Biomedical subjects

M Dragunow

Publications and source records attributed to M Dragunow.

At least 127 records · Page 7Linked to original sources

PubMed1990

NMDA and kainic acid receptors have a complementary distribution to AMPA receptors in the human cerebellum.

The distributions of N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-S-methyl-4-isoxazole propionic acid (AMPA) and kainic acid (KA) receptors were determined in the human cerebellum using autoradiography. In contrast to the cerebral cortex, where KA receptors have a complementary distribution to NMDA and AMPA receptors, AMPA receptors were concentrated in the cerebellar molecular layer while NMDA and KA receptors were concentrated in the granular layer.

Aged↗

PubMed1990

Effects of hypoxia-ischemia and seizures on neuronal and glial-like c-fos protein levels in the infant rat.

Unilateral carotid ligation in immature rats, followed by 2 h of hypoxia led to ischemic cell change from 2 h after the insult, on the ligated side of the brain. There was a time-dependent induction of immunoreactive c-fos protein in neurones but not glia or ependyma on the non-ligated side of the brain. Induction only occurred in rats that had seizures post hypoxia-ischemia. In the ligated hemisphere c-fos protein was induced in glial-like cells in the corpus callosum, fornix/fimbria and internal capsule and in ependymal cells lining the lateral ventricle starting from 2 h after hypoxia but subsiding by 3 days. No neuronal c-fos induction was seen in areas showing neuronal damage. MK-801 or carbamazepine, which prevented hypoxia-ischemia-induced seizures, also prevented c-fos induction in the non-ligated hemisphere while MK-801 was associated with increased c-fos induction in hippocampal neurones from the ligated side, as well as in glial-like and ependymal cells. These results suggest several processes are involved following the hypoxic-ischemic insult. Firstly, severe hypoxia-ischemia is associated with a reduction in neuronal c-fos protein levels, probably as a result of neuronal failure and death. Secondly, post hypoxic seizures cause c-fos induction in surviving neurones. Thirdly, glial-like from regions in which there is neural loss also exhibit induction of c-fos, which may be important for their subsequent proliferation or for the production of growth factors.

Animals↗

PubMed1990

Haloperidol induces Fos and related molecules in intrastriatal grafts derived from fetal striatal primordia.

Haloperidol induces Fos and related molecules (Fos-related antigens, FRAs) in adult striatal neurons. We tested whether a similar induction of Fos and FRAs by haloperidol injection would occur in fetal striatal neurons transplanted into adult quinolinic acid-lesioned striatum. We found that Fos and FRAs were induced in striatal neurons after haloperidol. This induction had a time course in transplanted neurons that was identical to the time course of induction in normal adult striatum. Furthermore, the relative numbers of Fos- and FRA-immunopositive neurons induced by haloperidol were identical for both transplanted and normal striatal neurons. These results provide the first demonstration that neurons in intrastriatal grafts derived from fetal striatal primordia have similar intracellular biochemical characteristics to normal adult striatal neurons.

Animals↗

PubMed1990

Induction of Fos in glia-like cells after focal brain injury but not during wallerian degeneration.

Focal brain injury or perforant-path transections respectively led to an increase in the number of glial-fibrillary acidic protein (GFAP)-immunopositive astrocytes around the focal wound or in the terminal fields of the perforant path in the dentate molecular layer. This GFAP accumulation occurred 48-72 h after focal brain injury or perforant-path transection (wallerian degeneration). Focal brain injury also led to an accumulation of c-fos protein (Fos) in glial cells, ependyma and cells in the pia mater of the brain within 6 h of injury and this effect dissipated within 72 h. However, perforant-path lesions were not associated with accumulation of Fos in glial cells in the dentate molecular layer suggesting that c-fos induction in glial cells after injury is not necessary for GFAP accumulation. Induction of Fos in glia, ependyma and pia after focal brain injury may be associated with proliferation of these cells after injury.

Animals↗

PubMed1990

MK801 induces c-fos protein in thalamic and neocortical neurons of rat brain.

MK801, a non-competitive NMDA receptor antagonist, leads to a dramatic induction of c-fos-like protein in neurons in deep layers of the neocortex, in dorsal and ventral midline thalamic nuclei and in neurons in the central grey of rat brain. This induction of c-fos by MK801 is dose- and time-dependent occurring within 2 h and dissipating by 24 h after injection (0.5-8.0mg/kg, i.p.). The mechanism of this paradoxical induction of c-fos by MK801 is unclear, however the pattern of induction appears to follow the distribution of the antagonist-preferring NMDA receptor site.

Animals↗

PubMed1990

MK-801 induces c-fos protein in thalamic and neocortical neurons of rat brain.

MK-801, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, leads to a dramatic induction of c-fos-like protein in neurons in deep layers of the neocortex, in dorsal and ventral midline thalamic nuclei and in neurons in the central grey of rat brain. This induction of c-fos by MK-801 is dose-and time-dependent occurring within 2 h and dissipating by 24 h after injection (0.5-8.0 mg/kg, i.p.). The mechanism of this paradoxical induction of c-fos by MK-801 is unclear; however, the pattern of induction appears to follow the distribution of the antagonist-preferring NMDA receptor site.

Animals↗

PubMed1990

MK-801, an antagonist of NMDA receptors, inhibits injury-induced c-fos protein accumulation in rat brain.

Unilateral lesions of the rat hippocampus produced by needle insertion lead to ipsilateral accumulation of c-fos protein in dentate granule cells and neurons in the piriform cortex, as well as in glial-like cells in the corpus callosum and in ependymal cells lining the lateral ventricle adjacent to the lesion site. C-fos protein was detected immunocytochemically using two different antibodies in formalin-fixed brain sections. The N-methyl-D-aspartate (NMDA) antagonist MK-801 produced a dose- and time-dependent inhibition of c-fos protein accumulation in dentate granule cells and in neurons in the piriform cortex, but did not affect glial or ependymal c-fos protein accumulation. MK-801 at 4 mg/kg injected two hours before lesion inhibited c-fos accumulation. Thus, c-fos protein accumulation in hippocampal neurons and in neurons in the piriform cortex induced after traumatic brain injury involves activation of NMDA receptors.

Animals↗

PubMed1990

Sigma receptors are highly concentrated in the rat pineal gland.

The distribution of sigma (sigma) receptors in the rat brain was studied with autoradiography using [3H]1,3-di-ortho-tolyl-guanidine ([3H]DTG) as a ligand. The highest concentration of sigma receptors was seen in the pineal gland, an area which has not been previously studied. This result is of interest as both sigma receptors and the pineal gland have recently been shown to play a role not only in the nervous system but also in the immune and endocrine systems.

Animals↗

PubMed1990

Autoradiographic localisation of NMDA, quisqualate and kainic acid receptors in human spinal cord.

The phencyclidine (PCP) binding site of the N-methyl-D-aspartate receptor, the kainic acid (KA) receptor and the quisqualate (QA) receptor were visualised, using autoradiography in the human spinal cord and the distributions compared with that of benzodiazepine (BDZ) receptors and substance P (SP). All of the receptor types, and SP, were concentrated in lamina II of the dorsal horn, consistent with physiological data indicating that glutamate is a neurotransmitter of primary afferent terminals in the spinal cord.

Adult↗

PubMed1990

Induction of c-fos mRNA and protein in neurons and glia after traumatic brain injury: pharmacological characterization.

Focal brain injury in mice induced c-fos mRNA and protein in neurons throughout the damaged neocortex, including the piriform and the entorhinal cortices, as well as in nonneural brain cells (e.g., glia, pia, ependyma). The pattern of c-fos induction after injury suggested that injury led to spreading depression which then led to c-fos induction in neurons. Human neurons in the temporal cortex and hippocampus also showed c-fos protein induction after neurosurgical trauma. The c-fos mRNA and protein induction in mouse neurons was prevented by the noncompetitive NMDA antagonist ketamine but only partially inhibited by the voltage-dependent calcium channel antagonist nifedipine and the calmodulin antagonist trifluoperazine. The c-fos protein induction in nonneural brain cells after injury was not affected by these drugs. Thus, induction of c-fos in neocortical neurons after focal brain injury is partly NMDA receptor mediated.

Animals↗

PubMed1990

Adenosine receptor antagonism accounts for the seizure-prolonging effects of aminophylline.

The mechanism of action of aminophylline in prolonging seizures was tested in amygdala-kindled rats. Aminophylline prolonged the afterdischarge duration of kindled seizures. This seizure-prolonging action of aminophylline was strongly antagonized by the adenosine A1 agonist cyclohexyladenosine and partially antagonized by the benzodiazepine partial agonist RO 15-1788. However, the specific benzodiazepine antagonist CGS 8216 did not affect the seizure-prolonging action of aminophylline. Also, the potent anticonvulsant effect of diazepam on kindled seizures, which was completely antagonized by CGS 8216, was unaffected by aminophylline. Furthermore, a range of benzodiazepine inverse agonists, GABA antagonists, phosphodiesterase inhibitors and xanthines did not prolong afterdischarge durations. These results demonstrate that the seizure-prolonging action of aminophylline is due to block of A1 adenosine receptors since it is prevented by adenosine A1 agonists.

Adenosine↗

PubMed1990

Induction of Fos-like immunoreactivity and the maintenance of long-term potentiation in the dentate gyrus of unanesthetized rats.

Memory formation in the mammalian central nervous system may require long-lasting alterations in gene expression. However, it is not yet known whether the candidate memory mechanism long-term potentiation (LTP) requires alterations in gene expression for its maintenance, nor the extent to which the time course of LTP can be manipulated at the time of induction. In this study we influenced the time course of LTP decay for the perforant path input to the dentate gyrus in awake rats by manipulating conditions at the time of induction, and correlated the outcome with the induction of c-fos protein(s) (Fos), as measured immunohistochemically in the dentate gyrus of separate animals 2 h post-tetanization. Sodium pentobarbital, which blocks the induction of Fos-like immunoreactivity (Fos-IR), also blocked a long-duration form of LTP maintained over weeks. On the other hand, two different patterns of delivery of 50 trains, that produced similar time courses of LTP decay, produced markedly different degrees of Fos-IR induction. In addition, while stimulation consisting of only 10 trains induced a sizable Fos response, it only produced LTP lasting a few days. When the 10-train stimulation was repeated on 3 or 5 consecutive days, there appeared to be no additional Fos-IR induction, yet the LTP decay time constant was considerably prolonged. Thus there is little correlation between the degree of Fos-IR induction and the subsequent durability of LTP.

Animals↗

PubMed1990

Alzheimer's disease: changes in hippocampal N-methyl-D-aspartate, quisqualate, neurotensin, adenosine, benzodiazepine, serotonin and opioid receptors--an autoradiographic study.

The following receptors were assessed post-mortem in the hippocampi (anterior region) of eight patients with Alzheimer's disease and nine age-matched controls, using autoradiography: N-methyl-D-aspartate (including glutamate, phencyclidine and glycine binding sites), quisqualate, kainic acid, adenosine A1, benzodiazepine, serotonin (1 and 2), muscarinic cholinergic, beta-adrenergic, neurotensin and opioid receptors. In CA1 there were significant parallel losses of binding to the three N-methyl-D-aspartate-linked sites (average reduction 46%) and also losses of quisqualate (38%) and serotonin2 (58%) receptor binding, with a 47% loss of binding to A1 sites. Binding to all of these receptors was also reduced in CA3 (except binding to A1 sites which was normal) but only the serotonin2 receptor binding loss reached significance (52%). A significant reduction in binding was also observed in the entorhinal area to the N-methyl-D-aspartate receptor-linked sites (average reduction = 39%), benzodiazepine (40%) and serotonin2 receptors (45%), and there was a loss of binding to neurotensin (57%) and opioid receptors (42%). Significant reductions in the dentate gyrus molecular layer were seen for serotonin2 receptors (44%), and binding to opioid (44%) and A1 receptors (46%). Levels of ligand binding to muscarinic cholinergic, serotonin1, beta-adrenergic and kainic acid receptors were not significantly different from control values in any of the four areas examined. These results provide support for observations of selective receptor changes in Alzheimer's disease involving a broad range of receptor types which encompass both excitatory amino acid and other receptors (notably serotonin2, A1, benzodiazepine, neurotensin and opioid receptors). The implications of the pattern of receptor changes for the suggestion that excitotoxicity plays a role in the disease are discussed, as is the possible contribution of the receptor changes to the symptomatology of Alzheimer's disease.

Aged↗

PubMed1990

GABA, GABA receptors and benzodiazepine receptors in the human spinal cord: an autoradiographic and immunohistochemical study at the light and electron microscopic levels.

The regional, cellular and subcellular distribution of GABA, GABA receptors and benzodiazepine receptors was investigated by light and electron microscopy in the human lumbar spinal cord taken post-mortem from eight cases aged 20-76 years. Firstly, the regional distribution of GABA receptors and benzodiazepine receptors was studied using autoradiography following in vitro labelling of cryostat sections with tritiated ligands. This was followed by a detailed study of the cellular and subcellular distribution and localization of GABA and benzodiazepine/GABAA receptors by light and electron microscopy using immunohistochemical techniques with monoclonal antibodies to GABA and to the alpha and beta subunits of the benzodiazepine/GABAA receptor complex. The results showed a close correspondence in the regional distributions of GABA, GABA (GABAA and GABAB) receptors and benzodiazepine receptors. The highest density of GABA-like immunoreactivity, GABA receptors and benzodiazepine receptors was localized as a dense band within lamina II of the dorsal horn (especially inner lamina II) with moderately high densities in laminae I and III. The remaining laminae of the spinal gray matter showed much lower levels of labelling. A close correspondence was also seen in the distribution of GABA-like immunoreactivity and of benzodiazepine/GABAA receptor immunoreactivity at the cellular and subcellular levels. At the cellular level, the greatest number of GABA-immunoreactive cells was found in lamina II; they comprised small, round to oval cells and, on the basis of soma size, shape, orientation and dendromorphology, they corresponded to previously described islet and filamentous cells. Benzodiazepine/GABAA receptor immunoreactivity was also localized on the same cell types in lamina II. At the subcellular level in lamina II, GABA-immunoreactive axon terminals mainly established axodendritic synaptic contacts. Small numbers of GABA-immunoreactive axon terminals appear to form possible axo-axonic contacts in complex synaptic arrays. Benzodiazepine/GABAA receptors were localized within the same types of synaptic complexes in which GABA-immunoreactive axon terminals were found. In these synaptic complexes, benzodiazepine/GABAA receptor immunoreactivity was associated with presynaptic and postsynaptic membranes and on apparent non-synaptic membranes. These results show a high concentration of GABA, GABA receptors and benzodiazepine receptors in lamina II of the dorsal horn of the human spinal cord and suggest a possible role for GABA in spinal sensory functions.

Autoradiography↗

PubMed1990

D2 dopamine receptor antagonists induce fos and related proteins in rat striatal neurons.

Rats injected with haloperidol, which binds to both D2 dopamine and sigma receptors or the specific D2 dopamine receptor antagonist YM 09151-2, but not the specific D1 dopamine receptor antagonist SCH 23390, showed induction of c-fos protein and c-fos-related antigens in striatal neurons. This effect of haloperidol and YM 09151-2 was inhibited by the N-methyl-D-aspartate antagonist MK801 but was not affected by 1,3-di-O-tolylguanidine, a selective sigma receptor ligand. Two different antisera were used to detect c-fos protein: one was specific for c-fos protein itself while the other recognized c-fos protein as well as c-fos protein-related antigens. In time-course immunocytochemical studies, the c-fos protein was induced maximally by 1 h and had returned to baseline by 24 h. However, c-fos protein-related antigens were induced maximally after 2 h and remained elevated for at least three days after haloperidol injection. Furthermore, the c-fos protein-specific antiserum detected two to three times fewer immunopositive striatal cells than the antiserum which detected both c-fos protein-related antigens and c-fos protein in haloperidol-treated rats. This result suggests that some striatal neurons express c-fos protein-related antigens but not c-fos protein after haloperidol injection. In some striatal sections from haloperidol-injected rats immunostained with the antiserum which recognizes both c-fos protein and c-fos protein-related antigens, there were large areas of immunopositive neurons interspersed with "areas" of striatum devoid of immunostaining. The implications of these results for theories concerning the biochemical mechanism of action of haloperidol are discussed.

Animals↗

PubMed1989

Rolipram induces c-fos protein-like immunoreactivity in ependymal and glial-like cells in adult rat brain.

We tested the effects of the cyclic AMP-dependent phosphodiesterase inhibitor 4- (3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone (rolipram) on c-fos protein-like immunoreactivity (FOS-IR) in adult rat brain. Rolipram (25-100 mg/kg, i.p.) did not detectability alter basal FOS-IR in neurons but induced FOS-IR in glial-like cells scattered in white matter regions and in ependymal cells lining the lateral and third ventricles. This induction was observed at 1 and 4 h after injection but was not detectable 10 min or 24 h after rolipram injection.

Animals↗

PubMed1989

Long-term potentiation and the induction of c-fos mRNA and proteins in the dentate gyrus of unanesthetized rats.

We tested the hypothesis that the nuclear proto-oncogene c-fos is involved in long-term potentiation (LTP) of the perforant path-dentate gyrus synapse in awake freely moving rats. High-frequency stimulation that produced LTP induced c-fos mRNA and protein in the dentate granule cells but not in CA1, CA3, or the entorhinal cortex. However, the degree of LTP induction did not correlate with the degree of c-fos induction. Agents that interfered with the production of LTP (e.g. NMDA antagonists) also prevented c-fos induction. Low-frequency stimulation did not lead to either LTP or c-fos induction. However, c-fos induction did not necessarily follow LTP production because some high-frequency stimulation protocols that produced good LTP did not lead to c-fos induction. Thus, c-fos induction is clearly not related to LTP production in unanaesthetized rats, but it remains to be determined if it plays some role in LTP maintenance.

Adaptation, Physiological↗

PubMed1989

The distribution of neurotensin receptors and acetylcholinesterase in the human caudate nucleus: evidence for the existence of a third neurochemical compartment.

The distribution of neurotensin receptors in the human caudate nucleus was studied using autoradiographic methods following in vitro labelling of cryostat sections with [3H]neurotensin, and the pattern of receptor labelling was compared to the distribution of acetylcholinesterase (AChE) staining in adjacent sections. A heterogeneous pattern of neurotensin receptors was found in the caudate nucleus. Patches of low receptor density aligned with the AChE-poor striosomes, regions of moderate receptor density corresponded with the AChE-rich matrix zone, and annular regions of high receptor density aligned with the AChE-negative border zone lying between the AChE-poor striosome and the AChE-rich matrix compartments. These results suggest the existence of 3 neurochemical compartments within the human caudate nucleus.

Acetylcholinesterase↗