Biomedical subjects

H C Fibiger

Publications and source records attributed to H C Fibiger.

At least 181 records · Page 10Linked to original sources

PubMed1984

Force requirements in lever-pressing and responding after haloperidol.

One hypothesis regarding the actions of neuroleptic drugs on operant responding is that they interfere in some manner with the motoric capability of the animal. To further explore this possibility, we investigated the effects of haloperidol on a bar press response after animals were trained on levers with different force requirements. In the first experiment, two groups of rats were trained to press levers having either low (30 g) or high (100 g) force requirements. The effects of haloperidol on bar pressing when both groups were responding on the light lever were then examined. Under these conditions, the groups showed similar declines in response rates, indicating little transfer between previous experience on the heavy lever and responding in the presence of haloperidol. In the second experiment, the same groups of rats received further training exclusively on either the heavy or the light lever; the rate of responding was similar for the two groups. The effects of haloperidol on pressing either the heavy or the light lever were then examined. It was found that the rate-decreasing effects of haloperidol were similar in both groups. However, when the lever-pressing response was subsequently extinguished, rats working on the heavy lever were significantly more resistant to extinction than the light lever groups. The results of these experiments fail to indicate that the putative motoric effects of haloperidol interact significantly with response force demands. Furthermore, the data provide yet further evidence that blockade of dopamine receptors and removal of reinforcement are not equivalent.

Animals↗

PubMed1984

Spontaneous and delayed spatial alternation following damage to specific neuronal elements within the nucleus medianus raphe.

Previous studies have shown that rats with electrolytic lesions of the nucleus medianus raphe (MR) show alterations in spontaneous alternation and in the acquisition of a delayed spatial alternation task. The current study was designed to investigate whether these changes are secondary to forebrain serotonin depletion or if they are due to the destruction of MR cells or fibers of passage within the region of the MR. To this end, rats were prepared with either an electrolytic lesion of the nucleus, or were given an intra-MR injection of either the serotonin neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) or the excitotoxin ibotenate. Rats were then tested for the presence of spontaneous alternation in a T-maze, and were subsequently also trained on a contingently-reinforced delayed alternation task. Only the group with electrolytic lesions showed significant response perseveration in the spontaneous alternation task, although both the electrolytic and ibotenate groups were impaired in acquiring the delayed alternation task. Rats with 5,7-DHT injections performed comparable to controls in both tasks despite the fact that forebrain serotonin levels in this group were reduced at least as much as in the other two lesioned groups. These results suggest that these behavioral effects of MR lesions are due to the destruction of non-serotonergic fibers and/or cells within the region of the nucleus.

5,7-Dihydroxytryptamine↗

PubMed1984

The neurobiological substrates of depression in Parkinson's disease: a hypothesis.

Evidence from a variety of sources indicates that the mesolimbic-mesocortical dopamine projections may play an important role in some types of reward or reinforcement processes in animals. There is circumstantial evidence that this is also true in humans. Since a reduced ability to experience pleasure or reward (i.e. anhedonia) is a cardinal feature of clinical depression, and since the mesolimbic and mesocortical dopamine projections have been shown to degenerate in Parkinson's disease, it is suggested that damage to these reward-related systems may contribute directly to the high incidence of depression that has been reported in this disease.

Animals↗

PubMed1983

NADPH-diaphorase: a selective histochemical marker for the cholinergic neurons of the pontine reticular formation.

Choline acetyltransferase immunohistochemistry has identified a large group of cholinergic neurons in the pontine tegmentum. By combined immunohistochemical and enzyme histochemical studies this particular cholinergic cell group was found to contain an enzyme, NADPH-diaphorase, that can be visualized histochemically. Thus NADPH-diaphorase histochemistry provides a simple, reliable method to selectively stain the cholinergic neurons of the brainstem reticular formation. The resolution obtained by this novel histochemical technique is similar to that found with the Golgi stain, and it should therefore be of great value in morphological studies of this cholinergic cell group.

Animals↗

PubMed1983

Dopaminergic mediation of reward produced by direct injection of enkephalin into the ventral tegmental area of the rat.

A conditioned place preference paradigm was employed to demonstrate the rewarding property of unilateral injections of 200 ng (D-ala2)-met5-enkephalinamide into the ventral tegmental area of the rat brain. This effect was attenuated in a dose-related manner by systemic injections of the dopamine receptor blocker haloperidol. In addition, selective lesions of the ascending dopamine (DA) pathways ipsilateral to the injection site blocked the rewarding effect when DA levels were reduced by more than 90%. Similar lesions in the contralateral hemisphere had no influence on this behavior. These data suggest that forebrain DA pathways can mediate some of the rewarding properties of opioid drugs.

Animals↗

PubMed1983

Cholinergic-dopaminergic interactions and the mechanisms of action of antidepressants.

A series of experiments was performed to evaluate the mechanism(s) by which chronic administration of desipramine (DMI) facilitates the locomotor stimulant action of d-amphetamine, a response thought to be dependent on the mesolimbic dopaminergic system. Prior lesions of central noradrenergic or serotonergic neurons, induced by neonatal treatment with 6-hydroxydopamine (6-OHDA) or intraventricular injections of 5,7-dihydroxytryptamine (5,7-DHT) respectively, failed to block DMI-induced facilitation of amphetamine hypermotility. Chronic administration of DMI did not significantly influence specific [3H]spiperone binding in the striatum or the nucleus accumbens. In other experiments it was found that chronic administration of some (amitryptyline, imipramine, mianserin, iprindole) but not all (zimelidine, nomifensine, fluoxetine) antidepressants enhanced the locomotor response to d-amphetamine. The weak anticholinergic effects of the latter compounds suggest that the positive results obtained with the former drugs may be related to their anticholinergic properties. This hypothesis is consistent with the observation that chronic administration of scopolamine also increased the locomotor response to d-amphetamine. The results suggest that the facilitation by chronic DMI of amphetamine-induced locomotor activity is not mediated by primary actions of this tricyclic antidepressant on central noradrenergic or serotonergic systems. In addition, the results argue against an effect of DMI on dopamine receptors as measured by [3H]spiperone binding. Instead, the facilitation of the amphetamine response by some of these antidepressant compounds may be related to their anticholinergic effects.(ABSTRACT TRUNCATED AT 250 WORDS)

5,7-Dihydroxytryptamine↗

PubMed1983

Evidence against a role of the rat's dorsal noradrenergic bundle in selective attention and place memory.

In Experiment 1, 6-hydroxydopamine-induced lesions of the dorsal noradrenergic bundle (DNB) in rats did not impair either acquisition of non-delayed alternation, retention of non-delayed alternation, or performance of alternation with delays in a T-maze, whether or not the goal arms of the maze were visually distinctive. These results were in contrast with those of a previous report indicating that DNB lesions impair learning of spatial alternation. In Experiment 2, the lack of a reliable effect of DNB lesions on learning performance of spatial alternation was confirmed. However, the rats with DNB lesions showed an impairment of spontaneous alternation. The negative results of the present study do not support either the hypothesis that depletion of forebrain noradrenaline impairs selective attention or the hypothesis that such depletion induces an amnesia for past places. On the other hand, the finding of impaired spontaneous alternation is consistent with previous observations suggesting that depletion of forebrain noradrenaline impairs habituation of fear reactions.

Afferent Pathways↗

PubMed1983

An analysis of neuronal elements within the median nucleus of the raphe that mediate lesion-induced increases in locomotor activity.

Electrolytic lesions of the median nucleus of the raphe (MR) are known to result in large increases in motor activity. The present studies were concerned with identifying the neuronal elements within or near the MR (e.g. fibers of passage, serotonergic or non-serotonergic cells) which, when destroyed, lead to these increases in ambulation. Groups of rats were given either an electrolytic MR lesion or were injected locally with the serotonin neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) or the excitotoxin ibotenic acid, and their subsequent locomotor activities were compared in the open field and in photocell cages. In a 5 min open field test, rats with either electrolytic or ibotenate lesions of the MR were more active compared to all other groups, although rats in the former group were also more active than those in the latter. In a longer activity test conducted in photocell cages, rats with electrolytic lesions were more active than all other groups during the first 20 min period, after which their activity did not differ from the ibotenate group; however, both of these groups were hyperactive compared to all others. Both electrolytic and ibotenate groups showed exaggerated hyperactivity in response to D-amphetamine. Lesions produced by 5,7-DHT failed to significantly increase either spontaneous or D-amphetamine-induced locomotor activity. When the results from all of the activity measures are considered, it appears that damage to at least two different neuronal populations may be responsible for the hyperactivity observed in MR lesioned rats. However, damage to the serotonergic system does not appear to contribute to these locomotor effects.

5,7-Dihydroxytryptamine↗

PubMed1983

Histochemical demonstration of separate populations of somatostatin and cholinergic neurons in the rat striatum.

Striatal neurons containing acetylcholine and somatostatin were examined using a pharmacohistochemical procedure for acetylcholinesterase and NADPH-diaphorase histochemistry respectively. The use of these two histochemical procedures allowed both cholinergic and somatostatin cells to be visualized simultaneously in single sections of the striatum. The results indicate that somatostatin and acetylcholine are contained in separate populations of striatal neurons and illustrate the utility of simple histochemical procedures to visualize biochemically defined neurons.

Acetylcholine↗

PubMed1983

Attenuation of heroin reward in rats by disruption of the mesolimbic dopamine system.

The rewarding properties of systemically administered heroin were investigated with a conditioned place-preference paradigm. Reinforcing effects were observed with all doses of heroin tested (0.5, 1.0, 2.0 mg/kg) as indicated by a significant increase in preference for the place paired with drug injections. No similar change in preference was observed following saline injections. The rewarding effect of heroin (2 mg/kg) was attenuated by pretreatment with haloperidol (0.2 mg/kg), but haloperidol alone did not produce a place aversion. Lesions induced by 6-hydroxydopamine (6-OHDA) of the mesolimbic dopaminergic pathway at the level of the nucleus accumbens also attenuated the heroin-induced place preference. In contrast, depletion of central and peripheral noradrenaline induced by 6-OHDA had no significant effect on heroin-induced place preference. These data suggest an important role for the mesolimbic DA system in mediating the reinforcing effects of heroin.

Animals↗

PubMed1983

The effects of dose and duration of chronic pimozide administration on dopamine receptor supersensitivity.

The neuroleptic drug pimozide was administered chronically to rats at different doses (0.75, 1.5 or 3.0 mg/kg, twice daily for 10 days) or for different durations (1.5 mg/kg twice daily for 5, 10, 20 or 40 days). At various intervals (4-40 days) after withdrawal dopamine (DA) receptor density in the striatum was assessed directly using specific [3H]-spiroperidol binding and indirectly by means of apomorphine-induced stereotypy and amphetamine-induced locomotor activity. The increase in the density of DA receptors was shown to be dependent upon the dose but not upon the duration of chronic pimozide. In contrast, the enhanced apomorphine-induced stereotypy was influenced by the duration but not by the dose of chronic pimozide. The potentiation of d-amphetamine-induced locomotor activity was found to vary as a function of both dose and duration of chronic pimozide administration. The results indicate that the augmentation of these apomorphine- and amphetamine-induced behaviors cannot be attributed solely to striatal DA receptor supersensitivity and that other, presently unspecified factors must contribute. It is also argued that in the absence of pharmacologically-induced DA receptor stimulation, the functional consequences of neuroleptic-induced increases in the density of striatal DA receptors are not apparent and remain unknown. In addition, these findings support the view that neuroleptic-induced proliferation of DA receptors cannot be the sole mechanism underlying tardive dyskinesia in man.

Animals↗

PubMed1983

The effects of estrogen on apomorphine-induced hypothermia and stereotypy in the rat.

The effects of various doses of estrogen on apomorphine (Apo)-induced hypothermia and stereotypy were investigated in ovariectomized rats. Daily administration of estradiol (5, 15 or 100 micrograms/kg) for 4 days or estradiol (100 micrograms/kg) for 3 days, followed by 4 and 72 hr withdrawal periods respectively, had no effect on apomorphine-induced hypothermia or stereotypy in a cold (4 degrees C) environment, although both effects were blocked by haloperidol. Large doses of estradiol (100 micrograms/kg) given for 3 days, followed by either 24 or 72 hr withdrawal, slightly attenuated apomorphine-induced stereotypy at 22 degrees C. Stereotypy observed at 22 degrees C was of greater magnitude than that seen at 4 degrees C. The results indicate that although high, non-physiological levels of estrogen may attenuate striatal-dependent stereotypies, this hormone has no detectable influence on dopaminergic mechanisms in the preoptic-anterior hypothalamic regions that are thought to mediate apomorphine-induced hypothermia.

Animals↗

PubMed1983

Prior training and intermittent retraining attenuate pimozide-induced avoidance deficits.

Although the effects of neuroleptics on avoidance behavior have been studied extensively, no studies have systematically investigated the possible relationship between these effects and prior training. This paper reports the effects of prior training and intermittent retraining on pimozide-induced avoidance deficits. Experiment 1 investigated the effects of pimozide (0.5 or 1.0 mg/kg IP) on one-way avoidance responding in groups of rats (n = 15 or 16) that had received 0, 2, 3, or 10 prior sessions of training (10 trials per session). All trained groups were more resistant to the disruptive effects of the drug than the groups receiving no prior training but the 2, 3, and 10 session pretrained groups did not differ significantly from one another. However, the avoidance responding of the pretrained groups eventually was impaired across the 15 sessions of testing under the drug condition; this effect was shown not to be attributable to an accumulation of the drug with repeated dosing. Experiment 2 showed that periodic retraining in the absence of pimozide reversed the cumulative session-to-session disruptive effects of the low and high dose of pimozide on avoidance responding, a finding not previously reported. The results suggest that dopaminergic systems play a role in the acquisition and maintenance of operant response learning. Avoidance learning fails to occur if training is conducted in untrained, pimozide-treated animals. Pretrained animals, when injected with pimozide, can maintain avoidance responding for several sessions but lose this ability in the continued absence of normal dopamine function; however, intermittent retraining can prevent this eventual loss of avoidance responding.

Animals↗

PubMed1983

Forebrain noradrenaline and oral self-administration of ethanol by rats.

The effects of 6-hydroxydopamine-induced depletion of forebrain noradrenaline (NA) on oral intake of ethanol were studied in male Wistar rats. Prior depletion of NA produced a smaller and significantly less variable intake of a concentrated solution of ethanol than that of control rats, and this effect was not accompanied by hyperreactivity to aversive solutions of quinine. NA-depleted rats also displayed rejection 'thresholds' for ethanol solutions that were significantly lower than those of controls. Depletion of forebrain NA did not, however, affect the punishing effects of ethanol injections measured in the conditioned taste aversion paradigm. In contrast to these effects of NA depletion on initiation of ethanol intake, depletion of forebrain NA after a preference for ethanol had been established failed to affect subsequent intake of ethanol. These results suggest that forebrain NA is involved in the initiation of ethanol intake by naive rats but not in the maintenance of established patterns of intake by experienced rats. Possible mechanisms for this differential involvement of NA are discussed.

Alcohol Drinking↗

PubMed1983

Strategies for studying the neurochemical substrates of drug reinforcement in rodents.

Results from three different experimental paradigms for studying drug reinforcement are reviewed. Rate-increasing effects of amphetamine on intracranial self-stimulation are abolished by lesions to ascending dopamine neurons. Rate-increasing effects of intracranial microinjection of opioids on self-stimulation are localized to the vicinity of dopamine cell bodies in the ventral tegmentum. Conditioned reinforcement produced with intracranial microinjection of opioids into the ventral tegmental area is blocked by the dopamine antagonist haloperidol and lesions to ascending dopamine pathways. Intravenous self-administration of cocaine is blocked by intracerebral microinjection of spiroperidol into the nucleus accumbens but not into the caudate nucleus. Ascending dopamine neurons appear to mediate some of the reinforcing properties of both psychomotor stimulants and opioids.

Amphetamine↗

PubMed1983

Ultrastructural observations of the cholinergic neuron in the rat striatum as identified by acetylcholinesterase pharmacohistochemistry.

In order to examine the ultrastructural features of the cholinergic neuron in the striatum (caudatoputamen) of the rat, cytochemistry for acetylcholinesterase was conducted 2-12 h after intramuscular injection of the irreversible acetylcholinesterase inhibitor diisopropylphosphorofluoridate. Light microscopic examination of Epon sections reacted from acetylcholinesterase showed that only large-sized cells in the striatum (25-35 microns in the long axis) were stained intensely. In the case of longer survival periods (10-12 h), some lightly stained cells (medium-sized) were seen dispersed amongst the large acetylcholinesterase-rich cells. Electron microscopic observations were made on ultrathin sections of selected large acetylcholinesterase-rich neurons that were first studied by light microscopy. The nucleus of these cells has an eccentric position and possesses several indentations of the nuclear envelope. The cytoplasm contains abundant organelles, many exhibiting features unique to this cell type. Many stacks of granular endoplasmic reticulum, arranged in a parallel manner and forming typical Nissl bodies, were observed in the periphery of the perikarya, and many distinct golgi complexes were seen in the perinuclear zone. At all post-diisopropylphosphorofluoridate survival times, heavy deposits of acetylcholinesterase reaction product were found within the perikarya of this cell type, for the most part within the cisternae of the granular endoplasmic reticulum. At the longer post-diisopropylphosphorofluoridate survival times, reaction product within the cytoplasm was very dense and appeared to have reached a maximum level. At these times reaction product also appeared in the secondary and tertiary dendritic branches of the large-sized neurons. Of the other cell types in the striatum, two types of medium-sized cells displayed a light deposit of reaction product in their perikarya, but this was observed only at longer recovery times (8-12 h). The majority of cells in the striatum lacked reaction particles. Throughout the early post-diisopropylphosphorofluoridate period, the recovery of enzyme activity in the neuropil was moderate compared to that seen within cell bodies. These findings indicate that the large-sized neuron is the only striatal structure that shows rapid regeneration of acetylcholinesterase activity during the early recovery phase after diisopropylphosphorofluoridate administration. Previous studies have indicated that this type of neuron represents the cholinergic interneuron of the striatum. (ABSTRACT TRUNCATED AT 400 WORDS)

Acetylcholine↗

PubMed1983

A comparison of the distribution of central cholinergic neurons as demonstrated by acetylcholinesterase pharmacohistochemistry and choline acetyltransferase immunohistochemistry.

The topographical distribution of cholinergic cell bodies has been studied in the rat brain and spinal cord by choline acetyltransferase (ChAT)-immunohistochemistry and acetylcholinesterase (AChE)-pharmacohistochemistry using diisopropylfluorophosphate (DFP). The ChAT-containing cells and the cells that stained intensely for AChE 4-8 hr after DFP were mapped in detail on an atlas of the forebrain (telencephalon, diencephalon) hindbrain (mesencephalon, rhombencephalon) and cervical cord (C2, C6). Striking similarities were observed between ChAT-positive cells and neuronal soma that stained intensely for AChE both in terms of cytoarchitectural characteristics, and with respect to the distribution of the labelled cells in many areas of the central nervous system (CNS). In the forebrain these areas include the caudatoputamen, nucleus accumbens, medial septum, nucleus of the diagonal band, magnocellular preoptic nucleus and nucleus basalis magnocellularis. In contrast, a marked discrepancy was observed in the hypothalamus and ventral thalamus where there were many neurons that stained intensely for AChE, but where there was an absence of ChAT-positive cells. No cholinergic perikarya were detected in the cerebral cortex, hippocampus, amygdala and dorsal diencephalon by either histochemical procedure. In the hindbrain, all the motoneurons constituting the well-established cranial nerve nuclei (III-VII, IX-XII) contained ChAT and exhibited intense staining for AChE. Further, a close correspondence was observed in the distribution of labeled neurons obtained by the two histochemical procedures in the midbrain and pontine tegmentum, including the laterodorsal tegmental nucleus, some areas in the caudal pontine and bulbar reticular formation, and the central gray of the closed medulla oblongata. On the other hand, AChE-intense cells were found in the nucleus raphe magnus, ventral part of gigantocellular reticular nucleus, and flocculus of the cerebellum, where ChAT-positive cells were rarely observed. According to both techniques, no positive cells were seen in the cerebellar nuclei, the pontine nuclei, or the nucleus reticularis tegmenti pontis. Large ventral horn motoneurons and, occasionally, cells in the intermediomedial zone of the cervical cord displayed ChAT-immunoreactivity and intense AChE staining. On the other hand, AChE-intense cells were detected in the dorsal portion of the lateral funiculus, but immunoreactive cells were not found in any portion of the spinal cord white matter.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetylcholine↗

PubMed1983

Intact selective attention in rats with lesions of the dorsal noradrenergic bundle.

Mason's hypothesis (1980) was tested that lesions of the dorsal noradrenergic bundle (DNB), which induce depletion of forebrain noradrenaline, alter performance of discrimination tasks because they retard habituation to naturally attractive, but instrumentally irrelevant, stimuli. In Experiment 1, groups of rats with either vehicle or 6-hydroxydopamine injections into the DNB were assigned to five different discrimination tasks in a cross-maze with black and white goal arms. The tasks were acquisition and reversal of position, visual, or turn discrimination, and acquisition of visual or turn discrimination followed by a shift to the alternative discrimination. In spite of evidence that the rats preferred to attend more to the visual stimuli of the goal arms than to directions of turns, lesions of the DNB did not impair acquisition and reversal of turn discrimination with visual stimuli irrelevant, and did not facilitate performance of turn-to-visual shift. In fact, the lesions did not alter performance of any tasks. In Experiment 2, control and noradrenaline-depleted rats were trained in a task of light-dark discrimination followed by shift to position discrimination in a Y-maze. At the onset of training, the rats of both groups reliably avoided the bright goal arm and responded to the dark goal arm, thus demonstrating predominant attention for the relevant brightness stimuli rather than the irrelevant position stimuli. The DNB lesions impaired acquisition of brightness discrimination only when the positive stimulus was the illuminated goal arm, and they did not alter shift performance. These results do not support the hypothesis at test. On the other hand, they indicate that DNB lesions in the rat can impair habituation of light avoidance.

Animals↗