Biomedical subjects

G Forloni

Publications and source records attributed to G Forloni.

At least 55 records · Page 3Linked to original sources

PubMed1991

Modulation of cortical in vivo acetylcholine release by the basal nuclear complex: role of the pontomesencephalic tegmental area.

Acetylcholine (ACh) release in vivo from rat cortices was determined by microdialysis either after injection of drugs into the basal nuclear complex (NBM) or after electrolytic lesion of the pontomesencephalic tegmental nucleus (PPT). Scopolamine (SCOP) (5-10 micrograms) increased and oxotremorine (10 micrograms) reduced cortical ACh release, indicating that an inhibitory mechanism operates within the area. The gamma-aminobutyric acid (GABA)ergic antagonist, picrotoxin (2.5 micrograms), by disinhibiting the cholinergic basocortical neurons, induced an increase that was not affected by SCOP. Acute lesion of the cholinergic PPT efferents to NBM raised cortical basal release. Thus, ACh released from the PPT terminals apparently modulates the function of basocortical neurons mainly through a polysynaptic link via GABAergic neurons.

Acetylcholine↗

PubMed1991

Long-term acetyl-L-carnitine treatment in Alzheimer's disease.

In a double-blind, placebo-controlled, parallel-group, randomized clinical trial, we studied the efficacy of long-term (1-year) oral treatment with acetyl-L-carnitine in 130 patients with a clinical diagnosis of Alzheimer's disease. We employed 14 outcome measures to assess functional and cognitive impairment. After 1 year, both the treated and placebo groups worsened, but the treated group showed a slower rate of deterioration in 13 of the 14 outcome measures, reaching statistical significance for the Blessed Dementia Scale, logical intelligence, ideomotor and buccofacial apraxia, and selective attention. Adjusting for initial scores with analysis of covariance, the treated group showed better scores on all outcome measures, reaching statistical significance for the Blessed Dementia Scale, logical intelligence, verbal critical abilities, long-term verbal memory, and selective attention. The analysis for patients with good treatment compliance showed a greater drug benefit than for the overall sample. Reported adverse events were relatively mild, and there was no significant difference between the treated and placebo groups either in incidence or severity.

Acetylcarnitine↗

PubMed1990

Decrease in [3H]hemicholinium binding to high-affinity choline uptake sites in deafferented striatum: restoration by oxiracetam.

Frontal cortical deafferentation of the rat striatum reduces the tone of striatal cholinergic neurons. We used biochemical and autoradiographic techniques to investigate whether the [3H]hemicholinium-3 ([3H]HCh-3) binding to sodium-dependent high-affinity choline uptake sites was influenced by this lesion. Frontal deafferentation produced a reduction of about 30% in the number of [3H]HCh-3 binding sites (Bmax) in striatum, with no significant changes in the binding affinity (Kd). Autoradiography showed a significant reduction of [3H]HCh-3 binding sites in the anteromedial portion of the striatum, but not in the posterior part of frontal deafferented rats. Oxiracetam (100 mg/kg), a nootropic drug, did not affect the distribution of [3H]HCh-3 binding sites in sham-operated rats but completely overcame the reduction in the number of [3H]HCh-3 binding sites in deafferented striatum.

Afferent Pathways↗

PubMed1990

Developmental expression of somatostatin in mouse brain. I. Immunocytochemical studies.

The postnatal development of the distribution of somatostatin immunoreactive (SOMLI) neurons and fibers in the forebrain of the Balb/C mouse and their relationship to cholinergic afferents have been examined. SOMLI was first discernable in the hypothalamus on postnatal day (PND) 3 and increased gradually to reach adult levels by PND 30. In the limbic system, SOMLI is detectable at birth. In all other structures of the forebrain, SOMLI could be observed by PND 3 but the distribution, density and morphology of the immunoreactive neurons evolved over the following 2-3 weeks. In general, SOMLI cells and fibers increased for 1-3 weeks after their initial appearance and subsequently declined to achieve adult levels. The distribution pattern of SOMLI elements in adult mouse brain was similar to previous reports in rat with a few notable differences in thalamus, olfactory structures and, to a lesser degree, cortex and hippocampus. The temporal pattern of SOMLI expression in extrahypothalamus forebrain regions, during development, suggests a role of this peptide in differentiation and synapse formation. Such an hypothesis receives further support from neonatal lesions of the basal forebrain which resulted in transient cortical cholinergic deafferentation, a delay of cortical differentiation and a transient increase in the number of SOMLI cells in cortex.

Aging↗

PubMed1990

Developmental expression of somatostatin in mouse brain. II. In situ hybridization.

The distribution and the levels of expression of preprosomatostatin (PPSOM) mRNA were examined during pre- and postnatal development of the mouse brain using the in situ hybridization technique. The signal obtained by in situ hybridization of embryonic tissues at day 14 and day 17 of gestation was highest over the neurons of the pyriform cortex, amygdala, and entopeduncular nucleus. The signal was very low over cells of the neocortex and the developing hippocampal formation. The density of grains overlying the neurons of the amygdala and pyriform cortex continued to be high during early postnatal life, but decreased as the animals became adults. A progressive increase of PPSOM mRNA expression was observed in postnatal animals in the stratum oriens and dentate gyrus of the hippocampal formation. In the cerebral cortex and striatum, the number of these neurons became maximal between postnatal weeks 1 and 3. In the diencephalon, the highest densities of grains were found over neurons in the nucleus reticularis thalami and zona incerta at postnatal day 21; these levels declined slightly thereafter. The cells of the periventricular nucleus of the hypothalamus had high densities of grains as early as postnatal week 1 and continued to have high densities of grains in adult animals. These patterns of hybridization density parallelled the distribution of SOM-like immunoreactivity in the mouse brain. When PPSOM mRNA expression was examined in the cerebral cortices of mice that received lesions of the nucleus basalis of Meynert as neonates, a transient increase in the number of cells expressing PPSOM mRNA was observed in the frontoparietal cortex ipsilateral to the lesion at postnatal day 10, but not at postnatal day 30. Importantly, the density of grains over the individual cells was not altered in lesioned animals at these two ages.

Aging↗

PubMed1990

Increased tryptophan hydroxylase mRNA in raphe serotonergic neurons spared by 5,7-dihydroxytryptamine.

Neurons expressing the tryptophan hydroxylase (TPH) mRNA within the raphe nuclei of control rats showed a distribution similar to that observed using an antibody for TPH. Numerous packed cells expressing the TPH mRNA were observed in the ventral and dorsal zone of the nucleus raphe dorsalis (NDR) and in the pars dorsalis of the nucleus centralis superior (NCS) whereas fewer and more scattered neurons were found in the pars medialis of NCS. Five days after the intracerebroventricular injection of 5,7-dihydroxytryptamine (5,7-DHT), which markedly reduced the serotonin (5-HT) content in the hippocampus, caudate putamen and cortex, the hybridization signal had completely disappeared in the dorsal region of the NDR. In the ventromedial region, above and between the medial longitudinal fasciculus (MLF), which includes the pars dorsalis of NCS, there was a partial decrease of cell number and a marked increase of the grain density over spared neurons. No significant change was noted in the number of TPH-positive cells and hybridization signal in individual neurons of the pars medialis of NCS. Consistent with previous evidence of increased TPH activity in the residual 5-HT terminals, the present study shows that synthesis of the TPH mRNA may be augmented in some neurons surviving the lesion.

5,7-Dihydroxytryptamine↗

PubMed1990

Production and characterization of monoclonal antibodies to N-acetyl-aspartyl-glutamate.

N-acetyl-aspartyl-glutamate (NAAG) is a putative neuromodulator/neurotransmitter in the mammalian nervous system. Immunohistochemical studies with polyclonal NAAG antisera have revealed immunoreactive neurons and processes in several brain regions. However, these antisera crossreact to some degree with N-acetyl-aspartate (NAA), which is present in mM concentrations in brain, prompting the development of monoclonal antibodies (MAb) more specific for NAAG. By fusing spleen lymphocytes obtained from BALB/c mice pre-immunized with NAAG covalently linked to bovine serum albumin by carbodiimide with SP2/0-Ag 14 mouse myeloma cells, we produced three IgG2a (kappa) MAb which specifically reacted with NAAG. These MAb exhibited negligible crossreactivity with NAA or with structurally similar peptides, as shown by solid-phase radioimmunoassay. Antibody activity was absorbed out selectively by both NAAG-thyroglobulin conjugate and free NAAG. These MAb stained many nuclei of the medulla-pons and midbrain, mitral cells in the olfactory bulb, pyramidal neurons in sensorimotor cortex, locus ceruleus, and several cholinergic cranial nuclei. The staining pattern strongly correlated with NAAG levels determined by HPLC. Monoclonal antibodies significantly enhanced sensitivity of staining, allowing visualization of dorsal horn neurons in spinal cord, which were not readily detectable with polyclonal antiserum. Availability of these MAb now facilitates further clarification of the role of NAAG in the brain.

Animals↗

PubMed1989

The postnatal expression of acetylcholinesterase in somatostatin-positive cells of mouse hippocampus.

The neuroanatomical distributions of acetylcholinesterase (AChE) staining and somatostatin-like immunoreactivity (SOMLI) of neurons intrinsic to the mouse hippocampal formation have been evaluated during postnatal development. Besides the progressive development of neuropil staining for AChE, as a consequence of the septohippocampal innervation, intense AChE staining was also expressed in a subpopulation of neurons intrinsic to the stratum oriens and the hilus of dentate gyrus. In the stratum oriens, the number of AChE-positive cells increased between postnatal day (PND) 3 and PND 10 and declined slightly after PND 21. In the hilus of the dentate gyrus, the number of AChE-stained cell bodies increased progressively until PND 21 when the adult complement was achieved. The AChE-positive neurons of strata radiatum and lacunosum-moleculare, which were few and scattered, increased progressively from PND 7 until adulthood. SOMLI-positive neurons were present in the hippocampal formation by PND 3, and their density showed initial increases followed by decreases in the second to third postnatal week. SOMLI cell distribution on the other hand did not change remarkably during subsequent maturation. Because of the similar developmental time course and localization of AChE and SOMLI neurons, co-localization was assessed by a double-staining method. A large percentage of the neurons staining for one of these markers also stained for the other. In the stratum oriens, from PND 3 to PND 10, the number of SOMLI neurons expressing AChE was increased while a slight decrease from the PND 21 to adulthood was evident. Virtually all SOMLI-positive neurons in the dentate gyrus stained for AChE from PND 7 through adulthood, although the intensity of AChE reactivity declined with maturation.

Acetylcholinesterase↗

PubMed1989

The effects of N-acetylated alpha-linked acidic dipeptidase (NAALADase) inhibitors on [3H]NAAG catabolism in vivo.

N-Acetylated, alpha-linked acidic dipeptidase (NAALADase) is a chloride-activated, membrane bound, metallopeptidase that cleaves the endogenous neuropeptide N-acetyl-aspartyl-glutamate (NAAG) in vitro. To determine whether NAALADase is the catabolic enzyme of NAAG in vivo, we have examined the effects on [3H]NAAG metabolism of intrastriatal co-injections of agents that affect NAALADase activity in vitro. Co-injections of NAALADase inhibitors, such as quisqualate (Quis), phosphate, dithiothreitol and EGTA were found to prolong the t1/2 of [3H]NAAG, whereas cobalt, a NAALADase activity stimulator, accelerated [3H]NAAG catabolism. These results are consistent with a role for NAALADase in the extracellular disposition of endogenous NAAG.

Animals↗

PubMed1988

Enhancement of opioid cataleptic response by cortical frontal deafferentation or intrastriatal injection of NMDA-receptor antagonists.

The cataleptic activity of morphine and methadone was markedly potentiated in frontally decorticated rats with no apparent changes in the onset or duration of action. Enhancement of the opioid cataleptic response was not due to changes in the availability of the drugs in the brain. The potentiation of methadone-induced catalepsy in decorticated rats was mimicked in naive rats by intrastriatal (i.s.) application of 2-amino-7-phosphonoheptanoic acid (AP7), a potent and selective antagonist of N-methyl-D-aspartate (NMDA) receptors. Therefore, degeneration of glutamatergic synapses following decortication could be responsible for the changes in behavioral effects caused by opioids. The failure of AP7 to elicit an effect after injection into the n. accumbens fits with the possibility of a selective involvement of the striatum in this phenomenon. That the striatum plays a critical role in the expression of opioid-induced catalepsy was substantiated by the findings that: (1) naloxone, an opioid antagonist, injected i.s., prevents the potentiation of catalepsy induced by methadone and morphine in decorticated animals, (2) oxotremorine, a muscarinic agonist, injected i.s., reverses the enhancement of opioid-catalepsy in decorticated rats, (3) earlier studies by others showed that ablation of the striatum had a facilitatory action on opioid-induced catalepsy. In conclusion, evidence is given that the corticostriatal pathway exerts an inhibitory effect upon narcotic-induced cataleptic behavior. The possibility that this effect is mediated through striatonigral GABAergic output is discussed. The data further suggest that the neuronal mechanisms through which the corticostriatal pathway mediates narcotic catalepsy is operative through activation of NMDA receptors within the striatum.

2-Amino-5-phosphonovalerate↗

PubMed1988

Calcium-dependent evoked release of N-[3H]acetylaspartylglutamate from the optic pathway.

N-Acetylaspartylglutamate (NAAG) is a neuropeptide localized to several putative glutamatergic neuronal systems, including the rodent optic pathway. To determine whether the peptide is released by depolarization, the superior colliculus of the rat was perfused with 2 microCi of [3H]NAAG, then with Krebs-bicarbonate buffer for 1 h, using a microdialysis system. Subsequently, 10-min fractions were collected and analyzed by HPLC for [3H]NAAG. Addition of 100 microM veratridine resulted in a several-fold increase in the evoked release of [3H]NAAG that was virtually abolished by coperfusion with Ca2+-free Krebs buffer containing 1 mM EGTA. When [3H]glutamate was used as the precursor, veratridine depolarization resulted in only an 80% increase in the release of [3H]NAAG. Prior enucleation of the right eye reduced the spontaneous release of [3H]NAAG by 50%, and the veratridine-evoked release by greater than 85%, from the left superior colliculus. These results suggest that NAAG is released upon depolarization and may serve as a neurotransmitter/neuromodulator in the optic tract.

Animals↗

PubMed1987

Striatal cholinergic function reflects differences in D-2 dopaminergic receptor activation.

The ergot derivatives, bromocriptine, lisuride and quinpirole (Ly-171555), activators of D-2 receptors, increased striatal acetylcholine (ACh) content by about 40% and induced a 30% inhibition of ACh evoked release from striatal slices, similar to the effects of the dopaminergic agonist apomorphine. These actions were a consequence of dopaminergic activation since they were antagonized by pretreatment with the neuroleptic agent, pimozide. In contrast, pretreatment with L-sulpiride (100 mg/kg), a specific antagonist for the D-2 dopaminergic receptor only, prevented the rise of ACh levels induced by apomorphine or quinpirole but did not interfere with the lisuride- or bromocriptine- induced ACh increases. Similarly, inhibition of the ACh evoked release produced by lisuride (3 microM) was prevented by pimozide (1 mg/kg) but not by pretreatment with L-sulpiride. Addition of L-sulpiride (5 microM) to the Krebs solution had no effect on the inhibition of ACh-evoked release induced by lisuride, but a lower concentration (1 microM) antagonized the inhibition induced by quinpirole. Lisuride and bromocriptine responses were both insensitive to sulpiride. These results are discussed in terms of different interaction with the dopaminergic D-2 receptors by the drugs studied.

Acetylcholine↗

PubMed1987

Co-localization of N-acetyl-aspartyl-glutamate in central cholinergic, noradrenergic, and serotonergic neurons.

An immunohistochemical technique for simultaneously visualizing two different antigens has been used to investigate the presence of the acidic dipeptide, N-acetyl-aspartyl-glutamate (NAAG), in cholinergic, noradrenergic-adrenergic, and serotonergic neurons within CNS. The brain slices were processed sequentially with purified antisera against NAAG and then monoclonal antibody against choline acetyltransferase (ChAT), a marker for cholinergic neurons, or antiserum against dopamine-beta-hydroxylase (DBH), a marker of noradrenergic-adrenergic neurons, or antiserum against serotonin (5HT). Both antigens were revealed by the peroxidase reaction but with different chromogens, which are easily distinguishable. An intense double staining of NAAG-like immunoreactivity (NAAG-LI) and ChAT was observed in the motoneurons of the spinal cord as well as in the several motor components of cranial nerve nuclei including facial, ambiguus, and trigeminal nuclei. A partial colocalization of NAAG-LI and ChAT was evident in the perikarya of the basal forebrain cholinergic system, whereas cholinergic neurons of the medial septum exhibited only sporadic staining for NAAG-LI. A complete coexistence of NAAG-LI and DBH was observed in the locus coeruleus. Most of the other noradrenergic and adrenergic cell groups of the medulla region exhibited substantial co-localization with the exception of the A2 cell group, which was virtually devoid of NAAG-LI. In the dorsal raphe, only a low percentage of serotonergic neurons stained for NAAG-LI. The co-existence of NAAG-LI and serotonin was more evident in the neurons of the median raphe, although the majority of cells failed to show double staining.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1986

Frontal decortication and adaptive changes in striatal cholinergic neurons in the rat.

Interruption of the corticostriatal pathway by undercutting the cortex resulted in a reduction of glutamate uptake by 55% and in a depression of acetylcholine (ACh) synthesis by 30% in striatum after two postlesion weeks without affecting the content of ACh and choline, the specific binding of [3H]dexetimide to muscarinic receptors, the activity of choline acetyltransferase and the levels of noradrenaline, serotonin, dopamine and 3,4-dihydroxyphenylacetic acid. The influence of this excitatory pathway on striatal cholinergic neuropharmacology was investigated. It was found that the effect of a number of agonists (R-apomorphine, bromocriptine, lisuride, quinpirole, JL-14389, 2-chloroadenosine, oxotremorine and methadone), capable of depressing cholinergic activity in the striatum through receptor-mediated responses--reflected as an increase in ACh content--is operative only when the corticostriatal pathway is intact. By contrast, antagonists capable of decreasing ACh content, i.e. the typical neuroleptics pimozide, haloperidol and the atypical ones clozapine, L-sulpiride, as well as the anti-muscarinic agent scopolamine, were not influenced by the lesion. The possibility that the lesion non-specifically damaged striatal cells on which the agonists, but not the antagonists acted was excluded by results showing, firstly, that the increase in striatal ACh elicited by the ACh precursor, choline, was not blocked by decortication, and secondly, that the degeneration of the corticostriatal neurons did not prevent the ACh-increasing effect of bromocriptine, a long-acting ergot alkaloid, when sufficient time was allowed for the drug to act. It was furthermore possible to restore the inhibitory action of apomorphine on cholinergic neurons either by short-term chemical lesion of the nigrostriatal dopaminergic input or by the administration of choline.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗

PubMed1986

Role of the hippocampus in the sex-dependent regulation of eating behavior: studies with kainic acid.

Marked hyperphagia with an increase in the rate of body weight gain was noted in adult female rats 4 days after injections of 2 nmoles of kainic acid into the dorsal and ventral parts of hippocampus. The effect was still present 70 days later. At this time the increase in daily food intake and body weight gain amounted, respectively, to 39% and 93% over the control value. There was no change in water intake. The injection of kainic acid into only one part of the hippocampus--either dorsal or ventral--did not induce hyperphagia. Male rats with kainic acid lesion did not show changes in food intake or body weight gain as compared to vehicle-treated controls. In both sexes the degeneration of hippocampal perikarya induced by kainic acid was associated with a 50-60% decrease in glutamic acid decarboxylase activity and [3H]glutamate uptake, as well as with a small decrease in [3H]glutamate uptake in the hypothalamus, an area that receives glutamatergic fibers from the hippocampus. The results show that the hippocampus appears to play an important role in appetite motivation control by a mechanism which is sex-related.

Amygdala↗

PubMed1985

Blockade of the diazepam-induced increase in rat striatal acetylcholine content by the specific benzodiazepine antagonists ethyl-beta-carboline-3-carboxylate and Ro 15-1788.

Diazepam increased the acetylcholine content in the striatum and the hippocampus of the rat. This effect was antagonized in both brain areas by treatment with the specific central benzodiazepine blockers ethyl-beta-carboline-3-carboxylate and Ro 15-1788, whereas the peripheral antagonist Ro 5-4864 was ineffective. Pretreatment with picrotoxin, a known GABA antagonist did not interfere with the diazepam-induced acetylcholine increase. These results indicate a specific involvement of benzodiazepine receptors in the cholinergic action of diazepam and this effect appears to be independent of GABA receptor activation.

Acetylcholine↗

PubMed1984

In vitro and in vivo evidence for the existence of presynaptic muscarinic cholinergic receptors in the rat hippocampus.

The intrahippocampal injection of kainic acid cleared 50% of muscarinic receptors and favored the detection of a further 20% loss in hippocampal presynaptic muscarinic receptors produced by electrolytic lesion of the medial septal nucleus as determined by Scatchard analysis of the saturation isotherms of [3H]dexetimide binding. In accordance, a decrease of about 20% in the in vivo accumulation of [3H]dexetimide in the hippocampus was found in animals lesioned in the medial septal nucleus. This effect occurred at both the dose of 5 micrograms/kg and at the saturating dose of 100 micrograms/kg of [3H]dexetimide. The results suggest that the loss was due to decreased receptor number rather than decreased receptor affinity.

Animals↗

PubMed1981

Studies on the indirect feedback inhibition of cholinergic neurons triggered by oxotremorine in striatum.

Oxotremorine produced 30-75% increases in rat striatal acetylcholine content and 10-15% decreases in choline content at the subtremorogenic doses of 0.34-1.34 mumol/kg, without affecting choline acetyltransferase and acetylcholinesterase activities and the sodium-dependent high affinity uptake of choline. The increase in acetylcholine was blocked by atropine and by reserpine indicating that oxotremorine indirectly influences the intrinsic striatal cholinergic neurons through a monoamine-mediated negative feedback loop. Experiments designed to interfere with neurotransmitter function indicated that noradrenaline and not dopamine or serotonin, mediated the response to oxotremorine.

Acetylcholine↗