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Biomedical subjects

H C Fibiger

Publications and source records attributed to H C Fibiger.

At least 199 records · Page 11Linked to original sources
PubMed1983

Striatal GABAergic neuronal activity is not reduced in Parkinson's disease.

The content of gamma-aminobutyric acid (GABA) and the activities of glutamic acid decarboxylase (GAD) and tyrosine hydroxylase (TH) were measured in whole putamen obtained at autopsy from 13 patients dying with idiopathic Parkinson's disease and 13 appropriate control subjects. Mean GABA content was significantly elevated (by 28%) in the putamen of the Parkinson's disease patients. TH activity was markedly reduced, while there was no significant reduction of GAD activity in the putamen of these patients. GABA content was also measured in both sides of the striatum in rats which had received unilateral injections of 6-hydroxydopamine (6-OHDA) in the vicinity of the axons of the nigrostriatal projection. Mean GABA content was found significantly elevated (by 33%) in the ipsilateral striatum. Loss of dopaminergic nigrostriatal neurons, in both human Parkinson's disease and in the rat 6-OHDA model, is accompanied by increased striatal GABA content. The assumption that GABAergic neurotransmission is reduced in the striatum in Parkinson's disease may not be correct.

Amino Acids↗
PubMed1982

Dopaminergic substrates of amphetamine-induced place preference conditioning.

The conditioned place preference paradigm was used to study the reinforcing properties of D-amphetamine. Rats were injected (i.p.) with D-amphetamine sulphate (0.5, 1.0 or 5.0 mg/kg) and 10 min later confined for 30 min to one side of a shuttle box in which each of the two compartments had distinctive features. On alternate (control) days they received saline injections and were confined for 30 min to the opposite side. At all doses D-amphetamine produced place preference for the distinctive compartment that previously had been associated with the drug. Pretreatment with haloperidol (0.15 or 1.0 mg/kg) antagonized the place preference produced by amphetamine (1.5 mg/kg). By itself, haloperidol (0.15 or 1.0 mg/kg) did not produce place aversion. In separate experiments the D-amphetamine-induced place preference was examined in rats that had received 6-hydroxydopamine (6-OHDA) lesions of the nucleus accumbens. Animals with the greatest depletion of dopamine did not show preference for the compartment associated with D-amphetamine. Furthermore, the time spent on the amphetamine-reinforced side correlated significantly with the levels of dopamine remaining in the nucleus accumbens but not with the dopamine content in the striatum. Depletion of peripheral catecholamines by systemic injections of 6-OHDA did not affect D-amphetamine-induced place preference conditioning. Other groups of animals that received the dopamine receptor agonist, apomorphine, also developed a conditioned preference for the compartment that had been associated with the drug treatment. These findings support the view that the reinforcing effects of D-amphetamine are mediated by central dopamine-containing neurons, and in particular those of the mesolimbic system.

Animals↗
PubMed1982

Cocaine-induced place preference conditioning: lack of effects of neuroleptics and 6-hydroxydopamine lesions.

The conditioned place preference paradigm was used to investigate the reinforcing properties of cocaine. Rats were injected (i.p.) with cocaine hydrochloride (0.625-20 mg/kg) and then immediately confined for 30 min to one side of a shuttle box in which each of the two compartments had distinctive features. On alternate (control) days they received saline injections and were confined for 30 min to the opposite side. Cocaine produced a significant, dose-related preference for the distinctive environment that previously had been paired with the drug. Pretreatment with pimozide (0.5 or 1.0 mg/kg) or haloperidol (1.0 mg/kg), both of which blocked the locomotor stimulant effects of cocaine, failed to influence place preference produced by cocaine (5.0 mg/kg). In addition, neither 6-hydroxydopamine lesions of dopamine terminals in the nucleus accumbens nor 6-hydroxydopamine-induced destruction of central and/or peripheral noradrenergic systems affected cocaine-induced place preference conditioning. In other experiments it was found that injections of the local anaesthetic procaine, at doses that did not affect locomotor activity (25 and 50 mg/kg), also resulted in significant place preference conditioning. It is concluded that cocaine can produce place preference conditioning through a mechanism that is independent of its effects on catecholamine-containing neurons and that may be related to its local anaesthetic properties. It is noted, however, that if cocaine's local anaesthetic properties could be blocked selectively, the drug might still produce place preference conditioning through its enhancement of central dopaminergic function.

Animals↗
PubMed1982

Crossed connections of the substantia nigra in the rat.

The existence of crossed multisynaptic pathways that allow for the interdependent control of activity in one substantia nigra and its contralateral counterpart has been inferred from a number of recent biochemical and neurophysiological investigations. This prompted a reexamination of the connections of the substantia nigra with an emphasis on crossed inputs to and crossed projections from that nucleus. Male albino rats received 20-50-nl pressure injections of a 1% wheat germ agglutinin-conjugated horse-radish peroxidase (WGA-HRP) solution into the substantia nigra or into surrounding areas as controls. Following a 24-hour survival period the animals were processed according to the tetramethylbenzidine protocol for the visualization of HRP. The pattern of anterograde transport of WGA-HRP after substantia nigra injections, confirming for the most part previous reports, demonstrated ipsilateral nigral efferent projections to the striatum; globus pallidus; subthalamic nucleus; the lateral dorsal, paralamellar mediodorsal, ventromedial, and parafascicular thalamic nuclei; central gray, midbrain reticular formation; superior colliculus; and peribrachial area, including the pedunculopontine nucleus. Additionally, the nigral projections to the paralamellar mediodorsal and ventromedial thalamic nuclei and to the superior colliculus were demonstrated to be bilateral. Most of these connections were confirmed by the complementary retrograde experiment. In accordance with previous reports, intranigral WGA-HRP injections retrogradely labeled neurons located in the ipsilateral prefontal cortex, motor cortex, striatum, globus pallidus, central nucleus of the amygdala, anterior hypothalamic area, subthalamic nucleus, and dorsal raphe. Additionally, labeled perikarya were observed in the ipsilateral parafascicular thalamic nucleus, in the contralateral posterior lateral hypothalamic area, and in the ipsilateral and contralateral peribrachial-pedunculopontine area. These latter nigral afferents were confirmed with complementary WGA-HRP injections into each of the regions of origin. While bilateral peribrachial-pedunculopontine innervation of the substantia nigra has been reported in the cat there has been no previous demonstration of a crossed nigral afferent system from the contralateral posterior lateral hypothalamic area. The results are discussed with reference to the pathways that may mediate the interdependent control of the activity of neurons in the left and right substantia nigra. Additionally, the association of the substantia nigra with a variety of neuronal circuits, including the cerebellofugal, tectothalamic, thalamocortical, thalamostriatal, and basal ganglia pathways, are discussed.

Animals↗
PubMed1982

Alterations in drug induced catalepsy and post-decapitation convulsions following brain and spinal cord depletion of norepinephrine by the neurotoxin DSP-4.

The effects of central norepinephrine depletion produced by DSP-4 on drug-induced catalepsy and pot-decapitation convulsions were examined in the rat. Haloperidol-induced catalepsy was potentiated in DSP-4 treated rats, while arecoline-induced catalepsy was attenuated. Furthermore, post-decapitation convulsions were eliminated in DSP-4 treated animals. DSP-4 may prove to be a useful tool with which to investigate the behavioral consequences of damage to the locus coeruleus noradrenergic system.

Amines↗
PubMed1982

On the use of lesions of afferents to localize neurotransmitter receptor sites in the striatum.

Rats received lesions of either the cortico-striatal or the nigrostriatal projections. Two to three days after either type of lesion, evidence for degenerating dendritic spines that were postsynaptic to degenerating striatal boutons was often encountered. This type of transsynaptic degeneration of spines indicates that it is inappropriate to conclude that decreases in the number of neurotransmitter receptors after these types of lesions necessarily indicates that these receptors are located presynaptically on striatal afferents.

Afferent Pathways↗
PubMed1982

Attenuation by haloperidol of place preference conditioning using food reinforcement.

The place preference conditioning paradigm was used to examine the reinforcing properties of food in hungry rats. Availability of food in one of two distinctive environments increased the amount of time they spent in the environment associated with food in a test when the animals were no longer food deprived and neither environment contained food. Pretreatment with haloperidol (0.1 or 0.2 mg/kg) during the conditioning phase blocked the establishment of place preference even though the animals consumed the food in the drugged state. The results are interpreted as demonstrating a role for dopamine-containing neurons in mediating the reinforcing properties of food.

Animals↗
PubMed1982

Clonidine-induced sedation in rats: evidence for mediation by postsynaptic alpha 2-adrenoreceptors.

The effect of low doses of clonidine on exploration and motility was investigated in rats after destruction of central noradrenergic systems by 6-hydroxydopamine (6-OHDA) or DSP-4. In accordance with previous results, clonidine decreased exploration and motility in control animals. This sedative effect of clonidine was potentiated in animals that suffered selective and extensive depletions of brain NA as a result of neonatal treatment with 6-OHDA. Depletion of NA by administration of DSP-4 to adult animals did not influence clonidine's sedative effects. Yohimbine, but not phentolamine, antagonized clonidine-induced hypomotility both in control and in neonatal 6-OHDA treated groups. The results suggest that clonidine-induced sedation is mediated by postsynaptic alpha 2-adrenoreceptors.

Adrenergic alpha-Antagonists↗
PubMed1982

The inhibitory effect of diazepam on conditioned defensive burying is reversed by picrotoxin.

The ability of picrotoxin to reverse the effect of diazepam was studied using the conditioned defensive burying paradigm. Although picrotoxin alone had no detectable effect on the conditioned defensive burying response of rats, picrotoxin was able to reverse the usual inhibitory effect of diazepam on defensive burying. These results suggest that the anxiolytic effect of diazepam may depend upon the integrity of GABAergic neural systems.

Animals↗
PubMed1982

The effect of DSP-4 on some positively reinforced operant behaviors in the rat.

The effects of a new neurotoxin for noradrenergic (NA) neurons, DSP-4, on the acquisition, retention and extinction of positively reinforced operant responses were studied in rats. The acquisition of an L-shaped runway task for food reward, of a simultaneous light-dark discrimination in a Y-maze task and of a lever press response for food was not affected in DSP-4 treated animals. No deficit in retention behavior was found in the Y-maze task after DSP-4 treatment. The DSP-4 treated animals showed increased resistance to extinction in the L-shaped runway. However, the extinction of the lever press response for food (CRF) was unaffected in the same animals. In accordance with previous results, DSP-4 resulted in a widespread depletion of NA in cortex, hippocampus, cerebellum and spinal cord. One week after the DSP-4 administration, histochemical studies at the light microscopic level indicated that the cell bodies of the locus coeruleus remained intact in DSP-4 treated animals. Desipramine pretreatment provided only partial protection from the neurotoxic effects of DSP-4. The results are discussed in relation to the mechanism by which DSP-4 produced the long-term depletion of central NA ans with reference to the role of central NA neurons in behavior.

Amines↗
PubMed1982

Enhanced neophobia but normal plasma corticosterone levels in rats with dorsal noradrenergic bundle lesions.

The effects of dorsal noradrenergic bundle (DNB) lesions on plasma corticosterone levels were determined in male albino rats. DNB lesions did not affect baseline plasma corticosterone levels. Furthermore, the increased corticosterone levels produced by various environmental manipulations did not differ between control and DNB lesioned groups. However, the lesioned group did exhibit longer latencies to eat familiar food in novel environments, as well as to eat novel foods in a familiar environment. Latencies to eat novel food in novel environments did not differ between the two groups and this was attributed to a "ceiling" effect. These endocrinological data fail to support the hypothesis that the enhanced "neophobia" observed in DNB lesioned rats is due to an increase in the intensity of the emotional reaction to novel stimuli. The data do not preclude the possibility, however, that the enhanced neophobic reactions reflect impaired habituation to these stimuli.

Animals↗
PubMed1982

Effects of kainic acid lesions of the striatum on self-stimulation in the substantia nigra and ventral tegmental area.

Unilateral kainic acid lesions of the dorsal striatum provided evidence for a dissociation of neural substrates of brain-stimulation reward at sites in the ventral tegmental area and substantia nigra. The lesions caused a significant increase in current intensity thresholds at substantia nigra placements, whereas similar lesions had no effect on self-stimulation thresholds at sites in the ventral tegmentum. In addition, the rate-increasing effects of D-amphetamine (0.1-1.0 mg/kg) on self-stimulation were determined before and after lesions to the dorsal striatum. No significant changes in dose-response curves were observed at either loci. Amphetamine-induced rotation was used to confirm damage to the dorsal striatum and lesioned animals were observed to rotate towards the side of the lesion. In contrast, sham-lesioned animals showed turning away from the side stimulated electrically in previous tests. The results of the self-stimulation and rotation experiments are discussed in the context of neural substrates of reward and motor activity.

Animals↗
PubMed1981

Increased intracranial self-stimulation in rats after long-term administration of desipramine.

The effects of long- and short-term administration of the tricyclic antidepressant desipramine on intracranial self-stimulation in rats were studied with electrodes in the A10 region of the dopamine-containing cell bodies of the ventromedial tegmentum. Long-term desipramine administration resulted in a significant shift to the left in the ascending portion of the rate--current intensity function, indicating that the activity of the mesolimbic dopamine system was enhanced. These findings point to a possible dopaminergic mechanism of action of antidepressants and support speculations concerning the role of dopamine-containing neurons in the pathophysiology of depression.

Animals↗
PubMed1981

Kainic acid injections in the striatum alter the cataleptic and locomotor effects of drugs influencing dopaminergic and cholinergic systems.

Rats with bilateral injections of kainic acid into the striatum were tested for their motor responsiveness to drugs influencing dopaminergic and cholinergic systems. The kainic acid-induced lesions potentiated the locomotor response to both the dopaminergic agonist, d-amphetamine, and the cholinergic antagonist, scopolamine, attenuated the cataleptic response to the dopaminergic antagonist, haloperidol, and potentiated the cataleptic acid and convulsive responses to the cholinergic agonist, pilocarpine. The analogy of these pharmacological effects with those induced by similar drugs in patients with Huntington's disease supports the view that this animal preparation is a useful model of Huntington's disease. The opposite effects of haloperidol and pilocarpine on catalepsy in kainic acid-lesioned rats suggest that more work should be done to elucidate the mechanism behind this conflict before full support can be given to its use as a model system for evaluating possible pharmacotherapy in Huntington's disease.

Animals↗
PubMed1981

Behavioural evidence for supersensitivity of postsynaptic dopamine receptors in the mesolimbic system after chronic administration of desipramine.

The effects of acute and chronic administration of desipramine (DMI) on a number of behaviors thought to be dependent on central dopaminergic (DA) systems were examined in the rat. Chronic but not acute administration of DMI potentiated the locomotor response to d-amphetamine within a narrow dosage range. The potentiation of the amphetamine response was observed up to 5 days after cessation of chronic DMI but had nearly returned to baseline by 10 days. Neither amphetamine- nor apomorphine-induced stereotypy was affected by chronic DMI. Chronic administration of iprindole but not fluoxetine potentiated amphetamine-induced locomotor activity. Chronic DMI administration did not affect the concentration or distribution of [3H]d-amphetamine in the brain. Furthermore, residual anticholinergic effects of DMI did not appear to be responsible for the potentiated amphetamine response. Chronic administration of DMI did not significantly influence the hypomotility induced by low doses of apomorphine. The increased locomotor activity and rearing produced by moderate doses of apomorphine were significantly increased by chronic DMI administration. The results suggest that chronic DMI may produce supersensitivity of postsynaptic receptors in the mesolimbic DA projection, a system that has been associated with the mediation of amphetamine- and apomorphine-induced increases in locomotor activity. There was no evidence for subsensitivity of presynaptic DA receptors after DMI. The findings are discussed with reference to the possible role of central DA neurons in the antidepressant mechanism of action of the tricyclic compounds.

Animals↗
PubMed1981

Body weight and dietary factors in Huntington's disease patients compared with matched controls.

A longitudinal study using medical records has confirmed that, even when eating high energy diets, loss of body weight is characteristic of Huntington's disease patients in comparison with a group of matched control subjects. Further analysis showed that although some Huntington's disease patients initially may gain weight rapidly after a period in hospital, they eventually lose weight to below their admission levels. This pattern was not seen in the control group. The findings are discussed in terms of striatal pathology.

Adult↗