Biomedical subjects

R Quirion

Publications and source records attributed to R Quirion.

At least 145 records · Page 8Linked to original sources

PubMed1996

Autoradiographical and immunohistochemical analysis of receptor localization in the central nervous system.

Quantitative receptor autoradiographic methods have been widely used over the past two decades. Some of the advantages and limitations of these techniques are reviewed here. Comparison with immunohistochemical and in situ hybridization methods is also highlighted, as well as the use of these approaches to study receptor gene over-expression in cell lines. Together, data obtained using these various methodologies can provide unique information on the potential physiological roles of a given receptor protein and/or binding sites in various tissues.

Animals↗

PubMed1996

Ionotropic glutamate receptor subtypes in the aged memory-impaired and unimpaired Long-Evans rat.

The comparative quantitative autoradiographic distribution of ionotropic glutamate receptor subtypes were investigated in young adults (six months) and aged (24-25 months) cognitively impaired and unimpaired male Long-Evans rats. Aged rats were behaviorally characterized as either cognitively impaired or unimpaired based upon their performances in the Morris water maze task compared to the young adult controls. The status of the N-methyl-D-aspartate, [125I]dizocilpine maleate, [3H]kainate and amino-3-hydroxy-5-methylisoxasole-4-propionate (AMPA, [3H]AMPA) receptor binding sites were then established in these three subgroups of animals as a function of their cognitive performance in the Morris water maze task. The apparent densities of both N-methyl-D-aspartate/[125I]dizocilpine maleate and kainate binding sites were significantly decreased in various regions of the aged rat brain. Marked losses in [125I]dizocilpine maleate binding sites were observed in outer laminae of the frontal, parietal and temporal cortices, and the stratum radiatum of the CA3 subfield of the hippocampus. Interestingly, losses in [125I]dizocilpine maleate binding sites were generally most evident in the cognitively unimpaired aged subgroup, suggesting a possible inverse relationship between losses of this receptor subtype and cognitive performances in the Morris water maze task. The levels of [3H]kainate binding were most significantly diminished in various cortical and hippocampal areas as well as the striatum and septal nuclei of both groups of aged rats. In contrast, the apparent density of [3H]AMPA binding was increased in most hippocampal subfields and the superficial laminae of the occipital cortex of the cognitively impaired vs young adult rats. Changes in [3H]AMPA labeling failed to reach significance in the unimpaired cohort. Taken together, these results show that while losses in [3H]kainate binding were similar in both subgroups of aged rats, differences were seen with respect to cognitive status for both [125I]dizocilpine maleate/N-methyl-D-aspartate and [3H]AMPA binding sites. Decreases in [125I]dizocilpine maleate binding sites were mostly restricted to cortical areas of cognitively unimpaired rats, while increases in the AMPA binding subtype were seen in the memory-impaired subgroup. It would thus appear that changes in N-methyl-D-aspartate and AMPA receptor subtypes may be more critical than alterations in kainate binding sites for the emergence of the functional deficits seen in the aged cognitively impaired rat.

Aging↗

PubMed1996

Autoradiographic evidence for the modulation of in vivo sigma receptor labeling by neuropeptide Y and calcitonin gene-related peptide in the mouse brain.

Peptides of the neuropeptide Y (NPY) and calcitonin gene-related peptide (CGRP) families have been reported to modulate, in vivo, sigma receptor systems in the mouse and rat hippocampal formation. In an attempt to determine if these interactions were specific to the hippocampal formation, quantitative ex vivo autoradiography was used with (+)(-)[3H]SKF 10,047 as sigma ligand after i.c.v. injections of various NPY and CGRP peptides. High levels of specific (+)(-)[3H]SKF 10,047 labeling were concentrated in various cranial nerve nuclei, whereas lower but still significant amounts of labeling were seen in the cortex, hippocampus, various hypothalamic nuclei, red nucleus, substantia nigra, central gray and cerebellum. In all brain areas enriched with specific (+)(-)[3H]SKF 10,047/sigma labeling, the Y1 receptor subtype agonist [Leu31Pro34]-NPY, as well as peptide YY and rCGRP beta, inhibited, to a rather similar extent, (+)(-)[3H]SKF 10,047 labeling. The Y2 receptor agonist NPY13-36 had no effect in any of the regions studied. These results extend findings obtained in the hippocampal formation and demonstrate the existence of in vivo modulatory effects of NPY and CGRP-related peptides on sigma sites throughout the mouse brain.

Animals↗

PubMed1996

Effect of nicotine and nicotinic receptor agonists on latent inhibition in the rat.

The present experiments assessed the influence of nicotinic cholinergic receptors on latent inhibition (LI), which is the decrement in Pavlovian conditioning resulting from extensive preexposure to a conditioned stimulus (CS). LI was assessed within a conditioned emotional response paradigm involving three phases: preexposure [either 0 (nonpreexposed) or 60 (preexposed) presentations of a 60 sec tone], conditioning (two-tone, 0.6 mA; 0.5-sec footshock pairings) and test (assessment of CS-induced suppression of lever press responding). LI was obtained in that untreated preexposed-animals displayed less conditioned suppression compared to nonpreexposed controls. Administration of nicotine (0.4 mg/kg i.p.) augmented LI when administered during conditioning. In addition, nicotine enhanced LI when administered during preexposure, suggesting that nicotine can enhance the ability of an animal to filter irrelevant stimuli. The nicotinic agonists cytisine (5 mg/kg) and lobeline (10 mg/kg) also augmented LI. Nicotine did not influence the behavior of nonpreexposed animals, suggesting that nicotine's effect was specific to mechanisms mediating LI. The nicotinic antagonists hexamethonium (10 mg/kg) and mecamylamine (5 mg/kg) reversed nicotine's enhancement of LI. Finally, nicotine's effect on LI was found to depend upon CS preexposure parameters; nicotine attenuated, rather than enhanced, the LI observed after 40 presentations of a 5-sec CS. These results suggest that stimulation of nicotine receptors can either amplify or curtail the efficacy of mechanisms involved in filtering irrelevant stimuli from further cognitive processing and that the direction of this modulation depends on the CS preexposure parameters.

Alkaloids↗

PubMed1995

Expression of the neuropeptide Y Y1 receptor in human embryonic kidney 293 cells: ligand binding characteristics, in situ hybridization and receptor autoradiography.

The human neuropeptide Y Y1 receptor cDNA was transfected into human embryonic kidney 293 (HEK 293) cells and used to determine the selectivity of newly developed Y1 and Y2 radioligands in a model which expresses a single NPY receptor subtype. The Y1 receptor probe, [125I][Leu31,Pro34]PYY, binds with high afinity (KD of 0.4-0.6 nM) to Y1-transfected HEK 293 cells whereas the Y2 radioligand, [125I]PPY3-36 failed to demonstrate any significant labelling. Only non-selective (PYY) or selective Y1 receptor agonists behaved as potent competitors for [125I][Leu31,Pro34]PYY binding in transfected cells. Additionally, the efficacy of the transfection method used was evaluated at both the transcriptional and translational levels. In situ hybridization revealed the heterogeneous distribution of the NPY Y1 receptor mRNA expressed in transfected HEK 293 cells. Similarly, the levels of NPY Y1 binding sites per transfected cell varied as shown using [125I][Leu31,Pro34]PYY receptor autoradiography. Taken together, these results demonstrate that HEK 293 cells transfected with the NPY Y1 receptor cDNA expressed both the related receptor mRNA and protein albeit at different levels depending upon each transfected cell. Additionally, these data further establish the selectivity of the newly developed Y1 and Y2 radioligands.

Autoradiography↗

PubMed1995

Apolipoprotein E4 allele as a predictor of cholinergic deficits and treatment outcome in Alzheimer disease.

Apolipoprotein E (apoE) is critical in the modulation of cholesterol and phospholipid transport between cells of different types. Human apoE is a polymorphic protein with three common alleles, APO epsilon 2, APO epsilon 3, and APO epsilon 4. ApoE4 is associated with sporadic and late-onset familial Alzheimer disease (AD). Gene dose was shown to have an effect on risk of developing AD, age of onset, accumulation of senile plaques in the brain, and reduction of choline acetyltransferase (ChAT) activity in the hippocampus of AD subjects. To characterize the possible impact of the apoE4 allele on cholinergic markers in AD, we examined the effect of apoE4 allele copy number on pre- and postsynaptic markers of cholinergic activity. ApoE4 allele copy number showed an inverse relationship with residual brain ChAT activity and nicotinic receptor binding sites in both the hippocampal formation and the temporal cortex of AD subjects. AD cases lacking the apoE4 allele showed ChAT activities close or within age-matched normal control values. The effect of the apoE4 allele on cholinomimetic drug responsiveness was assessed next in a group (n = 40) of AD patients who completed a double-blind, 30-week clinical trial of the cholinesterase inhibitor tacrine. Results showed that > 80% of apoE4-negative AD patients showed marked improvement after 30 weeks as measured by the AD assessment scale (ADAS), whereas 60% of apoE4 carriers had ADAS scores that were worse compared to baseline. These results strongly support the concept that apoE4 plays a crucial role in the cholinergic dysfunction associated with AD and may be a prognostic indicator of poor response to therapy with acetylcholinesterase inhibitors in AD patients.

Age of Onset↗

PubMed1995

In vivo modulation of sigma receptor sites by calcitonin gene-related peptide in the mouse and rat hippocampal formation: radioligand binding and electrophysiological studies.

Possible interactions between sigma (sigma) receptor sites and calcitonin gene-related peptides (CGRP) were investigated using receptor subtype-related analogues and fragment in in vivo [3H](+)SKF 10 047/sigma binding in the hippocampus, and electrophysiological recording of the N-methyl-D-aspartate (NMDA)-induced activation of CA3 pyramidal neurons, two well-established sigma assays. In both paradigms, CGRP and the agonist [Cys(ACM)2,7]hCGRPalpha modulated sigma systems. In vivo binding experiments demonstrated that CGRP and [Cys(ACM)2,7]hCGRPalpha inhibited 25-40% of specific [3H](+)SKF 10 047 labelling in the mouse hippocampal formation while the purported antagonist hCGRP8-37 was inactive. The specificity of this modulation was demonstrated further by the lack of effect of other vasoactive peptides, including the atrial natriuretic peptide, substance P, and its N-terminal fragment, substance P1-7. In the CA3 subfield of the rat dorsal hippocampus, hCGRP alpha decreased (up to 61%) the NMDA-induced activation of the pyramidal neurons. Conversely, the linear analogue [Cys(ACM)2,7]hCGRP alpha enhanced (by 85%) the NMDA-induced activation of CA3 pyramidal neurons, while the antagonistic fragment hCGRP8-37 had no effect. Haloperidol, a high-affinity sigma receptor ligand, inhibited by 90% the in vivo [3H](+)SKF 10 047 labelling, and prevented the modulation of the NMDA-induced activation by hCGRP alpha and [Cys(ACM)2,7]hCGRP alpha. It thus appears that CGRP can modulate sigma-related systems in the hippocampal formation.

Animals↗

PubMed1995

[3H]phorbol 12,13-dibutyrate/PKC binding in thoracic spinal cord: no change in amyotrophic lateral sclerosis.

[3H]phorbol 12,13-dibutyrate ([3H]PDBu), a selective ligand for various protein kinase C isozymes (PKC), was used to investigate the distribution of [3H]PDBu/PKC binding sites in thoracic spinal cords of patients who died with amyotrophic lateral sclerosis (ALS) and subjects free of neurological disease. In controls, binding of [3H]PDBu was mostly concentrated in the substantia gelatinosa and to a lesser extent in other dorsal horn regions (laminae III and IV). [3H]PDBu binding sites were also present in the ventral horn and laminae X but in somewhat lower quantities. The distribution of [3H]PDBu binding in thoracic spinal cords of patients who died with ALS was unchanged compared to controls and no significant differences were observed in the amount of specific binding in ALS. The present results on the distribution of [3H]PDBu binding sites in human spinal cord are consistent with previous studies of [3H]PDBu binding in rodents indicating that high levels of PKC are present in the dorsal horn. The results also suggest that levels of PKC isozymes are not altered in ALS spinal cord.

Aged↗

PubMed1995

Apparent affinity and potency of BIBP3226, a non-peptide neuropeptide Y receptor antagonist, on purported neuropeptide Y Y1, Y2 and Y3 receptors.

The newly developed, purported non-peptide neuropeptide Y Y1 receptor antagonist BIBP3226 was evaluated for its potential effect on the recently characterized Y3 receptor subtype and for its apparent affinity in rat and human brain membrane binding assays using highly selective neuropeptide Y Y1 and Y2 radioligands. BIBP3226 potently blocked (pA2 = 7.36) the contractile effect of neuropeptide Y in the rabbit saphenous vein, a Y1 receptor bioassay and demonstrated nM affinity for Y1/[125I][Leu31,Pro34]peptide YY binding sites. In contrast, it failed to antagonize the biological effects of neuropeptide Y in the rat vas deferens (Y2) and rat colon (Y3) and did not significantly competed for Y2/[125I]peptide YY-(3-36) binding sites in rat and human brain homogenates. Taken together, the results demonstrate further the high potency and selectivity of BIBP3226 for the neuropeptide Y Y1 receptor by establishing its lack of antagonist activity on the Y3 subtype.

Animals↗

PubMed1995

Neuropeptide receptors in developing and adult rat spinal cord: an in vitro quantitative autoradiography study of calcitonin gene-related peptide, neurokinins, mu-opioid, galanin, somatostatin, neurotensin and vasoactive intestinal polypeptide receptors.

A number of neuroactive peptides including calcitonin gene-related peptide (CGRP), substance P, neurokinin B, opioids, somatostatin (SRIF), galanin, neurotensin and vasoactive intestinal polypeptide (VIP) have been localized in adult rat spinal cord and are considered to participate either directly and/or indirectly in the processing of sensory, motor and autonomic functions. Most of these peptides appear early during development, leading to the suggestion that peptides, in addition to their neurotransmitter/neuromodulator roles, may possibly be involved in the normal growth and maturation of the spinal cord. To provide an anatomical substrate for a better understanding of the possible roles of peptides in the ontogenic development of the cord, we investigated the topographical profile as well as variation in densities of [125I]hCGRP alpha, [125I]substance P/neurokinin-1 (NK-1), [125I]eledoisin/neurokinin-3 (NK-3), [125I]FK 33-824 ([D-Ala2, Me-Phe4, Met(O)ol5]enkephalin)/mu-opioid, [125I]galanin, [125I]T0D8-SRIF14 (an analog of somatostatin); [125I]neurotensin and [125I]VIP binding sites in postnatal and adult rat spinal cord using in vitro quantitative receptor autoradiography. Receptor binding sites recognized by each radioligand are found to be distributed widely during early stages of postnatal development and then to undergo selective modification to attain their adult profile of distribution during the third week of postnatal development. The apparent density of various receptor sites, however, are differently regulated depending on the lamina and the stage of development studied. For example, the density of mu-opioid binding sites, following a peak at postnatal day 4 (P4), declines gradually in almost all regions of the spinal cord with the increasing age of the animal. [125I]substance P/NK-1 binding sites, on the other hand, show very little variation until P14 and then subsequently decrease as the development proceeds. In the adult rat, most of these peptide receptor binding sites are localized in relatively high amounts in the superficial laminae of the dorsal horn. To varying extents, moderate to low density of various peptide receptor binding sites are also found to be present in the ventral horn, intermediolateral cell column and around the central canal. Taken together, these results suggest that each receptor-ligand system is regulated differently during development and may each uniquely be involved in cellular growth, differentiation and in maturation of the normal neural circuits of the spinal cord. Furthermore, the selective localization of various receptor binding sites in adult rat spinal cord over a wide variety of functionally distinct regions reinforces the neurotransmitter/modulator roles of these peptides in sensory, motor and autonomic functions associated with the spinal cord.

Aging↗

PubMed1995

Decreased expression of the embryonic form of the neural cell adhesion molecule in schizophrenic brains.

The regulated expression of neural cell adhesion molecule (NCAM) isoforms in the brain is critical for many neurodevelopmental processes including neurulation, axonal outgrowth, and the establishment of neuronal connectivity. We have investigated the expression of the major adult isoforms of NCAM (NCAM-180, NCAM-140, and NCAM-120) and its embryonic highly polysialylated isoform (PSA-NCAM) in the hippocampal region of postmortem brains from 10 schizophrenic and 11 control individuals. Immunohistochemical analysis with a monoclonal antibody recognizing the PSA-NCAM revealed immunoreactivity primarily in the dentate gyrus and in a subset of cells in the hilus region. We have observed a 20-95% reduction in the number of hilar PSA-NCAM-immunoreactive cells in the great majority of schizophrenic brains. The change in PSA-NCAM immunoreactivity is not obvious in other hippocampal subfields. Western blots of tissues from the hippocampal region (as well as from the frontal cortex) probed with a polyclonal antibody recognizing all NCAM isoforms did not reveal significant changes in the overall expression of NCAM, suggesting that the decrease in PSA-NCAM-immunoreactive cells may be related to post-translational processing of the molecule. The expression of this embryonic form of NCAM has been proposed to be related to synaptic rearrangement and plasticity. Therefore, the decrease in PSA-NCAM immunoreactivity in schizophrenic hippocampi may suggest an altered plasticity of this structure in a large proportion of schizophrenic brains. These findings may bear significance to the "neurodevelopmental hypothesis" of schizophrenia.

Adult↗

PubMed1995

Interleukin-2 as a neuroregulatory cytokine.

Interleukin-2 (IL-2), the cytokine also known as T-cell growth factor, has multiple immunoregulatory functions and biological properties not only related to T-cells. In the past decade, substantial evidence accumulated to suggest that IL-2 is also a modulator of neural and neuroendocrine functions. First, extremely potent effects of IL-2 on neural cells were discovered, including activities related to cell growth and survival, transmitter and hormone release and the modulation of bioelectric activities. IL-2 may be involved in the regulation of sleep and arousal, memory function, locomotion and the modulation of the neuroendocrine axis. Second, the concept that IL-2 could act as a neuroregulatory cytokine has been supported by reports on the presence in rodent and human brain tissues of IL-2-like bioactivity, IL-2-like immunoreactivity, IL-2-like mRNA, IL-2 binding sites, IL-2 receptor (IL-2R alpha) and beta chain mRNA and IL-2R immunoreactivity. IL-2 and/or IL-2R molecules mainly localize to the frontal cortex, septum, striatum, hippocampal formation, hypothalamus, locus coeruleus, cerebellum, the pituitary and fiber tracts, such as the corpus callosum, where they are likely expressed by both neuronal and glial cells. Although the molecular biology of the brain IL-2/IL-2R system (including its relation to IL-15/IL-15R alpha) is not yet fully established by cloning and complete sequencing of all respective components, similarities (and to some extent differences) to peripheral counterparts are now apparent. The ability of IL-2 to readily penetrate the blood-brain barrier further suggests that this cytokine could regulate interactions between peripheral tissues and the central nervous system. Taken together, these data suggest that IL-2 of either immune and CNS origin can have access to functional IL-2R molecules on neurons and glia under normal conditions. Additionally, dysregulation of the IL-2/IL-2 receptor system could lead or contribute to functional and pathological alterations in the brain as in the immune system. Understanding the neurobiology of the IL-2/IL-2 receptor system should also help to explain neurologic, neuropsychiatric and neuroendocrine side effects occurring during IL-2 treatment of peripheral and brain tumors. Immunopharmacological manipulation either aiming at the activation or suppression of IL-2 signaling should consider functional interference with constitutive and inducible IL-2 receptors on brain cells in order to fulfil the high expectations associated with the use of this cytokine as a promising agent in immunotherapies, especially of brain tumors.

Animals↗

PubMed1995

Cholinergic markers in aged cognitively impaired Long-Evans rats.

Aged Long-Evans rats (24-25 months old) were classified into cognitively impaired or unimpaired subgroups based on their performances in the Morris Swim Maze task compared to young controls. Using quantitative in vitro receptor autoradiography, we investigated the status of various cholinergic markers in these two groups and in young adults (six months) animals. The apparent density of [3H]pirenzepine (muscarinic M1) sites was similar in the three groups of rats in various cortical areas, subfields of the hippocampus, medial septum and striatum. Similarly, choline acetyltransferase activity and the density of [3H]hemicholinium-3 (high-affinity choline uptake) and [3H]cytisine (nicotinic) binding sites were also unchanged in the brain regions studied between the aged cognitively impaired, unimpaired and young adult rats. In contrast, significant increases in [3H]AF-DX 384 (muscarinic M2) binding density were observed in various cortical areas and in the molecular layer of the dentate gyrus of aged cognitively impaired versus unimpaired rats and in few cortical regions of old as compared to young animals. Therefore, a selective alteration in the regulation of putative M2 receptor sites is apparent, particularly in the aged cognitively impaired rats. Increases in M2 binding sites could lead to a decrease in the capacity to release acetylcholine, as some of the M2 receptors are believed to act as negative autoreceptors. This could influence cognitive functions as selective M2 blockers have recently been reported to facilitate spatial memory in aged impaired rats [Doods et al. (1993) Life Sci. 52, 497-503: Quirion et al. (1995) J. Neurosci. 15, 1455-1462.

Aging↗

PubMed1995

Quantitative autoradiographic localization of [125I-Tyr8]bradykinin receptor binding sites in the rat spinal cord: effects of neonatal capsaicin, noradrenergic deafferentation, dorsal rhizotomy and peripheral axotomy.

In vitro receptor autoradiography was used to localize, quantify and characterize [125I-Tyr8]bradykinin binding sites in all major spinal cord segments of normal rats and animals subjected to various chemical treatments and surgical lesions. [125I-Tyr8]bradykinin specific binding sites were predominantly located to superficial laminae of the rat dorsal horn, with the substantia gelatinosa showing the highest density of labelling (values ranging from 3.1 fmol/mg tissue in cervical to 4.5 fmol/mg tissue in lumbar segments). A moderate density (1.8-3.0 fmol/mg tissue) of specific binding was observed in lamina III, whereas in other areas, i.e. laminae I and IV-X, lower amounts of labelling were detected. Within the superficial laminae of the dorsal horn, [125I-Tyr8]bradykinin binding was largely distributed over the neurophil with some perikarya showing concentrations of labelling. In contrast, the ventral horn showed a rather homogeneous distribution of [125I-Tyr8]bradykinin binding over the neuropil, with silver grain alignments surrounding motoneuron perikaryas and proximal processes. Bradykinin, [Tyr8]bradykinin and B2 receptor antagonists (D-Arg[Hyp3,Thi5,D-Tic7,Oic8]bradykinin (Hoe 140), D-Arg[Tyr3,D-Phe7,Leu8]bradykinin, D-Arg[Hyp3, Leu8]bradykinin, D-Arg[Hyp2, Thi5,8,-Phe7]bradykinin D-Arg[Hyp3, D-Phe7, Leu8]bradykinin, Tyr0, D-Arg[Hyp3, D-Phe7, Leu8]bradykinin inhibited [125I-Tyr8]-bradykinin binding with very high subnanomolar affinities, while the B1 receptor agonist (Tyr0,des-Arg10-kallidin) and antagonist ([Leu8]-des-Arg9-bradykinin) did not significantly affect [125I-Tyr8]bradykinin binding at up to micromolar concentrations. Two weeks after unilateral lumbar dorsal rhizotomy (L1-L6) or peripheral lesions of the sciatic nerve, significant decreases ( +/- 50%) in [125I-Tyr8]bradykinin binding sites were found in ipsilateral laminae I-III of lumbar spinal cord.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗

PubMed1995

Dopamine D1 receptor ligands modulate cognitive performance and hippocampal acetylcholine release in memory-impaired aged rats.

The possible modulation by D1 drugs of learning abilities of a population of aged memory-impaired animals was investigated in the present study. The level of D1/[3H]SCH 23390 receptors was first examined by quantitative autoradiography to ascertain if cognitive deficits seen in these animals could be related to alterations in the levels of these receptors. No significant differences in [3H]SCH 23390 binding were observed in any of the brain areas examined between young, and aged memory-unimpaired and aged memory-impaired animals. However, the cognitive deficits of the aged-impaired rats were modulated by D1 drugs. The D1 agonists SKF 38393 and SKF 81297 (3.0 mg/kg, i.p.) significantly reduced the latency period to find a hidden platform in the Morris Water Maze, reflecting improved cognitive functions, while the D1 antagonist SCH 23390 (0.05 mg/kg, i.p.) had no overall significant effect. Moreover, the D1 agonist SKF 38393 increased, whereas the antagonist inhibited, in vivo hippocampal acetylcholine release. Taken together, these results suggest that functional hippocampal acetylcholine-dopamine interactions exist in aged memory-impaired rats. More importantly, the cognitive deficits seen in the aged-impaired rats can be attenuated by stimulations of D1 receptors, hence suggesting an alternative approach to alleviate the cognitive deficits seen in the aged brain.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1995

Comparative laminar distribution of various autoradiographic cholinergic markers in adult rat main olfactory bulb.

To provide anatomical information on the complex effects of acetylcholine (ACh) in the olfactory bulb (OB), the distribution of different cholinergic muscarinic and nicotinic receptor sub-types was studied by quantitative in vitro autoradiography. The muscarinic M1-like and M2-like sub-types, as well as the nicotinic bungarotoxin-insensitive (alpha 4 beta 2-like) and bungarotoxin-sensitive (alpha 7-like) receptors were visualized using [3H]pirenzepine, [3H]AF-DX 384, [3H]cytisine and [125I] alpha-bungarotoxin (BTX), respectively. In parallel, labelling patterns of [3H]vesamicol (vesicular acetylcholine transport sites) and [3H]hemicholinium-3 (high-affinity choline uptake sites), two putative markers of cholinergic nerve terminals, were investigated. Specific labelling for each cholinergic radioligand is distributed according to a characteristic laminar and regional pattern within the OB revealing the lack of a clear overlap between cholinergic afferents and receptors. The presynaptic markers, [3H]vesamicol and [3H]hemicholinium-3, demonstrated similar laminar pattern of distribution with two strongly labelled bands corresponding to the glomerular layer and the area around the mitral cell layer. Muscarinic M1-like and M2-like receptor sub-types exhibited unique distribution with their highest levels seen in the external plexiform layer (EPL). Intermediate M1-like and M2-like binding densities were found throughout the deeper bulbar layers. In the glomerular layer, the levels of muscarinic receptor subtypes were low, the level of M2-like sites being higher than M1. Both types of nicotinic receptor sub-types displayed distinct distribution pattern. Whereas [125I] alpha-BTX binding sites were mostly concentrated in the superficial bulbar layers, [3H]cytisine binding was found in the glomerular layers, as well as the mitral cell layer and the underlying laminae. An interesting feature of the present study is the visualization of two distinct cholinoceptive glomerular subsets in the posterior OB. The first one exhibited high levels of both [3H]vesamicol and [3H]hemicholinium-3 sites. It corresponds to the previously identified atypical glomeruli and apparently failed to express any of the cholinergic receptors under study. In contrast, the second subset of glomeruli is not enriched with cholinergic nerve terminal markers but displayed high amounts of [3H]cytisine/nicotinic binding sites. Taken together, these results suggest that although muscarinic receptors have been hypothesized to be mostly involved in cholinergic olfactory processing and short-term memory in the OB, nicotinic receptors, especially of the cytisine/ alpha 4 beta 2 sub-type, may have important roles in mediating olfactory transmission of efferent neurons as well as in a subset of olfactory glomeruli.

Alkaloids↗

PubMed1995

Effect of MPTP and L-deprenyl on antioxidant enzymes and lipid peroxidation levels in mouse brain.

Excessive free radical formation or antioxidant enzyme deficiency can result in oxidative stress, a mechanism proposed in the toxicity of MPTP and in the etiology of Parkinson's disease (PD). However, it is unclear if altered antioxidant enzyme activity is sufficient to increase lipid peroxidation in PD. We therefore investigated if MPTP can alter the activity of the antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-PX) and the level of lipid peroxidation. L-Deprenyl, prior to MPTP administration, is used to inhibit MPP+ formation and its subsequent effect on antioxidant enzymes. MPTP induced a threefold increase in SOD activity in the striatum of C57BL/6 mice. No parallel increase in GSH-PX or CAT activities was observed, while striatal lipid peroxidation decreased. At the level of the substantia nigra (SN), even though increases in CAT activity and reduction in SOD and GSH-PX activities were detected, lipid peroxidation was not altered. Interestingly, L-deprenyl induced similar changes in antioxidant enzymes and lipid peroxidation levels, as did MPTP. Taken together, these results suggest that an alteration in SOD activity, without compensatory increases in CAT or GSH-PX activities, is not sufficient to induce lipid peroxidation.

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

PubMed1995

Stimulation of CRH-mediated ACTH secretion by central administration of neurotensin: evidence for the participation of the paraventricular nucleus.

Central administration of neurotensin (NT) stimulates hypothalamic-pituitary-adrenal (HPA) activity in freely-moving rats. Increases in adrenocorticotropin hormone (ACTH) and corticosterone (B) were observed 15 min following central NT administration and remained elevated for up to 4 h. Of the two NT fragments tested, NT1-8 and NT8-13, only NT8-13 was found to significantly elevate ACTH and B levels. Moreover, NT8-13 activated the HPA axis with a temporal profile similar to NT1-13, suggesting an interaction with the pharmacologically and molecularly characterized NT receptor. Animals pre-treated intravenously with the corticotropin-releasing hormone (CRH) antagonist, alpha-helical CRH, showed attenuated plasma ACTH and B responses to central NT administration. This indicates that CRH receptor activation is necessary for the stimulatory effects of NT on HPA function. Bilateral lesions of the paraventricular nucleus (PVN) of the hypothalamus significantly reduced NT-induced stimulation of ACTH and B release suggesting that the PVN is essential for NT's stimulatory action. Median eminence content studies indicated that acute central NT administration stimulates CRH, but not arginine vassopressin (AVP), release in animals examined 60 min following NT injection. Taken together, these findings suggest that the stimulatory effects of NT on HPA activity occur via specific NT receptors and that one site of action of NT is likely at the level of the PVN where NT elicits the release of CRH.

Adrenocorticotropic Hormone↗