Biomedical subjects

G Jonsson

Publications and source records attributed to G Jonsson.

At least 73 records · Page 4Linked to original sources

PubMed1986

Attenuation of sensory preconditioning by noradrenaline depletion in the rat.

In order to investigate the effect of noradrenaline (NA) depletion upon an associative learning phenomenon, sensory preconditioning, rats were inflicted with either 6-hydroxydopamine-induced lesions of the dorsal noradrenergic bundle (DNAB) or the locus coeruleus (LC), or with systemic injections of the NA neurotoxin, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4). Using appropriate controls (the UP groups) sensory preconditioning was demonstrated clearly in the non-lesion conditions (Sham or saline), but was blocked or strongly attenuated in the DNAB and DSP4 conditions. LC lesions did not affect sensory preconditioning. These findings suggest that the loss of central NA may cause some disruption of some aspects of complex associative learning. The role of NA in sensory preconditioning may be relevant to current notions of NA function.

Animals↗

PubMed1986

Astrocyte responses to dopaminergic denervations by 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine as evidenced by glial fibrillary acidic protein immunohistochemistry.

Astrocytic responses to dopaminergic denervation by two widely used dopamine neurotoxins, 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were monitored using immunofluorescence with antibodies against glial fibrillary acidic protein (GFA) while neurofilament (NF) antibodies were used to monitor neuronal disturbances. Following stereotaxic injection of 6-OHDA into the nigrostriatal dopamine bundle in rats, an increased amount of GFA-immunoreactivity in striatum was detectable after 24 hours and remained after one month. Retrograde degeneration of nigral neurons led to gliosis in the cell body area. At the site of injection, astrocytes were destroyed and NF-immunoreactivity increased. New astrocytes invaded the injection area during the first month after injection. MPTP given systemically to mice in a dose that causes marked dopaminergic denervation of striatum also caused marked increases of GFA-immunoreactivity in striatum. These changes were larger in C57 BL/6 mice, known to be more sensitive to MPTP, than in N.M.R.I. mice, which are less sensitive to MPTP. The glial responses to MPTP-induced dopaminergic denervation did not occur when the dopamine neurotoxic effects were prevented by pretreatment with nomifensine or pargyline. It is concluded that dopaminergic denervation by neurotoxins causes rapid and profound changes in striatal astrocytes characterized by increased GFA-immunoreactivity. These changes remained up to a month after denervation and should be taken into account when functional consequences of dopaminergic denervations are discussed.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1986

Astroglial development in microencephalic rat brain after fetal methylazoxymethanol treatment.

Treatment of pregnant rats on gestation day 15 with methylazoxymethanol (MAM) leads to a marked microencephaly in the offspring with a considerable atrophy in cerebral cortex, hippocampus and striatum. The development of the astrocytic populations in these atrophic regions was studied by means of immunohistochemistry using an antiserum against glial fibrillary acidic protein (GFA). The distribution and density of GFA-positive structures were not notably altered in the parietal cortex, hippocampal formation and striatum after prenatal MAM-treatment as compared to control. Also the individual astrocytes were morphologically similar in experimental and control animals in all regions analyzed. We suggest that an adjustment of the astrocytic development has occurred in response to the changed neuronal environment. Alternatively, MAM-treatment may affect neuronal and glial precursor cells leading to a seemingly normal astrocytic cell density.

Animals↗

PubMed1986

Selective attention and place navigation in rats treated prenatally with methylazoxymethanol.

Prenatal treatment of rats on gestation day 15 with methylazoxymethanol (MAM) caused forebrain microencephaly. The behavioral analyses included measures of spontaneous motor activity and tests for cognitive deficits, and were performed when the rats had reached adult age. Female MAM-treated rats failed to demonstrate contextual control of latent inhibition, which confirms earlier findings with male rats. Male MAM-treated rats demonstrated a notable impairment of place navigation in a swim-maze, but showed as strong sensory preconditioning as the control animals. Biochemical analyses indicated considerable increases in catecholamine levels in the cerebral cortex, hippocampus and striatum. The cognitive deficits, characterised by the various conditioning (taste-aversion) and instrumental learning (swim-maze) tasks, suggested that the MAM rats are deficient in their capacity to attend selectively to the relevant stimulus in complex arrangements of the stimulus situation.

Abnormalities, Drug-Induced↗

PubMed1986

Spinal and locus coeruleus noradrenergic lesions abolish the analgesic effects of 5-methoxy-N,N-dimethyltryptamine.

Two experiments were performed on Sprague-Dawley rats to study the effects of noradrenaline and 5-hydroxytryptamine depletion upon the antinociceptive effects of acute 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) administration. 6-Hydroxydopamine-induced lesions following microinjections to either the locus coeruleus or the spinal cord (lumbar) abolished completely 5-MeODMT-induced analgesia in the tail-flick, hot-plate, and shock titration tests whereas 5,7-dihydroxytryptamine-induced lesions of the nucleus raphe magnus and the lumbar spinal cord attenuated 5-MeODMT analgesia in the tail-flick and shock titration tests. Thus, the experiments serve to demonstrate an important interaction between descending noradrenergic and serotonergic pathways, possibly at a spinal locus.

Analgesics↗

PubMed1986

5-Methoxy-N,N-dimethyltryptamine-induced analgesia is blocked by alpha-adrenoceptor antagonists in rats.

The effects of the alpha-adrenoceptor antagonists prazosin, phentolamine and yohimbine upon 5-methoxy-N,N-dimethyltryptamine (5-MeODMT)-induced analgesia were tested in the hot-plate, tail-flick and shock-titration tests of nociception with rats. Intrathecally injected yohimbine and phentolamine blocked or attenuated the analgesia produced by systemic administration of 5-MeODMT in all three nociceptive tests. Intrathecally administered prazosin attenuated the analgesic effects of 5-MeODMT in the hot-plate and tail-flick tests, but not in the shock titration test. Intrathecal yohimbine showed a dose-related lowering of pain thresholds in saline and 5-MeODMT-treated animals. Phentolamine and prazosin produced normal dose-related curves in the hot-plate test and biphasic effects in the shock titration and tail-flick tests. These results demonstrate a functional interaction between alpha 2-adrenoceptors and 5-HT agonist-induced analgesia at a spinal level in rats.

Adrenergic alpha-Antagonists↗

PubMed1986

Regional distribution and extracellular levels of amino acids in rat central nervous system.

The extracellular levels of aspartate, glutamate, serine, glutamine, glycine, alanine and GABA were studied in vivo with the microdialysis technique in 15 different regions of the rat brain. The effect of high K+ on the overflow of these amino acids was also studied. These results were compared with those from a regional dissection of 17 brain regions in which the tissue content of the same amino acids was determined. The in vivo data showed an unevenly distributed KCl response of aspartate, glutamate, taurine and GABA, all of which are putative neurotransmitters. It was not possible to predict the response to high K+ from the magnitude of the unstimulated overflow. Glutamine overflow was inversely related to that of glutamate during the high K+ stimulus, which is consistent with glutamine being the main precursor of glutamate. Only for GABA and alanine was overflow proportional to the tissue level in the different regions studied.

Amino Acids↗

PubMed1986

Effect of MPTP and its pyridinium metabolites on monoamine uptake and on central catecholamine neurons in mice.

The effect of MPTP and its pyridinium metabolites MPDP+ and MPP+ on the in vitro [3H]monoamine uptake in synaptosomal preparations from mouse striatum and cerebral cortex was investigated. All compounds inhibited [3H]monoamine uptake in a dose-dependent manner in both regions analysed. MPP+ had the highest affinity to dopamine and noradrenaline uptake sites, while MPTP had the highest affinity to serotonin uptake sites. The results indicate that the affinity of MPP+ to different monoamine uptake sites appears to be better correlated to MPTP neurotoxicity as expressed in vivo than MPTP and MPDP+. Intracerebral injection of MPP+ into substantia nigra produced an almost complete disappearance of dopamine in striatum and noradrenaline in cerebral cortex, while injection of MPTP or MPDP+ had no or only moderate catecholamine-depleting effects. The MPP+-induced catecholamine depletion could be partially reversed by pretreatment with the catecholamine uptake blocker nomifensine. Histological analysis disclosed that MPP+ was a potent generally cytotoxic agent, while MPDP+ less and MPTP least so. The present results are compatible with the view that an interaction with the catecholamine uptake mechanism, probably through an uptake and accumulation of extraneuronally formed MPP+, is most likely the explanation for neuron-specific neurotoxic action on catecholamine neurons following MPTP administration.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1986

Effects of the parkinsonism-inducing neurotoxin MPTP and its metabolite MPP+ on sympathetic adrenergic nerves in mouse iris and atrium.

The effect of systemic administration of the parkinsonism-inducing neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and its metabolite MPP+ (1-methyl-4-phenylpyridine) on sympathetic adrenergic nerves in mouse iris and atrium has been investigated employing histo- and neurochemical techniques. The results indicate that MPTP does not have any potent neurotoxic effects on sympathetic adrenergic nerves. The effects of MPTP noted appear mainly to be restricted to a noradrenaline (NA) -depleting action and an acutely transient impairment of the NA uptake mechanism. This latter effect could be counteracted by monoamine oxidase inhibition. MPP+ was found to have more potent neurotoxic actions than MPTP as reflected i.e. by a patchy loss of histochemically demonstrable adrenergic nerves in iris which persisted for at least 7 days. Pretreatment with the NA uptake blocker desipramine antagonised the effects of MPP+, indicating that neurotoxicity is mediated via the NA uptake mechanism. The difference in neurotoxic potency of MPTP between sympathetic adrenergic nerves and central catecholamine neurons might be related to differences in metabolism of MPTP in the CNS and the periphery and/or due to the sympathetic adrenergic nerves being more resistant towards the cytotoxic actions following MPTP administration.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1986

[Locus ceruleus: the regulation of hemato-encephalic barrier function normally and under emotional stress].

To study the role of locus ceruleus in maintaining the blood-brain barrier function in conditions of emotional stress, the blood-brain barrier permeability was estimated after locus ceruleus damaging with DSP4 (N-2-chloroethyl-N-ethyl-2-bromobenzylamine). The importance of locus ceruleus for the integrity of blood-brain barrier functions in control animals and especially in rats exposed to emotional stress was revealed. The data obtained prove the homeostatic role of locus ceruleus, which is the most prominent in conditions of emotional stress.

Animals↗

PubMed1985

Determination of catecholamines in tissue and body fluids using microbore HPLC with amperometric detection.

Performance of microbore reverse phase HPLC coupled with amperometric detection is detailed for the analysis of catecholamines in small tissue samples and human blood plasma and cerebrospinal fluid. Extraction procedures for pre-concentration and clean-up of these samples are described. Marked signal enhancement is observed due to the smaller column volume as well as the increased coulometric yield which results from the lower flow rates used with this technique. Detection limits of 0.2 to 0.5 picograms are obtained allowing analysis of catecholamines in extremely small tissue samples or small volumes of cerebrospinal fluid or plasma.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1985

The hindlimb extension reflex is not a reliable marker of post-decapitation convulsions or spinal noradrenaline depletion in rats.

The degree of hindlimb extension reflex (ER), post-decapitation reflex (PDR) and noradrenaline (NA) depletion was measured under various treatment regimens involving the neurotoxins DSP4 and 6-OHDA. Neither neonatal 6-OHDA treatment, direct application of 6-OHDA to the locus coeruleus nor DSP4 treatment produced a blockade of ER that could be associated with the loss of PDR and the spinal NA depletion, whereas intrathecal 6-OHDA treatment caused a strong loss of both ER and PDR related to severe spinal NA depletion. No correlation was obtained between the ER and PDR in a large number of DSP4-treated rats.

Animals↗

PubMed1985

Deficits in behavioral initiation and execution processes in monkeys with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism.

Administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to two monkeys led to hypokinesia, tremor, rigidity, adipsia and aphagia. Quantitative assessment of hypokinesia revealed increased reaction time, delayed onset of muscle activity and prolonged movement time in a forelimb reaching task after selective degeneration of the nigrostriatal dopamine (DA) system sparing mesocortical dopamine neurons. The losses of pars compacta cells of substantia nigra, of striatal [3H]mazindol binding and of striatal DA content (more than 90%) quantitatively paralleled the severity of behavioral deficits. Additional monoamine systems were affected with stronger MPTP effects.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1985

Noradrenaline depletion increases noradrenaline-induced antinociception in mice.

Mice were treated with N-2-chloroethyl-N-ethyl-2-bromobenzylamine hydrochloride (DSP4), which causes severe noradrenaline (NA) depletions in brain regions and the spinal cord, or vehicle i.p. They were tested 14 days later for antinociception induced by intrathecal injections of different doses of NA. A potentiation of the NA effect upon pain sensitivity was observed, with both an increase in the magnitude and duration of the antinociceptive responses. Upon biochemical analysis of spinal cords, it was found that DSP4-treated mice had a 80% depletion of NA, whereas dopamine and 5-hydroxytryptamine were unaffected. Radioligand binding of [3H]clonidine in membranes prepared from spinal cord, showed no differences in density of alpha 2-adrenoceptors, but the affinity had been increased, probably explaining the supersensitivity.

Animals↗

PubMed1985

Pharmacological interference with the neurotoxic action of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on central catecholamine neurons in the mouse.

The effect of pretreatment with various MAO and catecholamine uptake inhibitors on the MPTP-induced reduction of endogenous catecholamine levels and [3H]catecholamine uptake in mouse striatum and cerebral cortex associated with the neurotoxic action of MPTP on dopamine and noradrenaline neurons was investigated. Pargyline and deprenyl almost completely reversed the MPTP-induced reduction of these parameters in both regions while chlorgyline was without effect. Pretreatment with the dopamine uptake inhibitor amfolenic acid preferentially counteracted the depleting effect of MPTP on striatal dopamine levels. The noradrenaline uptake inhibitors desipramine, nortriptyline and LY 139603 all antagonized the MPTP-induced reduction of noradrenaline levels in cerebral cortex, while none of these inhibitors affected the action of MPTP on striatal dopamine. The results suggest that MAO-B and the catecholamine uptake system may be critically involved at certain steps in the neurotoxic action of MPTP on catecholamine neurons. The interaction with the uptake mechanism most likely explains the selective neurotoxic action of MPTP on catecholamine neurons.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1985

Electrophysiological and neurochemical correlates of the neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on central catecholamine neurons in the mouse.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is an agent which produces a parkinsonian syndrome in man. To explore the use of MPTP in a rodent model of parkinsonism, male albino mice (NMRI) were given MPTP (50 mg/kg, s.c.) twice with a 6-8 h interval. Up to 10 weeks after injection, mice were killed and high-pressure liquid chromatography was used to assay dopamine (DA) and noradrenaline (NA) concentrations in various regions of the CNS. At 4 and 10 weeks after injection, DA levels were significantly reduced in occipital cortex (-40%), hippocampus (-30%), and striatum (-60%). NA levels were reduced by 60-80% in frontal and occipital cortex, hippocampus, and cerebellum. Neither DA nor NA concentration was reduced in spinal cord. Dopaminergic denervation was also suggested by electrophysiological data which showed that treatment with MPTP increased the spontaneous discharge rate of caudate neurons and decreased the potency of locally administered phencyclidine, an indirect DA agonist. However, denervation was evidently not complete enough to produce postsynaptic receptor supersensitivity, as MPTP treatment did not increase the potency of locally applied DA, and it did not increase 3H-spiperone binding in striatal membrane preparations. These results suggest that MPTP causes regionally selective and long-term reductions of catecholamine transmission in the CNS of the mouse.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1985

Active and passive avoidance following the administration of systemic DSP4, xylamine, or p-chloroamphetamine.

Groups of rats were administered either DSP4 (50 mg/kg, ip), xylamine (50 mg/kg, ip), or p-chloroamphetamine (2 X 10 mg/kg, ip), either 2 weeks or 1 week before the testing of two-way active avoidance. DSP4 and xylamine, the selective noradrenaline (NA) neurotoxins, caused a two-way avoidance impairment but p-chloroamphetamine, the selective 5-hydroxytryptamine (5-HT) neurotoxin, did not do so. Pretreatment with desipramine (20 mg/kg, ip) blocked the avoidance impairment caused by DSP4 and xylamine treatment. Neither DSP4 nor xylamine caused any alteration of passive avoidance retention. The biochemical analyses indicated severe NA, but not 5-HT, depletions in the DSP4 and xylamine conditions and drastic 5-HT, but not NA, depletions in the p-chloroamphetamine conditions. These results confirm and extend earlier findings concerning the role of NA in avoidance behavior.

Amphetamines↗

PubMed1985

Neurochemical and histochemical characterization of neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine on brain catecholamine neurones in the mouse.

Systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) caused a rapid and long-lasting reduction of both 3,4-dihydroxyphenylalanine (dopamine, DA) and noradrenaline (NA) in mouse brain, as observed histo- and neurochemically. The depleting effects were more pronounced after repeated MPTP administration and the most marked reductions were observed after 2 X 50 mg MPTP/kg s.c., when DA in striatum and NA in frontal cortex were reduced by greater than 90% 1 week after MPTP. Mice with such catecholamine depletions were markedly sedated and almost completely immobilized. The behavioural syndrome after MPTP resembled that seen after reserpine, a monoamine-depleting drug. MPTP also caused a long-lasting reduction of catecholamine uptake in striatal DA and cortical NA nerve terminals and reduced tyrosine hydroxylase activity in these regions. There was no evidence that MPTP caused any marked DA and NA cell body death. MPTP given acutely transiently elevated serotonin levels. The results are compatible with a neurotoxic action of MPTP on both DA and NA nerve terminals. The nigro-striatal DA and the locus coeruleus NA neurone systems appeared to be most susceptible. Synthesis and utilization of residual striatal DA and cortical NA were increased, as often observed in partially denervated monoamine-innervated brain regions. Both DA and NA showed a gradual recovery, which took months to become complete and may have been related to a regrowth of catecholamine nerve terminals.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗