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M Herrera-Marschitz

Publications and source records attributed to M Herrera-Marschitz.

At least 127 records · Page 7Linked to original sources
PubMed1985

Functional classification of different dopamine receptors.

A series of experiments is described in which behavioral models and intracerebral dialysis were used to study neurotransmitter release and which illustrate the functional properties of different dopamine receptors. Evidence is presented for the existence of postsynaptic D-1 dopamine receptors, which are preferentially stimulated by apomorphine and inhibited by SCH 23390, and postsynaptic D-2 receptors, which are preferentially stimulated by pergolide and inhibited by sulpiride. On the basis of results obtained following systemic and local treatment with picrotoxin it seems probable that D-2 receptors are located on GABA interneurons in the striatum. Furthermore, lesion studies indicate that the D-1 and D-2 receptors are related to different neuronal pathways. In contrast to postsynaptic dopamine receptors, presynaptic autoreceptors, as studied by recording the decrease in exploratory behavior and dopamine release, seem not to differ in their response to apomorphine and pergolide. Sulpiride selectively inhibits dopamine autoreceptors and is equally potent in inhibiting apomorphine and pergolide autoreceptor-dependent responses. In summary, the data strongly support the existence of functionally important D-1 and D-2 receptors.

Animals↗
PubMed1985

Chronic implants of chromaffin tissue into the dopamine-denervated striatum. Effects of NGF on graft survival, fiber growth and rotational behavior.

Adult rat chromaffin tissue was transplanted into striatum of adult rat recipients whose nigrostriatal dopamine pathway had been lesioned on the grafted side by 6-hydroxydopamine. Long-term survival of the intrastriatal chromaffin grafts and the effects of treatment with nerve growth factor (NGF) was studied histochemically using Falck-Hillarp fluorescence histochemistry and functionally using rotational behavior induced by apomorphine. Small, cortex-free adrenal chromaffin tissue grafts survived permanently in striatum. The number of surviving cells was significantly increased by NGF. NGF treatment also caused transformation of many cells towards a more neuronal phenotype and greatly enhanced the adrenergic nerve fiber outgrowth into host brain tissue. NGF was either injected stereotaxically into the site of transplantation or infused continuously using implantable osmotic minipumps and a stereotaxically placed chronic indwelling dialysis fiber through striatum. The latter arrangement permitted continuous infusion of NGF for 14-28 days and caused a vigorous adrenergic nerve growth response by the grafts directed towards the source of NGF in the brain. There was a clearcut correlation between morphological signs of taking and rotational behavior. Grafts, and in particular grafts treated with NGF, were able to significantly and permanently counteract the rotational behavior induced by apomorphine. There seemed to be a dose relationship between NGF treatments and amount of reduction of asymmetric behavior. NGF treatment probably decreased the relative importance of diffuse release of catecholamines from chromaffin cells in the graft and increased the importance of adrenergic innervation of host striatum by cells in the graft. Immunofluorescence using antibodies against glial fibrillary acidic protein did not reveal any marked gliosis around the grafts nor were there any marked gliotic reactions around chronic indwelling dialysis fibers. We conclude that implantation of chromaffin tissue into striatum in conjunction with NGF treatments is an effective means of counteracting some of the symptoms of experimentally induced unilateral parkinsonism in rats.

Adrenal Medulla↗
PubMed1985

Rotational behaviour elicited by intracerebral injections of apomorphine and pergolide in 6-hydroxy-dopamine-lesioned rats. I: Comparison between systemic and intrastriatal injections.

Rotational behaviour in unilaterally 6-hydroxy-dopamine-denervated rats has been attributed to stimulation of dopamine receptors on striatal as well as limbic areas. In the present study the rotational behaviour elicited by local intrastriatal injections of apomorphine or pergolide was compared to the rotation elicited by systemic injections of the drugs. We found that intrastriatal injections induced rotational behaviour almost identical to the behaviour occurring after systemic treatment. Furthermore, studies of the spread of [3H]apomorphine in brain tissue showed that at the peak of rotation the radioactivity was confined within the limits of the striatum. Non-significant amounts of radioactivity was found in the nucleus accumbens. On the basis of these data we conclude that rotational behaviour elicited by systemic injections of apomorphine or pergolide originates from stimulation of striatal sites. The difference in rotational patterns elicited by these drugs is more likely to relate to differences in receptor stimulation within the striatum than differences in, for example, relative distribution between limbic and striatal areas.

Animals↗
PubMed1985

Rotational behaviour elicited by intracerebral injections of apomorphine and pergolide in 6-hydroxy-dopamine-lesioned rats. II: The striatum of the rat is heterogeneously organized for rotational behaviour.

The present study compares the role of the nucleus accumbens and the striatum, as well as various regions of the striatum, in the ability of intracerebral injections of the dopamine agonists apomorphine and pergolide to elicit rotational behaviour in 6-hydroxy-dopamine-lesioned rats. We found that apomorphine and pergolide elicit rotational behaviour when injected into the denervated striatum, but not when injected into the ipsilateral nucleus accumbens. The striatum seems heterogeneously organized as regards rotational behaviour since maximal-apomorphine rotation was elicited from the corpus of the striatum as compared to the effects produced by injections into the head and the tail of the striatum. This topographical distribution is similar to the distribution of dopamine-stimulated cyclic AMP. The pergolide response is more evenly distributed in the striatum. It is suggested that the difference in the topographical distribution of the ability of apomorphine and pergolide to elicit rotational behaviour reflects a regional distribution of dopamine receptors in the striatum of the rat.

Animals↗
PubMed1985

Neuroleptic drugs and their action on different neuronal pathways.

The occurrence of tardive dyskinesia has been related to treatment with most typical neuroleptic drugs. It has been hypothesized that risk of the disorder may be less with some atypical antipsychotic agents. Other contributing risk factors may include an underlying vulnerability of the nervous system. Understanding of these features of tardive dyskinesia should be enhanced through more information on functional differences between dopamine receptors and on how different types of antipsychotic drugs affect such receptors. In our animal studies, we have found evidence that dopamine D-1 and D-2 receptors are functionally linked to different behavioral phenomena in the rat, that they are differently affected by dopamine agonist and antagonist drugs, and that they may be selectively localized to different postsynaptic neuronal systems. We suggest that the development of antipsychotic drugs with a low risk of inducing tardive dyskinesia or of novel treatments for this condition may arise from improved understanding of the functions of various dopamine receptors in the brain.

Animals↗
PubMed1984

Evidence that striatal efferents relate to different dopamine receptors.

It was proposed that apomorphine and the ergot derivative pergolide induce rotation in 6-hydroxy-dopamine (6-OHDA)-denervated rats by different receptor mechanisms, since these dopamine agonists induce different patterns of rotational behaviour, have different dose-response curves and are differently inhibited by neuroleptics acting on D1 or D2 type receptors. The synaptic continuation of the striatonigral pathway was interrupted in unilaterally 6-OHDA-lesioned rats by adding a kainic acid lesion to the 6-OHDA-lesioned nigra. This lesion affected apomorphine and pergolide rotation differently. After an initial short peak of contralateral rotation, apomorphine induced ipsilateral rotation that increased with dose, although a final contralateral peak was always maintained. The only change in pergolide rotation was a shift of the dose-response curve to the right. In another group of animals, the continuation of the striatonigral pathway was lesioned by unilateral kainic acid injections without previous 6-OHDA-lesions of the dopamine system. In these animals apomorphine but not pergolide induced rotational behaviour. In contrast, both drugs induced rotation in animals where all striatal efferents were lesioned unilaterally by kainic acid injections into one striatum. The results suggest that the apomorphine rotation is mainly dependent upon striatonigral pathways while the pergolide rotation is dependent upon other striatal efferent pathways.

Animals↗
PubMed1984

Effect of intranigral injections of dynorphin, dynorphin fragments and alpha-neoendorphin on rotational behaviour in the rat.

Peptides deriving from the proenkephalin B precursor were studied in the Ungerstedt rotational model after their unilateral injection into the substantia nigra. Dynorphin (DYN)-(1-17), DYN-(1-13) and DYN-(1-8) in 0.1-10 micrograms doses induced marked contralateral rotation. This effect was enhanced by subsequent systemic administration of D-amphetamine and blocked by previous treatment with naloxone. alpha-Neoendorphin produced similar effects although there was no evidence for dose-dependency. DYN-(6-17) which lacks opioid activity also produced contralateral rotation, which, however, was not naloxone reversible and D-amphetamine given subsequently did not induce asymmetric activation. Methionine enkephalin and leucine enkephalin, deriving from the proenkephalin A precursor were tested for comparison. Only the former produced weak contralateral rotation. GABA injected at the same site as DYN-(1-17) also induced contralateral rotation which was mimicked by nanogram doses of the gabaergic agonist muscimol. These findings suggest an interaction between peptides from the proenkephalin B precursor and nigro-striatal dopamine neurons as well as gabaergic striato-nigral efferents and/or interneurons.

Animals↗
PubMed1984

Adrenal medullary implants in the dopamine-denervated rat striatum. I. Acute catecholamine levels in grafts and host caudate as determined by HPLC-electrochemistry and fluorescence histochemical image analysis.

Rats with unilateral 6-hydroxydopamine-induced degeneration of the left nigrostriatal dopamine system were given intrastriatal implants of one cortex-free adrenal medulla divided into 4 pieces. Two pieces were placed in the center of the anterior part of the denervated caudate and two pieces in a more posterior position in lateral caudate. The distribution of catecholamines (CA) in grafts and host brain was studied 2, 100 and 400 min after grafting by HPLC-electrochemistry and Falck-Hillarp fluorescence histochemistry combined with computer-aided image analysis. Two minutes after implantation the chromaffin tissue grafts contained large amounts of adrenaline (A) and noradrenaline (NA) and small amounts of dopamine (DA). The chromaffin cells had a relatively normal fluorescence histochemical appearance. From the grafts, CA had spread into the surrounding host brain tissue where high levels of A and NA and low levels of DA were now found in the denervated host striatum. Fluorescence histochemistry and image analysis showed the CA to have spread 1-1.5 mm in all directions from the grafts. The CA concentrations decreased almost linearly with increasing distance from the grafts. At 100 min after implantation approximately a third of the chromaffin cells were still strongly fluorescent while the rest of the cells were very weakly fluorescent or non-fluorescent. The amounts of A, NA and DA in the host brain had decreased considerably, while the size of the fluorescent halo around the grafts had not diminished. At 400 min after grafting, only scattered cells in the chromaffin implants were strongly fluorescent and the surrounding host striatum contained low amounts of CA. It is concluded that intrastriatal adrenal medullary implants acutely release or leak large amounts of CA into surrounding host brain tissue. Taken together with results from the accompanying paper these data show that the grafts can maintain CA levels in host striatum high enough to elicit strong rotational responses during approximately 200 min.

Adrenal Medulla↗
PubMed1984

Adrenal medullary implants in the dopamine-denervated rat striatum. II. Acute behavior as a function of graft amount and location and its modulation by neuroleptics.

Rotational behavior was studied in rats with unilateral 6-hydroxydopamine-induced degeneration of the nigrostriatal dopamine system, following intrastriatal grafting of pieces of the adrenal medulla or nervus opticus. The rats were placed in rotometers immediately after the operation. No rotational response was seen in animals implanted with nervus opticus. Rats that received one whole adrenal medullary gland, divided into 4 pieces, showed a strong rotational response with a peak after 100 min and a duration of 400 min. Adrenal medulla-induced rotations were dose-dependent: when rats were grafted with 2, 4 or 8 pieces (where 4 pieces equals one whole adrenal medulla) into 2 sites, 2 pieces induced about half the amount of rotation as 4 pieces, while 8 pieces caused a higher total number of rotations with the 100 min peak approximately doubled compared with rats that had received 4 pieces. The coordinates for the implantation site were also important determinants of the rotational behavior: 4 implantation sites were tested and it was shown that the most central site in the caudate caused the highest total amount of rotations. The rotational behavior could be blocked in a dose-dependent manner by the dopamine-receptor antagonists haloperidol and cis-flupenthixol given immediately after grafting. It is concluded that implantation of chromaffin tissue from the adrenal medulla into the unilaterally 6-hydroxydopamine-denervated striatum causes highly reproducible acute rotational responses that vary with the amount and location of the implanted tissue and that can be blocked by neuroleptics. Thus the experiments permit screening of areas within neostriatum that produce different rotational responses to chromaffin implants.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Medulla↗
PubMed1984

Evidence that apomorphine and pergolide induce rotation in rats by different actions on D1 and D2 receptor sites.

Apomorphine and the ergot derivative pergolide induced dose-dependent contralateral rotation in rats with unilateral 6-hydroxydopamine denervation of the ascending dopamine pathways. This was interpreted as an action on supersensitive receptors. However, large differences were found when comparing apomorphine and pergolide dose-response curves as well as the patterns of rotational behaviour the compounds elicited. Pergolide had a steep dose-response curve, while apomorphine had a flatter curve reaching a plateau at the dose of 1 mg/kg s.c. In doses higher than 1 mg/kg, apomorphine induced self-mutilation, while this was infrequent after pergolide. Apomorphine induced a two-peak pattern of rotation that never occurred when the same rats were tested with the ergot derivative. Both drugs induced dose-dependent ipsilateral rotation in animals with unilateral striatal kainic acid lesions but at doses 100 times higher. This effect was interpreted as an action on normosensitive receptors situated on the intact side. The differences between apomorphine and pergolide may be explained in terms of actions on different dopamine receptors, since the agonists were differently inhibited by neuroleptics acting on D1- or D2-type receptors. The D1/D2 antagonist cis-flupenthixol blocked both apomorphine and pergolide with similar potency, while sulpiride, a substituted benzamide devoid of any effect on D1 receptors, was a poor inhibitor of the apomorphine response. In contrast, sulpiride blocked pergolide rotation at doses 1000 times lower than those needed to block apomorphine rotation. Our results suggest the existence of functionally distinct sites related to the D1/D2 receptor classification.

Animals↗
PubMed1984

Behavioural and biochemical studies with the benzamide sulpiride in rats.

We have studied the effects of the benzamide, sulpiride, on dopamine transmission using a functional approach combining brain dialysis experiments with behavioural studies utilising rotational and holeboard models. In the 6-OH-dopamine-rotational model, both apomorphine and pergolide induced a dose-dependent contralateral rotation. However, sulpiride blocks very effectively the pergolide responses whilst it inhibits poorly the apomorphine rotation. Further studies using the same model suggest different receptor mechanisms distinctly distributed in the striata of rats and involving different efferent pathways. A dialysis tube was implanted into the left striatum of rats in order to study changes in dopamine release after influencing dopamine autoreceptors. Apomorphine produced a decrease of dopamine release which was reversed by sulpiride. The dopamine autoreceptor regulation of exploratory behaviour has been studied using an automatic holeboard device. Apomorphine and pergolide inhibited locomotion in an dose-dependent manner. This inhibition was selectively reversed by sulpiride but not by cis-flupenthixol. The dialysis provided also another possibility to study the functional regulation of DA systems. It has been suggested that sulpiride most effectively blocks the dopamine receptors localized presynaptically on cortico-striatal glutamate afferent neurons. We have compared the effects of cis-flupenthixol and sulpiride on glutamate and GABA release as measured by dialysis in the striata of rats. We found no clearcut effect after cis-flupenthixol, while sulpiride caused a significant change in glutamate release.

Animals↗
PubMed1983

Functional studies with the opioid peptide dynorphin: acute effects of injections into the substantia nigra reticulata of naive rats.

When injected into the substantia nigra reticulata of naive rats, dynorphin-(1-17) caused a dose dependent contralateral rotation which was inhibited by naloxone in a dose dependent manner. Met-enkephalin injected in the same coordinates as the ones used with dynorphin also induced rotation but of lower intensity, while Leu-enkephalin did not elicit any significant response at the doses tested. D-amphetamine, injected subcutaneously 60 min after dynorphin, significantly enhanced the contralateral rotation induced by the intranigral administration of dynorphin. Experiments with dynorphin injections combined with D-amphetamine suggest that the dynorphin effects are mediated by neuronal loops involving dynorphin dopamine interactions.

Animals↗
PubMed1983

On the mechanism by which methylxanthines enhance apomorphine-induced rotation behaviour in the rat.

Methylxanthines, such as caffeine and theophylline, potentiate the rotation behaviour induced by dopamine receptor agonists in rats with unilateral lesions of the nigro-striatal pathway. In the present study we have examined the possibility that interaction with central adenosine mechanisms could influence rotation behaviour. Under in vitro conditions adenosine and N6-phenylisopropyl-adenosine (PIA) stimulate cyclic AMP accumulation. This effect was enhanced by the phosphodiesterase inhibitor rolipram, but blocked by alkylxanthines such as caffeine, theophylline and, particularly, 8-phenyl-theophylline. Rotation behaviour induced by apomorphine (0.05 mg/kg), was inhibited by PIA and rolipram and by a low dose of the adenosine deaminase inhibitor EHNA (2 mg/kg). By contrast, theophylline and 8-phenyl-theophylline caused a potentiation. The former drug stimulated rotation behaviour per se, while the latter did not. 8-Phenyl-theophylline entered the brain poorly and its concentration in brain it was less than 1/10 of theophylline. It is concluded that theophylline does not potentiate rotation behaviour secondarily to inhibition of phosphodiesterase. Antagonism of endogenous adenosine may partly explain the effect of methylxanthines. Possibly, some as yet unknown mechanism may also contribute to the effects of xanthine-derivatives on rotation behaviour.

Adenosine↗
PubMedDate not supplied

Neurocircuitry of the basal ganglia studied by monitoring neurotransmitter release. Effects of intracerebral and perinatal asphyctic lesions.

The neurocircuitries of the basal ganglia are studied with in vivo microdialysis, with special consideration to dopamine transmission and its interaction with other neurotransmitter systems. The aim is to develop experimental models to study the pathophysiology and therapy of neurodegenerative disorders of the basal ganglia, as well as to develop models to study the short- and long-term consequences of perinatal asphyctic lesions. A main goal of these studies is to find and to characterize new treatments for these disorders.

Alzheimer Disease↗
PubMedDate not supplied

Immunohistochemical studies on cholecystokinin (CCK)-immunoreactive neurons in the rat using sequence specific antisera and with special reference to the caudate nucleus and primary sensory neurons.

In the present immunohistochemical study the occurrence and distribution of CCK-immunoreactive neurons were analyzed in the brain, spinal cord and sensory ganglia using sequence specific antisera. Thus, antibodies directed towards the C-terminal portion of CCK-33, to the N-terminal portion of CCK-8 and to the mid portion of CCK-33 as well as monoclonal antibodies were used. For comparison antisera raised against calcitonin gene-related peptide (CGRP), tyrosine hydroxylase (TH) and 5-hydroxytryptamine (5-HT) were used. Untreated, colchicine treated, 6-hydroxydopamine (6-OH-DA) treated and ibotenic acid treated rats were analyzed. The results indicate that most CCK systems in the rat central nervous system contain genuine CCK. These include, for example, the hippocampal formation, the hypothalamus, several subcortical forebrain areas, the ventral mesencephalon, nucleus tractus solitarii, some neurons in the ventral medulla oblongata as well as local and possibly descending neurons in the spinal cord. An exception was primary sensory neurons in which CCK-like immunoreactivity (LI) could only be demonstrated with C-terminally directed antisera and probably represents cross-reactivity with CGRP or a similar peptide. The central branches of such primary afferents were found both in the dorsal vagal complex, in the spinal trigeminal nucleus and in the dorsal horn of the spinal cord. Special attention was focused on CCK-LI in mesencephalic dopamine neurons and in their projection areas including nucleus accumbens, tuberculum olfactorium and particularly the caudate nucleus. In the latter structure CCK-LI exhibited a heterogenous pattern probably representing fibres of different types and origin. Thus, CCK-LI coexists with dopamine in two anatomically and morphologically distinguishable systems, one located in the periventricular area, increasing in size in the caudal direction to occupy most of the cauda, and a second system consisting of very fine dots in the medial half of the caudate nucleus. These two fibre types disappeared after 6-OH-DA treatment. A third system consisted of strongly fluorescent patches distributed at all levels of the caudate nucleus, mainly in its medial half. A diffuse, weakly fluorescent network of CCK-positive fibres was also found over the entire caudate nucleus. The latter two systems did not disappear after 6-OH-DA. Finally, local CCK-positive cell bodies were seen in small numbers, mainly in the ventral aspects of the caudate nucleus.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗