Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q86TM3 (cage)
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The pedunculopontine tegmental nucleus (PPTg) contains a population of cholinergic neurons thought to be part of the ascending reticular activating system, and non-cholinergic neurons. In the previous study it was shown that various excitotoxins made effective lesions of cholinergic neurons in the PPTg but that quinolinate made smaller lesions in the non-cholinergic population, making it more selective than any other excitotoxin. The purpose of the present experiment was, first, to make lesions of cholinergic neurons throughout the length of the PPTg by infusing toxin at two different sites within it; and second, to examine simple motor activities in rats bearing either quinolinate or ibotenate lesions of the PPTg, and contrast these with the deficits seen after 6-hydroxydopamine (6-OHDA) induced lesions of mesostriatal dopamine (DA)-containing neurons. Post-mortem examination was carried out using choline acetyltransferase (ChAT) and tyrosine hydroxylase (TOH) immunohistochemistry, and routine Nissl staining. Both quinolinate and ibotenate destroyed approximately 75% of ChAT-positive neurons in the PPTg, but damage to non-cholinergic neurons (assessed by Nissl staining) was twice as great following ibotenate as quinolinate. 6-OHDA induced almost complete lesions of mesostriatal DA neurons, assessed by TOH immunohistochemistry. DA depleted rats showed deficits in drinking and spilled more food in the first 2 weeks after surgery, and were unable to reach or grasp food pellets in the staircase test. They also showed strong ipsilateral turning in response to amphetamine and contralateral turning to apomorphine. Quinolinate lesioned rats had no eating or drinking impairment in the home cage but showed a reaching (though not grasping) disability in the staircase test. They had a mild ipsilateral bias following amphetamine. Ibotenate lesioned rats, despite having larger lesions than the quinolinate, showed no deficits in eating or drinking in the home cage, or reaching or grasping disabilities in the staircase test. They did have a mild contralateral bias in response to amphetamine. This dissociation of the effects of quinolinate and ibotenate lesions of the PPTg is consistent with the suggestion that the PPTg has two functionally distinct components, and is attributed to the differential lesion of non-cholinergic neurons by the two excitotoxins.
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PMID:Excitotoxic lesions of the pedunculopontine tegmental nucleus of the rat. II. Examination of eating and drinking, rotation, and reaching and grasping following unilateral ibotenate or quinolinate lesions. 135 93

At 31 days of age, Long-Evans female rats sustained aspirative lesions of the septohippocampal pathways and, 14 days later, received intrahippocampal suspension grafts prepared from the region including the medial septum and the diagonal band of Broca (Group S, n = 11), from the region including the mesencephalic raphe (Group R, n = 11) or from both regions together (Group S+R, n = 11). Sham-operated (Group Sham, n = 9) and lesion-only (Group Les, n = 11) rats served as non-grafted controls. Seven Sham, 7 Les and 8 rats from each transplant group were tested for home cage activity (6 months after grafting) and radial maze performance (between 7.5 and 8.5 months post-grafting). One month after completion of behavioral testing, the dorsal hippocampi of these rats were prepared for measuring choline acetyltransferase (ChAT) activity and high affinity synaptosomal uptake of both [3H]choline and [3H]serotonin. The remaining rats were used for histological verifications on brain sections stained for acetylcholinesterase (AChE). The lesions increased locomotor activity, impaired radial maze learning and, in the dorsal hippocampus, reduced AChE positive staining, decreased ChAT activity (-73%) as well as high affinity uptake of both choline (-81%) and serotonin (-82%). Neither type of transplant produced any significant behavioral recovery. However, septal transplants increased hippocampal AChE positivity, restored ChAT activity and enhanced choline uptake to 116% and 70% of the values found in sham-operated rats, respectively; they had no significant effect on uptake of serotonin. Transplants from the raphe region had weak effects on hippocampal AChE positivity, increased both the ChAT activity and the choline uptake to 70% ad 38% of the sham-operated rats, respectively, and produced an (over)compensation of the serotonin uptake which reached 324% of the values found in sham-operated rats. The co-transplantation of both regions resulted in restoration of ChAT activity (113% of sham-operated rats values), choline uptake (83% of sham-operated rats) and serotonin uptake (129% of sham-operated rats). Our neurochemical data show that after extensive denervation of the hippocampus, intrahippocampal grafts of fetal neurons may foster a neurotransmitter-specific recovery which depends upon the anatomical origin of the grafted cells: a graft rich in serotonergic neurons overcompensates the serotonergic deficit, a graft rich in cholinergic neurons attenuates the cholinergic deficit, whereas a mixture of both types of grafts produces recovery from both types of deficits. Thereby, both the feasibility and the interest of the co-grafting technique are confirmed.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effects of septal and/or raphe cell suspension grafts on hippocampal choline acetyltransferase activity, high affinity synaptosomal uptake of choline and serotonin, and behavior in rats with extensive septohippocampal lesions. 151 8

Long-Evans female rats sustained electrolytic lesions of the fimbria and the dorsal fornix and, 10-14 days later, received intrahippocampal suspension grafts of septal-diagonal band tissue from either 14-day-old (Group S14, n = 8) or 16-day-old fetuses (Group S16, n = 10), or of parietal cortex from 16-day-old fetuses (Group Cx, n = 10). Sham-operated (Group S, n = 10) and lesion-only (Group Fifo, n = 21) rats served as non-grafted controls. Spontaneous alternation was assessed in a T-maze at three weeks and two months post-grafting. Home cage and open field activity as well as radial maze learning were assessed from two months post-grafting onwards. Fimbria-fornix lesions induced lasting hyperactivity in both the open field and the home cage, impaired radial maze learning and transiently reduced spontaneous alternation rates. Neither type of graft significantly affected home cage activity. Septal-diagonal band grafts improved open field habituation (within trial decline of ambulatory activity) and radial maze learning; the former was observed only in S16 rats, whereas the latter was observed only in S14 rats. Acetylcholinesterase histochemistry revealed an initial lesion-induced depletion of hippocampal acetylcholinesterase (eight days post-surgery) which was no longer observed at the end of the experiment. Acetylcholinesterase positivity was similar in S14 and S16 grafts, which also contained many choline acetyltransferase-positive neurons. Cortical grafts were found to be almost devoid of acetylcholinesterase positivity and no well-stained choline acetyltransferase-positive neurons could be identified. Septal-diagonal band grafts from 14-day-old fetuses and cortical grafts contained more parvalbumin-positive neurons than septal-diagonal band grafts provided by 16-day-old fetuses. These results suggest that grafts rich in cholinergic neurons may promote behavioral recovery from fimbria-fornix lesion-induced deficits. However, such a recovery may concern different behavioral deficits as a function of the age of the implanted tissue, suggesting that the maturity stage of the donor may critically influence the functional expression in the lesioned recipient. Also, such a recovery does not appear to be related solely to cholinergic hippocampal (re)innervation and might depend on the presence, not only of cholinergic neurons, but also of non-cholinergic neuronal populations, such as parvalbumin-positive (probably GABAergic) neurons.
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PMID:Graft-induced behavioral recovery from subcallosal septohippocampal damage in rats depends on maturity stage of donor tissue. 177 34

By means of radioisotope, the daily changes of cholinergic nervous markers, acetylcholine (ACh), choline acetyltransferase (ChAT), acetylcholinesterase (AChE) and muscarinic receptors in the mouse brain were measured in September and October. The mice were housed 5 animals to a cage under natural light-dark cycle (12 : 12) for 7 d in the laboratory room at 18-22 degrees C. The determinations of ACh were taken, every 2 h, to assess the brain ACh of 5 mice for 24 consecutive hours. M-cholinergic receptors, ChAT and AChE activity were examined at 10:00, 16:00 and 22:00. The results demonstrated that the ACh contents, ChAT activity and muscarinic receptor Bmax value were high at 10:00, low at 16:00 and 22:00. However, AChE maximum activity was found at 16:00, minimum activity at 22:00. But the affinity of muscarinic receptors to [3H]QNB did not show any significant daily changes. These data strongly suggested that in mouse brain the cholinergic nervous markers showed a clear daily rhythm.
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PMID:[Circadian changes of acetylcholine, choline acetyltransferase, acetylcholinesterase and muscarinic receptors in mouse brain]. 177 79

The purpose of this study was to determine the effects of subchronic administration of the organophosphate methylparathion (MPTH) during gestation on behavior and development of brain cholinergic neurons in the offspring. Pregnant rats received daily po doses of MPTH from Day 6 through Day 20 of gestation at doses causing no (1.0 mg/kg) or minimal (1.5 mg/kg) visible signs of maternal toxicity. Acetylcholinesterase (AChE) and choline acetyltransferase (CAT) activities, and [3H]quinuclidinyl benzilate (QNB) binding to muscarinic receptors, were determined in several brain regions at 1, 7, 14, 21, and 28 days postnatal age and in maternal brain at Day 19 of gestation. Prenatal exposure to 1.5 mg MPTH/kg reduced AChE and increased CAT activity in all brain regions at each developmental period and in maternal brain. Similar exposure to 1.0 mg MPTH/kg caused a significant but smaller and less persistent reduction in AChE activity but no change in brain CAT activity of the offspring. Both doses of MPTH decreased the Bmax of 3H-QNB binding in maternal frontal cortex but did not alter the postnatal pattern of 3H-QNB binding. In parallel studies, prenatal exposure to MPTH did not affect a variety of behaviors. However, cage emergence, accommodated locomotor activity, and operant behavior in a mixed paradigm were impaired in rats exposed to 1.0 but not to 1.5 mg/kg MPTH. No morphological changes were observed in hippocampal or cerebellar tissue. Thus, subchronic prenatal exposure to MPTH altered postnatal development of cholinergic neurons and caused subtle alterations in selected behaviors of the offspring.
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PMID:Brain cholinergic, behavioral, and morphological development in rats exposed in utero to methylparathion. 397 8

Five vervet monkeys were administered increasing doses (4--12 mg/kg/day) of d-amphetamine over a period of 35 days. Three phases od behavioural change were discerned: phase 1 during which animals exhibited repetitive stereotyped action sequences with rapid head movements, occasional abnormal grooming, picking at the cage, hand-staring and snatching; phase 2 in which behaviour became progressively more restricted and animals became markedly unresponsive to auditory, visual and tactile stimuli; phase 3 was characterised by the abrupt development of gross over-responsiveness to environmental stimuli, ataxia and tremor. At post-mortem, by comparison with controls, amphetamine-treated monkeys showed marked depletions of the monoamines dopamine (DA), noradrenaline (NA) and serotonin (5-HT) in corpus striatum and cerebral cortex and reductions in the activities of tyrosine hydroxylase and dopa decarboxylase in striatum. Turnover of these monoamines, assessed by high-performance liquid chromatography determinations of their respective metabolites, was also reduced. These findings are interpreted as evidence of monoamine neurone destruction, most severely in the case of DA neurones. Though there was a non-significant reduction in 3H-spiperone binding (reaching almost 50% in nucleus accumbens), numbers of receptors for the monoamines nA and 5-HT were not significantly changed, and the activities of the enzymes choline acetyltransferase and glutamine decarboxylase were similar in experimental and control animals. The contrast of these findings with those seen in post-mortem brains in schizophrenia is discussed.
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PMID:Behavioural and biochemical effects of chronic amphetamine treatment in the vervet monkey. 613 May 56

Brains from Cebus Apella monkeys have been mapped biochemically using a cryo-section technique which enables exact micro-dissectioning of tissue. Two neurotransmitters; noradrenaline (NA) and gamma-amino-butyric acid (GABA) were measured by gas chromatography-masspectrometry technique. In addition biochemical markers reflecting metabolic activity in the dopamine (homovanillic acid, HVA, 3, 4-dihydroxyphenylacetic acid, DOPAC), serotonin (5-hydroxyindoleacetic acid, 5-HIAA), noradrenaline (4-hydroxy-3-methoxy-phenylglycol, HMPG), acetylcholine (choline acetyltransferase, CAT) and GABA (glutamic acid decarboxylase, GAD) transmitter systems were assayed. The distribution of these transmitter markers roughly corresponded to earlier studies in other non-human primates, whereas similar studies on the human brain generally show lower concentrations and enzyme activities. One monkey exposed to severe stress immediately before death deviated from the normal animals with regard to HVA, 5-HIAA, GAD and GABA. For the study of neuroleptic drugs, and notably their neurological side-effects, Cebus Apella monkeys have turned out to be particularly useful. In our laboratory we have employed this species of monkey to develop a model for acute dystonia and tardive dyskinesia (Gunne and Barany 1976, 1979, Barany et al. 1979). As a first step in the topological mapping of brain neuro-chemistry in these animals we here present data from normal monkeys, not treated with neuroleptics. During the ongoing project there was an unplanned "stress experiment" in one monkey, which had a nightly fight with a cage partner and had to be sacrificed the morning after due to severe wounds. The present communication describes a method for obtaining well-defined samples from monkey brains and presents the data on homovanillic acid (HVA), 3.4-dihydroxyphenylacetic acid (DOPAC), 5-hydroxyindoleacetic acid (5-HIAA), noradrenaline (NA), 4-hydroxy-3-methoxy-phenyl glycol (HMPG), choline acetyltransferase (ChAT), glutamic acid decarboxylase (GAD), and gamma-amino-butyric acid (GABA) in discrete regions from 7 drug-naive control monkeys. Also data from the stressed animal are presented.
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PMID:Discrete regional distribution of biochemical markers for the dopamine, noradrenaline, serotonin, GABA and acetylcholine systems in the monkey brain (Cebus Apella). Effects of stress. 615 Jun 1

Rats were chronically injected with saline, clozapine, or haloperidol and tested for alterations in dopamine (DA)-mediated behavior, DA receptor binding, and both acetylcholine (ACH) concentration and choline acetylase activity. Behaviorally, chronic haloperidol significantly enhanced apomorphine-induced chewing and sniffing stereotypies, associated with DA nigrostriatal activation, while clozapine selectively enhanced apomorphine locomotor activity and cage-floor crossing, behavior associated with DA mesolimbic activation. Biochemically, chronic haloperidol significantly enhanced 3H-spiroperidol binding in striatum and in mesolimbic loci (nucleus accumbens/olfactory tubercle) while chronic clozapine failed to produce such enhancement. Acute haloperidol induced an initial decrease in striatal ACH concentration followed by a return of ACH to normal levels within 1 week. There was no change in choline acetylase activity during the same time interval. These findings suggest that haloperidol may inhibit DA mechanisms in both the nigrostriatal may inhibit DA mechanisms in both the nigrostriatal and mesolimbic systems, but that the effect of clozapine on DA mechanisms may be specific to mesolimbic rather than striatal structures. At the same time, the lack of effect of clozapine on 3H-spiroperidol binding may indicate that behaviorally important changes in DA sensitivity can develop independent of changes in post-synaptic DA receptors. The pattern of cholinergic changes with chronic haloperidol suggests that the increase in striatal DA receptor number seen with chronic treatment re-establishes DA inhibition of cholinergic firing within the striatum.
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PMID:Behavioral and biochemical aspects of neuroleptic-induced dopaminergic supersensitivity: studies with chronic clozapine and haloperidol. 680 29

This longitudinal study, extending over 12 months, assessed the behavioural and biochemical effects of hippocampal sympathetic ingrowth (HSI) into the partially denervated hippocampus. Male Long-Evans rats received fimbria-fornix lesions (FIFO) or sham operations at 90 days of age. At the same time half of the rats from each group sustained bilateral ablation of the superior cervical ganglia (SCGX). A battery of behavioural tests, measuring spontaneous alternation, activity in the open field and home cage, and radial-maze performance, were employed, starting after one very short (16 days) and one extended (216 days) post-operative delay. Neurochemical analyses measuring choline acetyltransferase (ChAT) activity, high-affinity choline (HACU) and noradrenaline uptake by hippocampal synaptosomes (HANU), hippocampal noradrenaline ([NA]), serotonin ([5-HT]) and 5-hydroxyindoleacetic acid ([5-HIAA]) concentrations were carried out in a dorsal, a "middle" and a ventral region of the hippocampus. Lesion of the FIFO induced a significant and enduring deficit in radial-maze performance, in addition to a persistent locomotor hyperactivity. ChAT and HACU were significantly depleted in all three regions of the hippocampus at 12 months, and these deficits were negatively correlated with maze performance. SCGX in the presence of the FIFO lesion significantly reduced [NA] in the middle region of the hippocampus, as compared to SCGX rats, and contributed to a restoration of lesion-induced depletions in [5-HT] and [5-HIAA] in the middle and ventral hippocampal regions, whilst failing to elicit any behavioural changes at either time point. It is concluded that if lesion-induced HSI indeed occurred, as is suggested by neurochemical evidence, it had no effect upon the observed behavioural deficits elicited by transection of the FIFO in the rat.
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PMID:Behavioural and neurochemical effects of superior cervical ganglionectomy in rats with septo-hippocampal lesions. 773 90

Long-Evans female rats sustained electrolytic lesions of the fimbria and the dorsal fornix and, two weeks later, received intrahippocampal suspension grafts of fetal tissue. The grafts were prepared from regions including either the medial septum and the diagonal band of Broca (septal grafts), or the mesencephalic raphe (raphe grafts), or from both these regions together (co-grafts). All rats were submitted to a series of behavioural tests (home cage and open-field locomotion, spontaneous alternation, radial-arm maze and Morris water maze performance) run over two periods after grafting (one to nine weeks and 20-35 weeks). Two weeks after completion of behavioural testing, histological (acetylcholinesterase and Cresyl Violet staining) and/or neurochemical (choline acetyltransferase activity, high-affinity synaptosomal uptake of choline and serotonin, noradrenaline, serotonin and 5-hydroxyindolacetic acid concentrations) verifications were performed on the hippocampus. Compared to sham-operated rats, lesion-only rats exhibited hyperactivity which was transient in a familiar environment (home cage) and lasting in an unfamiliar one (open field), decreased rates of spontaneous T-maze alternation, and impaired memory performance in both the radial-arm maze and the Morris water maze. These rats also showed decreased cholinergic and serotonergic markers with a maximal depletion in the septal two-thirds of the hippocampus. Noradrenaline concentration tended to be increased in the dorsal third of the hippocampus, but was not modified in the other two-thirds. While septal grafts specifically increased the cholinergic markers and raphe grafts the serotonergic ones, neither of these grafts produced a lasting effect on any behavioural variable. Conversely, the co-grafts, which increased both the cholinergic and serotonergic markers in the septal two-thirds of the hippocampus, completely normalized the Morris water maze probe trial performance, but failed to affect any of the other behavioural variables. Our present results confirm that grafts of fetal neurons injected into the denervated hippocampus may induce a neurochemical recovery that depends on the anatomical origin of the grafted cells, and that co-grafting two fetal brain regions allows the combination of their individual neurochemical properties. Furthermore, our results show that these neurochemical effects of the co-grafts may be involved in the recovery of behavioural function observed in the water maze. However, somewhat paradoxically, those effects appear inefficient for inducing any recovery in other behavioural tasks, even in the radial-arm maze; which is assumed to measure similar spatial functions.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The effects of intrahippocampal raphe and/or septal grafts in rats with fimbria-fornix lesions depend on the origin of the grafted tissue and the behavioural task used. 789 48


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