Karl L.R. Jansen

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 Alzheimers 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 Alzheimers 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 Alzheimers disease.

Excitatory amino acid receptors in the human cerebral cortex: A quantitative autoradiographic study comparing the distributions of [3H]TCP, [3H]glycine,l-[3H]glutamate, [3H]AMPA and [3H]kainic acid binding sites

The excitatory amino acids are probably the major neurotransmitters in the cerebral cortex, and they act through at least three receptors: the N-methyl-D-aspartate, the quisqualate and the kainic acid receptors. Under the appropriate conditions, [3H]1-(1-(2-thienyl)-cyclohexyl)piperidine [( 3H]TCP), [3H]glycine and L-[3H]glutamate label different sites on the N-methyl-D-aspartate receptor, [3H]-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid [( 3H]AMPA) labels the quisqualate receptor and [3H]kainic acid the kainic acid receptor. The anatomical localizations of these binding sites were studied in sections of blocks removed from the cerebral cortices of eight post-mortem human brains. The results showed that, in the human cerebral cortex, [3H]TCP, [3H]glycine and L-[3H]glutamate binding sites had congruent distributions, with [3H]AMPA binding sites showing a similar distribution. In the hippocampus, these four ligands had high binding site densities in the CA1 region and the dentate gyrus molecular layer. With the exception of the striate cortex, in the neocortex, a tri-laminar pattern was seen consisting of a high density across laminae I-III, a layer of low density corresponding to the region of lamina IV, and a band of moderate density across laminae V and VI, except for [3H]AMPA where the middle zone of low density was usually wider. [3H]Kainic acid showed a binding pattern which was generally complementary to that of the other four ligands. There were low levels of [3H]kainic acid binding sites in the CA1 region of the hippocampus with higher levels in the CA3 region, the hilus, and the inner third of the dentate gyrus molecular layer. In the neocortex there was a band of high density corresponding to laminae V and VI, with a thin band of moderate binding corresponding to lamina I and the outer region of lamina II. An exception was the motor cortex where the highest level of [3H]kainic acid binding was in laminae I and II. The high degree of congruence between the binding patterns of [3H]TCP, [3H]glycine and L-[3H]glutamate (using conditions appropriate for the N-methyl-D-aspartate receptor) supports data indicating that these ligands bind to different regions of the same receptor complex. The similar distribution of [3H]AMPA binding sites, with the exception of the striate cortex, supports observations made in rodents that N-methyl-D-aspartate receptors and quisqualate receptors have similar distributions and perform different but related functions in excitatory transmission.(ABSTRACT TRUNCATED AT 400 WORDS)

A review of the nonmedical use of ketamine: use, users and consequences.

Abstract Ketamine is a dissociative anesthetic with an accepted place in human medicine. Ketamine also has psychedelic properties, and there has been a recent increase in nonmedical use linked with the growth of the “dance culture.” This has attracted little comment in the formal literature but has been the subject of many reports in the media. Myths and misunderstandings are common. The psychedelic properties of ketamine have also led to its use as an adjunct to psychotherapy. This review is intended as a resource for the wide range of persons now requesting accurate information about the nonmedical use of ketamine. It accepts the current necessity of sometimes referring to anecdotal reports while seeking to encourage an increase in formal research. The review includes the history of ketamine, its growing role as a “dance drug,” the sought-after effects (including the neardeath experience) for which it is taken in a nonmedical context, how these are produced, common mental and physical adverse effects, and the ketamine model of schizophrenia.

Loss of A1 adenosine receptors in human temporal lobe epilepsy

Using quantitative receptor autoradiographic methods we have examined A1 adenosine receptors, adenosine uptake sites, benzodiazepine receptors, NMDA, AMPA, and kainic acid receptors in temporal lobes removed from patients suffering from complex partial seizures and in normal control post-mortem temporal cortex. Binding to A1 adenosine receptors and NMDA receptors was reduced in epileptic temporal cortex, while the other neurochemical parameters were unchanged. The reason for this A1 receptor loss is unclear as it occurred in both idiopathic and symptomatic cases and thus may be a consequence rather than an initial cause of seizures. However, because adenosine is a powerful anticonvulsant substance, loss of anticonvulsant A1 receptors may contribute to the human epileptic condition. It is also possible that the observed differences in A1 binding are due to autopsy vs. biopsy changes in the levels of A1 adenosine receptors.

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.

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.

The nonmedical use of ketamine, part two: A review of problem use and dependence.

Abstract This is the second part of a review of the nonmedical use of ketamine. Part one discussed the history of ketamine, the sought-after effects for which it is taken in a nonmedical context, how these are produced, common adverse effects, the ketamine schizophrenia model and the neurotoxicity issue. Part two reviews what is currently known about problem use of ketamine, ketamine dependence, treatment options and harm minimization issues. Some ketamine users become dependent on the drug in a manner resembling cocaine dependence, with craving and a high tolerance but no evidence of a physiological withdrawal syndrome. The likely mechanisms of this dependence are discussed in terms of what is known about the neurochemistry of ketamine, its psychological effects, and published case histories in both the formal and informal literature. The conclusions are that ketamine dependence is linked with effects that this complex drug has in common with not only cocaine and amphetamine but also with opiates, alcohol and cannabis, as well as the psychological attractions of its distinctive psychedelic properties.

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.

[3H]glycine binding sites, NMDA and PCP receptors have similar distributions in the human hippocampus: an autoradiographic study.

The distribution of [3H]glycine binding sites was compared with that of N-methyl-D-aspartate (NMDA) receptors labelled with L-[3H]glutamate, and with that of phencyclidine (PCP) receptors labelled with [3H]1-(1-(2-thienyl)-cyclohexyl)piperidine ([3H]TCP) in sections from 7 normal human hippocampi. The results indicate that strychnine-insensitive glycine binding sites are present in high concentrations in CA1 and the molecular layer of the dentate gyrus. This distribution is very similar to the distributions of NMDA and PCP receptors in the human hippocampus.

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.