematic relation between central catecholamines and behavioral aspects of the syndrome could be discerned.

Animals↗
PubMed1980

Depletion of central catecholamines alters amphetamine- and fenfluramine-induced taste aversions in the rat.

Conditioned taste aversions induced by pairing the consumption of saccharin with an amphetamine injection are attenuated in rats with depletion of central catecholamines caused by intraventricular administration of 6-hydroxydopamine (6-OHDA). The hypothesis that dopamine (DA) depletion is responsible for this effect was tested. The reduction in conditioning caused by intraventricular 6-OHDA could not be duplicated either with injections of 6-OHDA into the substantia nigra (Experiment 1) or with intraventricular 6-OHDA injections in animals pretreated with desmethylimipramine (Experiment 2). Both treatments, however, produced large depletions of telencephalic DA. 6-Hydroxydopa infusions caused a preferential loss of telencephalic norepinephrine (NE) but also failed to alter taste aversion learning. It is concluded that the effect of intraventricular 6-OHDA on amphetamine-induced aversions was the result of depletion of both NE and DA. In a third experiment the generality of the effect was examined by pairing saccharin consumption with injections of the amphetamine congener fenfluramine. Depletion of both NE and DA failed to alter fenfluramine-induced aversions. Infusion of 6-OHDA into the substantia nigra, however, retarded the extinction of such an aversion. Evidence is discussed for a peripheral site of action for fenfluramine in the conditioned aversion paradigm.

Animals↗
PubMed1979

Evaluation of the non-specific effects of catecholamine and serotonin neurotoxins by injection into the medial forebrain bundle of the rat.

Low doses of 6-hydroxydopamine (6-OHDA), 5,6-dihydroxytryptamine (5,6-DHT) and 5,7-dihydroxytryptamine (5,7-DHT) that have previously been shown to produce behavioral change following intracerebral infusion were injected into the medial forebrain bundle of the rat. This site contains serotonin (5-HT), norepinephrine (NE), and dopamine (DA) fibers whose anatomical locations have been described. Damage to these fiber systems was quantified by measuring depletion of telencephalic 5-HT, NE and DA. The effects of infusions of 6-OHDA, 5,6-DHT and 5,7-DHT were compared to the effects of unequivocally non-specific electrolytic lesions and copper sulfate infusions. Survival time was varied to evaluate the amount of regeneration that could be expected over periods from 8 to 60 days. Amine levels were found to be stable over the time period examined. With the doses used, evidence was found to support the position that non-specific damage caused by general cytotoxic effects of 6-OHDA and 5,7-DHT is minimized sufficiently to permit the acquisition of useful data on the function of central catecholamine and indoleamine systems.

5,6-Dihydroxytryptamine↗
PubMed1979

Effects of goldthioglucose lesions on central catecholamine levels in the mouse.

Male and female C57 B1/6J mice were injected with goldthioglucose (GTG) to induce an obesity syndrome. Significant increases in body weight were inversely correlated with pituitary dopamine (DA) levels. Significant reductions in hypothalamic norepinephrine (NE) and DA were also noted; however, these reductions did not appear to be related to body weight gain. The GTG injections did not produce any significant alterations in telencephalic NE or DA. The damage to catecholamine neurons is discussed in relation to the endocrine abnormalities of the GTG mouse and some current hypotheses on the control of food intake.

Animals↗
PubMed1979

Differential effects on body weight of central 6-hydroxydopamine lesions in obese (ob/ob) and diabetes (db/db) mice.

Obese (ob/ob) and diabetes (db/db) mice are genetic mutants that have been shown to have altered levels of central catecholamines as well as syndromes of obesity, hyperphagia, and hyperglycemia. Because of catecholamines, and particularly norepinephrine (NE), are implicated in the control of feeding, levels of central catecholamines were experimentally reduced in ob/ob and db/db mice to investigate the role of the catecholamines in these cases of spontaneously occurring obesity. Lesions produced by 6-hydroxydopamine (6-OHDA) were used to produce large depletions of NE and dopamine (DA) in both ob/ob and db/db mice and in lean control mice of the same background strains. In the db/db but not the ob/ob, central catecholamine depletion was accompanied by a significant and persistent weight loss and by a reduction in plasma glucose levels when compared with vehicle-infused controls. Treatment with the NE uptake blocker desmethylimipramine (DMI) prior to 6-OHDA infusions attenuated NE but not DA depletion. Diabetes mice that received DMI pretreatment showed a weight loss and decrease in plasma glucose proportional to the amount of NE depletion. Lean mice that received the 6-OHDA treatments showed only a transient weight loss and no significant change in blood glucose. It is concluded that abnormalities in central noradrenergic systems may account for part of the obesity syndrome observed in the diabetes mouse.

Animals↗
PubMed1978

Alteration of the characteristics of learned taste aversion by manipulation of serotonin levels in the rat.

Electrolytic lesions placed in the dorsal and median raphe nuclei of the rat brain deplete hypothalamic and telencephalic serotonin. These lesions also enhance the learned suppression of saccharin consumption which results from pairing the ingestion of a saccharin solution with the injection of a toxic drug. Pretreatment of rats with raphe lesions with the serotonin precursor DL-5-hydroxy-tryptophan (5HTP) immediately prior to the conditioning trial blocks the learning of the aversion to saccharin. In normal rats, 5HTP pretreatment also attenuates the suppressive effects of conditioning on saccharin drinking. These results differ from the findings of previous research using the flinch-jump technique. When sensitivity to shock is measured, 5HTP pretreatment in rats with forebrain serotonin depletion has been reported to restore both serotonin levels and behavior to normal. No behavioral effects are observed in normal animals. Possible explanations for the differential effects obtained in the two paradigms are discussed.

5-Hydroxytryptophan↗