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Biomedical subjects

R L Faull

Publications and source records attributed to R L Faull.

At least 109 records · Page 6Linked to original sources
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↗
PubMed1989

[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.

Adult↗
PubMed1989

Heat shock induces c-fos protein-like immunoreactivity in glial cells in adult rat brain.

Heat shocking of anesthetized rats lead to a massive increase in c-fos protein-like immunoreactivity (FOS-IR) in glial-like cells in white and gray matter regions of the brain. Neuronal FOS-IR was not detectibly altered by heat shock. This induction of FOS-IR was present 1 h, but not 10 min or 24 h, after heat shock. These results demonstrate that c-fos protein is expressed in glial cells following thermal stress.

Animals↗
PubMed1989

The organization of the projection from the cerebral cortex to the striatum in the rat.

The detailed organization of the corticostriate projection has been investigated in the brain of the rat using the technique of retrograde transport of horseradish peroxidase following the placement of small, iontophoretic injections of horseradish peroxidase conjugated to lectin throughout all major regions of the striatum (caudate-putamen, nucleus accumbens and olfactory tubercle). The results demonstrate that all major regions of the cerebral cortex project to the striatum on both sides of the brain with an ipsilateral predominance. The cells of origin of both the ipsilateral and contralateral corticostriate projections lie mainly in lamina V (especially lamina Va) with very small numbers in lamina III of the neocortex and mesocortex, and in the deep laminae of the allocortex. The results show that each striatal locus receives inputs from several cortical regions, i.e. there is extensive overlap in the corticostriate projection, and that, in general terms, each cortical region projects onto a longitudinally oriented region of the striatum. In particular, the major subdivisions of the cerebral cortex--the neocortex, mesocortex and allocortex--project onto defined but partially overlapping regions of the striatum: the neocortex projects to the caudate-putamen; the mesocortex projects mainly to the medial and ventral regions of the caudate-putamen but also to the ventral striatum (nucleus accumens and olfactory tubercle); and the allocortex projects mainly to the ventral striatum but also to the medial and ventral parts of the caudate-putamen. Within each of these major projection systems there is a further organization, with the constituent parts of each major cortical region projecting to smaller longitudinal components of the major projection fields. Each neocortical area projects to a longitudinal region of the dorsal striatum (caudate-putamen): the sensory and motor areas project topographically onto the dorsolateral striatum such that the rostral sensorimotor cortex (head areas) projects to central and ventral regions and the more caudal sensorimotor cortex (limb areas) projects to dorsal regions of the dorsolateral striatum; the visual area projects to the dorsomedial striatum; and the auditory area projects to the medial striatum. Each mesocortical area projects to a longitudinal area of the striatum: the most posteromedial mesocortex (the retrosplenial area) projects to the dorsomedial striatum; more anterior and lateral parts of the mesocortex project to more ventral parts of the striatum: and the most lateral mesocortex (the agranular insular and perirhinal areas) project to the ventrolateral striatum.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

Neurotensin receptors in the human spinal cord: a quantitative autoradiographic study.

The anatomical localization of neurotensin receptors in the human spinal cord was examined in 12 cases aged 4-68 years using quantitative autoradiographic methods following the incubation of fresh, unfixed cryostat sections with 4 nM [3H]neurotensin. Characterization of the pharmacological specificity of the [3H]neurotensin binding sites in the human spinal cord from displacement studies with neurotensin and various neurotensin fragments indicated that, whereas 1.0 microM neurotensin and the carboxy-terminal fragment neurotensin almost completely displaced [3H]neurotensin binding (4 nM), the amino-terminal fragments neurotensin and neurotensin1-11 were weak inhibitors. This requirement for the carboxy-terminal fragment neurotensin is consistent with [3H]neurotensin binding to specific neurotensin receptors in the human spinal cord. In all cases the autoradiograms demonstrated that neurotensin receptors were distributed in a similar fashion in the gray matter of the cervical, thoracic, lumbar, sacral and coccygeal regions of the human spinal cord. At all 21 spinal levels examined, the highest density of neurotensin receptors was localized in lamina II of the dorsal horn. Within lamina II the receptors were especially concentrated in the deeper inner segment (IIi) where they formed a dense band lying immediately dorsal to lamina III. The density of receptors in this inner region of lamina II (23.5 fmol/mg) was almost double that in the outer segment of lamina II (12.2 fmol/mg), which showed the next highest density of receptors, and more than three times that in the adjacent lamina I (6.9 fmol/mg) and lamina III (7.1 fmol/mg). A moderate density of receptors was present in the intermediomedial (8.0 fmol/mg) and intermediolateral (8.0 fmol/mg) nuclei of lamina VII, and in lamina IX (4.4 fmol/mg). The density of labelling in the remaining laminae of the spinal cord was very low. These results indicate that neurotensin receptors are mainly localized in somatic and visceral sensory and motor regions of the human spinal cord and suggest that neurotensin may play a role in modulating sensory-motor functions in the human spinal cord.

Adult↗
PubMed1989

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)

Adult↗
PubMed1989

Immediate-early genes, kindling and long-term potentiation.

The mechanism(s) by which long-term changes are induced and maintained in the nervous system are poorly understood. Kindling is an example of a permanent change in brain function that results from repeated elicitation of seizures. Recently, a class of genes called "immediate-early genes" that were previously thought to be only involved in cell division, differentiation and perhaps neoplasia have been shown to be rapidly and transiently induced in adult neurons following afterdischarges, ECS and chemically-evoked seizures. The products of these genes (e.g., FOS, JUN) are DNA-binding proteins and it is thought that they alter, perhaps in a coordinate fashion, the transcription of "late-effector genes." These late genes may code for enzymes, neuropeptides, receptors, ion channels, structural proteins, growth factors, etc. that may cause permanent biochemical and/or morphological changes in the brain that give rise to the kindled state. Thus, these early genes may act as molecular switches turning on a plasticity (kindling) program in neurons in a fashion similar to their induction of developmental programs in dividing cells.

Animals↗
PubMed1989

The neuroprotective actions of a calcium channel antagonist, flunarizine, in the infant rat.

One postulated final common pathway leading to neuronal death after hypoxic-ischemic insults is an increase in intracellular calcium concentrations. We examined the effect of pretreatment with flunarizine, a calcium channel antagonist known to pass the blood brain barrier, on the behavioral and histologic changes after an hypoxic-ischemic insult in the infant rat. The 21-d-old rats were subjected to unilateral carotid ligation, then to 2 h of hypoxia. They were pretreated with either flunarizine (30 mg/kg, intraperitoneally) or with an equal volume of diluent. After 5 days of observation they were killed for histology. Acute behavioral abnormalities were observed in more controls than treatment animals, 52 vs 11% (p less than 0.002). Cerebral injury was almost entirely confined to the ligated side and was significantly worse in the control rats. Full thickness cortical infarction was noted in 56% of controls (n = 27) vs 4% of flunarizine-treated rats (n = 24), (p less than 0.001). Mean and maximum damage scores for all areas assessed including cortex, corpus striatum, thalamus, amygdala, and hippocampus were improved markedly in treatment rats (p less than 0.005). These observations confirm that flunarizine, when given prophylactically, has a neuroprotective effect against hypoxic-ischemic injury in the developing brain.

Animals↗
PubMed1988

Connections of the paraflocculus of the cerebellum with the superior colliculus in the rat brain.

The interconnections between the paraflocculus of the cerebellum and the superior colliculus (SC) of the adult male Wistar albino rat were traced utilising the retrograde and anterograde transport of horseradish peroxidase conjugated with wheatgerm agglutinin (WGA-HRP). The study comprises three series of experiments. In the first series designed to trace the connections between the paraflocculus and the pre- and deep cerebellar nuclei, microiontophoretic injections of WGA-HRP filled either the entire paraflocculus or one of its subdivisions (ventral or dorsal paraflocculus). The results showed that, the ventral and dorsal paraflocculus receive afferents from distinct and separate regions of pontine nuclei, nucleus reticularis tegmenti pontis (Rtp) and the inferior olive. The efferents from the ventral and dorsal parafloccular subdivisions project to circumscribed regions of the lateral and posterior interpositus cerebellar nuclei. In the second series of experiments, unilateral iontophoretic WGA-HRP injections were placed at varying depths, through the rostrocaudal extent of SC and the tectal connections with the brainstem, and deep cerebellar nuclei were traced. The SC projects to well circumscribed regions of the pontine nuclei. Rtp and the inferior olive and receives afferents from the lateral and posterior interpositus cerebellar nuclei. In the third series of experiments involving combined injections of WGA-HRP into SC and the ventral paraflocculus, the collicular and ventral parafloccular connections were traced. The ventral paraflocculus receives afferents from regions of pons and Rtp which in turn receive inputs from the SC and projects to the lateral and posterior interpositus cerebellar nuclei which in turn give rise to efferents to the SC. These findings demonstrate that the ventral paraflocculus is linked to the contralateral superior colliculus via (i) a crossed afferent tecto-ponto/Rtp-parafloccular pathway, and (ii) a crossed efferent paraflocculo-nucleo-tectal pathway.

Afferent Pathways↗
PubMed1988

Benzodiazepine receptors in the human hippocampal formation: a pharmacological and quantitative autoradiographic study.

The pharmacological characteristics and anatomical distribution of benzodiazepine receptors in the human hippocampal formation were studied in seven cases aged 4-68 years. The pharmacology of the receptors was studied by computerized, non-linear least squares regression analysis of [3H]flunitrazepam displacement by flunitrazepam, CL218,872 and ethyl beta-carboline-3-carboxylate binding to membranes and the anatomical localization of these receptors was demonstrated using quantitative autoradiography following in vitro labelling of cryostat sections with [3H]flunitrazepam. The pharmacological studies indicated that the human hippocampal formation contained equal numbers of benzodiazepine receptors with high affinity (Type I) and low affinity (Type II) for CL218,872 and ethyl beta-carboline-3-carboxylate. The autoradiograms demonstrated that the benzodiazepine receptors were distributed in a heterogeneous fashion throughout the major regions of the human hippocampal formation; the highest concentrations of receptors were present in the dentate gyrus (molecular layer) and field CA1 of Ammon's horn (strata pyramidale, oriens, lacunosum), with moderate concentrations in field CA2 of Ammon's horn (stratum pyramidale) and in regions of the subicular complex and entorhinal cortex, and with considerably lower densities in fields CA3 and CA4. Quantitative analyses of the autoradiograms showed that the regions containing the highest densities of receptors (molecular layer of dentate gyrus and the strata oriens, pyramidale and lacunosum of CA1) were enriched with Type 1 receptors whereas other regions of lower receptor densities were enriched with either Type I or Type II receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1988

The nigrotectal projection and tectospinal neurons in the rat. A light and electron microscopic study demonstrating a monosynaptic nigral input to identified tectospinal neurons.

In order to investigate the nigro-tecto-spinal pathway in the rat, the pattern of termination of nigrotectal fibres and the distribution of tectospinal neurons have been investigated in a light and electron microscopic study of the superior colliculus. In addition, the pattern of termination of nigrotectal fibres was compared to the pattern of acetylcholinesterase staining. The light microscopic studies showed that the nigrotectal fibres, which had been identified by anterograde transport of horseradish peroxidase from the substantia nigra, terminated in a distinctive clustered pattern throughout the rostrocaudal extent of the stratum griseum intermedium, stratum album intermedium and adjacent dorsal portion of the stratum griseum profundum of the ipsilateral superior colliculus. The clusters of nigrotectal terminals formed a series of branching, interconnected longitudinal columns which largely corresponded with the pattern of acetylcholinesterase staining. The tectospinal neurons, which had been identified by retrograde transport of horseradish peroxidase from the spinal cord, had mainly large-sized somata, were stellate in shape with multiple long dendrites, and formed variable-sized clusters of 4-15 neurons within lateral regions of the ventral stratum album intermedium and dorsal stratum griseum profundum. In experiments where both the nigrotectal terminals and the tectospinal neurons were labelled by the transport of horseradish peroxidase, the clusters of tectospinal neurons largely corresponded with the regions of densest nigrotectal fibre termination in the lateral regions of the superior colliculus. In addition, a small contralateral nigrotectal projection was localized in the rostrolateral region of the superior colliculus where the crossed fibres terminated in a clustered pattern in alignment with clusters of tectospinal neurons in this region. Electron microscopic examination of the superior colliculus following ibotenic acid lesions in the substantia nigra and horseradish peroxidase injections in the spinal cord showed multiple degenerating nigrotectal boutons in synaptic contact with the soma and the mainstem and secondary dendrites of labelled tectospinal neurons in the lateral regions of the stratum album intermedium and stratum griseum profundum of the superior colliculus. The majority of the degenerating nigrotectal boutons showed electron-lucent degenerative changes and were in axodendritic contact. All of the identified nigrotectal synapses were of the symmetrical type.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetylcholinesterase↗
PubMed1988

Multiple benzodiazepine receptors in the human basal ganglia: a detailed pharmacological and anatomical study.

The pharmacological characteristics and anatomical distribution of benzodiazepine receptors in the striatum (dorsal striatum, comprising the caudate nucleus and putamen, and ventral striatum) and globus pallidus (dorsal pallidum, comprising the external and internal segments, and ventral pallidum) of the human basal ganglia were examined in twelve cases aged 4-71 years. The pharmacology of the receptors was studied using computerized, non-linear least-squares regression analysis of [3H]flunitrazepam displacement by flunitrazepam, CL218,872 and ethyl beta-carboline-3-carboxylate binding to membranes. The results showed that the dorsal striatum (caudate nucleus and putamen) contained higher concentrations of receptors than the dorsal pallidum (external and internal segments). The dorsal striatum contained equal numbers of sites with high affinity (Type I) and low affinity (Type II) for CL218,872 and ethyl beta-carboline-3-carboxylate whereas the globus pallidus contained sites with only high affinity (Type I) for these ligands. The anatomical localization of the benzodiazepine receptor subtypes (Type I and II) was studied using quantitative autoradiography following in vitro labelling of cryostat sections with [3H]flunitrazepam in the absence or presence of the discriminating ligand CL218,872. The autoradiograms showed that benzodiazepine receptors were distributed throughout all regions of the human striatum in a heterogeneous fashion, i.e. high-density patches of receptors were set against a background matrix of lower receptor densities. The highest densities of receptors were seen in the ventral striatum where the patches were particularly extensive and showed densities 56% higher than the receptor densities in the dorsal striatal patches. Quantitative analysis showed that the patches in all striatal regions contained mainly Type II receptors (83%-86%) whereas the matrix regions in the ventral and dorsal striatum contained different proportions of the receptor subtypes; Type I receptors predominated (60%) in the matrix of the ventral striatum and Type II receptors predominated (67%-71%) in the matrix of the dorsal striatum. By contrast, the autoradiograms showed that the globus pallidus contained considerably lower concentrations of receptors than the striatum. The highest density of receptors in the globus pallidus was present in the ventral pallidum with successively lower concentrations in the external (26% less) and internal (66% less) segments of the dorsal pallidum. In agreement with the membrane binding studies the receptors in the globus pallidus were mainly of the Type I variety.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗