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PubMed1993

Non-opioid antitussives and methadone differentially influence hippocampal long-term potentiation in freely moving rats.

Long-term potentiation (LTP) of monosynaptically evoked field potentials (MEFP) in the dentate gyrus of freely moving rats following tetanization of the perforant pathway was investigated after peripheral application of substances which have been shown to influence NMDA receptor-mediated effects (dextromethorphan, methadone) as well as structurally related substances with similar antitussive effects (codeine, normethadone). The noncompetitive NMDA receptor antagonist MK 801 was also tested for comparison. Whereas under control conditions the field e.p.s.p. (excitatory postsynaptic potential) and the population spike of the MEFP were largely uninfluenced by these substances, different effects were seen after the induction of LTP. MK 801 (0.2 mg/kg i.p.) suppressed the induction of LTP of both the field e.p.s.p. and the population spike. Dextromethorphan (40 mg/kg i.p.) also prevented the potentiation of the field e.p.s.p. and the population spike, thus resembling MK 801 in its effect. Codeine (20 mg/kg i.p.), the levorotatory structural analogue of dextromethorphan had no effect. Methadone and normethadone did not influence the potentiation of the field e.p.s.p. or interfere with the induction of potentiation of the population spike but depressed its maintenance. The results obtained with MK 801 confirm those reported by others. Comparison of the effects of dextromethorphan with those of MK 801, suggests that there is a direct interaction with the NMDA receptor-ionophore complex. The effects of methadone and normethadone appear not to be linked to an interaction with opioid receptors, since naloxone did not influence the suppression of LTP caused by methadone. The possibility of interference with the NMDA receptor-ionophore complex is discussed.

Animals↗
PubMed1989

Modification of evoked hippocampal dentate inhibition by diazepam and three antagonists in urethane-anesthetized rats.

Urethane-anesthetized rats with perforant pathway stimulating electrodes and recording electrodes placed in the hippocampal dentate gyrus were exposed to increasing doses of either the benzodiazepine agonist diazepam or an antagonist (PK-11195, CGS-8216, and RO15-1788). Analysis of the monosynaptic evoked field potentials indicated that none of the four compounds altered the threshold for eliciting the excitatory postsynaptic potential (EPSP). Reductions in field population spike (PS) amplitudes were seen after exposure to RO15-1788, CGS-8216, and diazepam, but not PK-11195. Using a paired-pulse paradigm, diazepam significantly increased early gamma-aminobutyric acid (GA-BAA)-mediated recurrent inhibition. The antagonist RO15-1788, but not CGS-8216 or PK-11195, also significantly increased early GABAA-mediated inhibition. The increase in GABAA-mediated inhibition after diazepam was reversed by the subsequent administration of the central antagonists RO15-1788 or CGS-8216, but not the peripheral antagonist PK-11195. Pretreatment with CGS-8216 or RO15-1788 prevented diazepam-induced inhibition. These data support the important modulatory role of the central benzodiazepine receptor in early GABAA-mediated inhibition at this synapse. They also suggest that basal granule cell excitability is not importantly modulated by this benzodiazepine receptor.

Anesthesia↗
PubMed1996

Increase in activin beta A mRNA in rat hippocampus during long-term potentiation.

We have used mRNA differential display to isolate genes that are induced by neural activity in rat hippocampus. One of these encodes activin beta A subunit. Convulsive seizure caused by kainate significantly induced the expression of activin beta A mRNA. Furthermore high frequency stimulation (HFS) of perforant pathway, which produced a persistent long-term potentiation (LTP) (>10 h), caused a marked increase at 3 h in the level of activin beta A mRNA at the dentate gyrus of urethane-anesthetized rat. The increase was NMDA receptor-dependent. By contrast the level of inhibin alpha mRNA was not changed following the induction of LTP. THe results suggest a role for activin in maintenance of neural plasticity in the adult brain.

Activins↗
PubMed1984

In vivo effects of nipecotic acid on levels of extracellular GABA and taurine, and hippocampal excitability.

The effect of nipecotic acid on the extracellular levels of the putative hippocampal inhibitory transmitters, gamma-aminobutyric acid (GABA) and taurine, and also excitability in the dentate gyrus, were studied in anaesthetised rats using the dialytrode technique. The dentate gyrus was perfused by means of a dialytrode , using Krebs-Ringer bicarbonate or nipecotic acid solutions. Dentate field potentials, evoked by electrical stimulation of the perforant pathway, were recorded. Nipecotic acid drastically elevated the levels of extracellular GABA and taurine and the amplitude of population spikes in the dentate was concomitantly decreased. These results indicate that changes in extracellular levels of endogenous GABA and/or taurine influence the excitability of the hippocampus.

Animals↗
PubMed1985

Localization and quantitation of proenkephalin-derived neuropeptides in the rat hippocampus.

We have measured the content of met- and leu-enkephalin and dynorphin B in the rat hippocampus, and localized these opioid peptides within the intrinsic hippocampal neuronal circuitry with specific lesions. Several enkephalins, two of which were shown to be met- and leu-enkephalin, were identified in rat hippocampus. The levels of the enkephalin-related peptides were unaffected by intrahippocampal injections of colchicine, which destroyed the great majority of the hippocampal granule cells, while the level of dynorphin B, which serves as a marker for the proenkephalin B-derived peptides, was markedly depleted. Entorhinal cortical lesions ablating the perforant pathway input to the hippocampus did not significantly alter dynorphin B nor enkephalin levels in the hippocampus. Unilateral fimbrial transection caused a small but significant increase in dynorphin B on the side of the lesion relative to the non-lesioned side, although neither side was significantly different from control, while at the same time causing a significant bilateral increase in both met- and leu-enkephalin levels. This may result from loss of a direct or indirect stimulatory input to peptide-containing neurons within the hippocampus. The enkephalins appear to be located in neuronal cell bodies intrinsic to the body of the hippocampus, while the dynorphins are likely to be intrinsic only to the granule cell-mossy fiber system originating in the dentate gyrus.

Animals↗
PubMed1985

Repeated electroconvulsive shocks alter the biosynthesis of enkephalin and concentration of dynorphin in the rat brain.

Ten daily electroconvulsive shocks (ECSs) caused a two-fold increase in (Met5)-enkephalin-like immunoreactivity (ME-LI) and an 80% increase in the level of mRNA coding for preproenkephalin A in the hypothalamus. These observations suggest that repeated ECSs increase the biosynthesis of hypothalamic ME. Ten daily ECSs also increased dynorphin A (1-8)-like immunoreactivity (DN-LI) in hypothalamus (45%) but not in frontal cortex. Unlike other brain regions, a 64% decrease of DN-LI was found in the hippocampus after 10 daily ECSs whereas a significant increase of ME-LI (40%) was observed. Furthermore, immunocytochemical studies revealed an increase of (Leu5)-enkephalin-like immunoreactivity in the perforant pathway and a decrease of DN-LI in the mossy fiber system of the hippocampus after 10 daily ECSs. These studies suggest that alterations in enkephalin and dynorphin in the limbic system may contribute to the behavioral changes observed after repeated ECSs.

Animals↗
PubMed1991

Vigabatrin pre-treatment prevents hilar somatostatin cell loss and the development of interictal spiking activity following sustained simulation of the perforant path.

Somatostatin-containing neurons in the hilus of the dentate gyrus are known to be exceptionally vulnerable in experimental models of epilepsy, as well as in human temporal lobe epilepsy. The position of these cells in the circuitry of the dentate gyrus is ideal for gating the activation evoked by afferents from the entorhinal cortex. In the present study we have shown that the loss of hilar somatostatin-containing neurons, and the development of interictal spiking activity induced by sustained perforant pathway stimulation can be prevented by high doses (500 mg/kg), but not by low doses (100 mg/kg) of vigabatrin, an irreversible inhibitor of GABA-transaminase.

4-Aminobutyrate Transaminase↗
PubMed1993

Modulation of paired-pulse activation in the hippocampal dentate gyrus by cholecystokinin, baclofen and bicuculline.

Paired-pulse stimulation was used to evaluate the effects of the sulfated octapeptide of cholecystokinin (CCK8-S), the gamma-aminobutyric acidB (GABAB) agonist (-) baclofen, and the GABAA antagonist (-) bicuculline on hippocampal dentate gyrus (DG) granule cell excitability. Evoked action potentials (EAPs) and excitatory postsynaptic potentials (EPSPs) were recorded in response to orthodromic stimulation of the medial (MPP) or lateral (LPP) perforant pathway. Paired-pulse indices were determined using interpulse intervals (IPIs) across the range of 5-1000 ms. As reported by others, three phases of paired-pulse effects were revealed under control (drug-free ACSF) conditions: early paired-pulse inhibition (PPI), intermediate paired-pulse facilitation (PPF) and late PPI. With EAPs, CCK8-S enhanced only the intermediate PPF on both pathways, with no effect on the early or late PPIs. The effects of (-) baclofen were similar to CCK8-S. (-) Bicuculline attenuated the early and late PPI as well as the PPF. No differences were measured on the MPP- or LPP-evoked EPSPs in any of the drug conditions. These results indicate a similarity of CCK8-S- with GABAB-mediated modulation on neuronal activation in the DG. CCK8-S disinhibition of DG granule cells may play a role in the induction of long-lasting synaptic modifications.

Action Potentials↗
PubMed1996

Studies of dentate granule cell modulation: paired-pulse responses in freely moving rats at three ages.

Dentate granule cell population responses to paired-pulse stimulations applied to the perforant pathway across a range of interpulse intervals (IPI) were examined in freely moving rats at 15, 30, and 90 days of age. The profile of the paired-pulse index (PPI), a measure of the type and degree of modulation of dentate granule cell excitability, was shown to change significantly as a function of age.

Animals↗
PubMed1989

Changes of proenkephalin and prodynorphin mRNAs and related peptides in rat brain during the development of deep prepyriform cortex kindling.

The effects of deep prepyriform cortex (DPC) kindling on the amount of proenkephalin and prodynorphin mRNAs, Met5-enkephalin (ME) and dynorphin (DYN) in rat brain were examined. Animals received electrical stimulation of the DPC until two consecutive stage 2 seizures (S2) or stage 5 seizures (S5) were attained. The proenkephalin mRNA and ME contents in the entorhinal cortex were increased 24 h after S2 and also 5 min and 24 h post S5. In the hippocampus, the proenkephalin mRNA level was reduced 24 h after S2 but increased 5 min and 24 h after S5. Elevated hippocampal ME concentration was observed 24 h after S2 and S5. Similarly, the ME level in the frontal cortex was increased 24 h after S2 and S5 but the proenkephalin mRNA content was only elevated at S5. In the striatum, the proenkephalin mRNA level was slightly increased 24 h after S2 and S5, but no change in ME content was found. The amount of prodynorphin mRNA in the hippocampus was attenuated only at 24 h after S5, whereas DYN concentration was reduced 5 min after S5. No change in striatal DYN concentration was observed despite a slight elevation of prodynorphin mRNA 24 h post S2 and S5. Six weeks after the last seizure, no difference in ME and DYN was found between kindled and control animals. These findings indicate that the enkephalin-containing perforant pathway in the entorhinal cortex-hippocampal region is particularly sensitive to electrical stimulations applied to the DPC. Its role and importance in the development of kindling are discussed.

Animals↗
PubMed1995

Limbic effects of repeated electroconvulsive stimulation on neuropeptide Y and somatostatin mRNA expression in the rat brain.

The aim of this study was to determine the effect of repeated electroconvulsive stimulation (ECS) on the expression of neuropeptide Y (NPY) and somatostatin (SS) mRNA in the rat brain. For that purpose, quantitative in situ hybridization histochemistry and RNA blot analysis were used. In the hippocampal formation the prevalence of NPY mRNA positive neurons increased in the hilus of the dentate gyrus and the CA3 while a decrease was seen in layers II-III of the entorhinal cortex. In contrast, SS mRNA was increased in the granule cells of the dentate gyrus and in most neurons of the outer parts of the layer III in the entorhinal cortex with cell bodies of perforant pathway projections to the hippocampal CA1 region. Both NPY and SS mRNA expressing neurons were increased in numerical density in the prefrontal cortex with similar amounts of mRNA in individual NPY positive neurons after the stimulations while SS mRNA levels decreased in hybridization positive neurons. In the striatum the only observed significant effect was an increased prevalence of NPY mRNA positive neurons in the caudal nucleus accumbens. Our results provide an outline of a complex functional anatomy of ECS in the rat brain. This type of investigations contributes to map the neuronal systems involved in the action of ECT used in the treatment of affective and schizophrenic disorders.

Animals↗
PubMedDate not supplied

Increase in perforant path quantal size in aged F-344 rats.

The data presented here confirm and extend the evidence for fewer, but stronger, perforant path synaptic connections onto the granule cells of the hippocampus in old F-344 rats. The old animals used in the present report were drawn from a population that showed deficits in the retention of a spatial problem in the Morris water task. Using the method of minimal-stimulation of perforant path afferents, unitary granule cell EPSPs were found to be larger in the 25-month than in the 6- and 9-month age groups. Furthermore, applying statistical methods for quantal analysis, data are presented that suggest that the larger synaptic responses of the old rats come about through an increase in quantal size. These experiments therefore suggest that individual synapses become more powerful in the perforant pathway of old rats, and that this strengthening occurs through an increase in quantal size. The implications of these findings for hippocampal information processing are discussed.

Aging↗
PubMedDate not supplied

Profiling of endogenous brain peptides and small proteins: methodology, computer-assisted analysis, and application to aging and lesion models.

Significant advances in the technology for the isolation of peptides and small proteins have permitted their identification as biologic markers and enhanced the study of the posttranslational life of proteins. The protocol described here examined large numbers of tissue-derived peptides and small proteins, extracted in low pH and boiled so that proteolysis was interrupted. These were then fractionated batchwise using size exclusion and ion-exchange chromatography. Profiles of species in the peptide pools were then generated on reverse-phase high-performance liquid chromatography (HPLC). The HPLC profiles were evaluated with chromatographic analysis software to identify and quantify peptide peaks and with data compilation programs to sort this information into spreadsheets for comparison of profiles among groups. Using rodent brain, the effects of postmortem delay or age were examined. Postmortem delay produced limited alterations to the profiles, but the effect of age was more pronounced. Many changes were apparent until 12 months, after which the profiles became more constant. Additional peptide profiling of the hippocampus demonstrated changes in peptide content as a function of perforant pathway ablation. The major strengths of HPLC-mediated peptide profiling are that it lends itself to automation and can be used to detect changes in peptides and small proteins among experimental groups or subjects without any prior assumptions concerning which ones might be altered.

Aged↗
PubMed1986

Variation of potassium ion concentrations in the rat hippocampus specifically affects extracellular taurine levels.

The effects of different K+ concentrations (3-100 mM) on both the extracellular amino acid levels and field potentials, evoked by perforant pathway stimulation, were studied 'in vivo' in the rat dentate gyrus by means of a brain dialysis device, formed by a hollow fiber plus a stainless-steel electrode. Perfusion with low K+ concentrations (3-12 mM; Krebs-Ringer bicarbonate) specifically enhanced the dialysate levels of taurine and concomitantly increased the population spike amplitude. High K+ concentrations in perfusate (greater than 25 mM) did not further increase the levels of taurine but enhanced both glutamate and gamma-aminobutyric acid levels, whereas the population spike diminished drastically. The absence of calcium ions in the perfusion liquid increased both basal and K+-enhanced taurine levels. The specific enhancement of extracellular taurine by physiological K+ concentrations may represent an autoregulative mechanism of nervous tissue excitability.

Action Potentials↗
PubMed1990

Tyrosine hydroxylase-like (TH) immunoreactivity in human mesolimbic system.

A practical methodology has been described for the use of human postmortem brain tissue in both tyrosine hydroxylase and dopamine beta-hydroxylase immunohistochemistry in which in situ perfusion with paraformaldehyde is followed by immersion fixation in Bouin's fixative. These studies indicate that TH-like immunoreactive fibers and terminals are not uniformly distributed in the human hippocampal complex. A distinctive lesser innervation is noted for the structures that compose the perforant pathway and may be important for the predilection of these areas for pathological change particularly as occurs in Alzheimer's disease.

Adult↗
PubMed1991

Long-term potentiation of synaptic responses in the rat dentate gyrus is due to increased quantal content.

Long-term potentiation (LTP) of synaptic responses in the dentate gyrus neurons of the rat hippocampus was studied in in vitro slices with the use of intracellular recordings. The goal of the study was to determine if the expression of LTP is pre- or postsynaptic. LTP was induced by tetanic stimulation of the perforant pathway in the presence of bicuculline. The expression of potentiation was measured during low-intensity stimulation at 1-5 Hz. It was found that a 104% (S.E.M. +/- 35, n = 5) increase in the amplitude of evoked synaptic potentials was associated with a reduction in the number of transmission failures to 38% (S.E.M. +/- 15, n = 5) of the control values. The size of quantal responses was determined on the basis of asynchronous release from stimulated synapses. The average size of the quanta remained unchanged during LTP. The evident increase of quantal content suggests a presynaptic locus for expression of LTP.

Animals↗
PubMed1996

Optical recording of rat entorhino-hippocampal system in organotypic culture.

It is difficult to comprehend the entorhino-hippocampal information processing using acute transverse hippocampal slice, because the dorsally inclined connections of the entorhino-hippocampal projections can be damaged easily. Therefore, we investigated the spatial-temporal propagation in organotypic cultures of the hippocampus attaching to the entorhinal cortex using a real-time optical recording system with a voltage-sensitive dye and suitability as an in vitro model. Real-time imaging demonstrated that the stimulation of the perforant pathway induced excitatory propagation in trisynaptic pathway of the hippocampus and sequentially in the layer V from the medial to the lateral entorhinal cortex. The horizontal propagation from the lateral to the medial site was also seen after the stimulation of the lateral entorhinal cortex. The analysis of the entorhino-hippocampal organotypic culture would contribute to understanding of the mechanism of learning and memory.

Animals↗
PubMed1985

Cholinergic influences on hippocampal glucose metabolism.

2-Deoxy-D-[3H]glucose autoradiography was employed to investigate the effects of acute cholinergic manipulations on hippocampal glucose metabolism. In general, manipulations designed to reduce cholinergic activity (medial septal ablation, atropine treatment) reduced hippocampal glucose metabolism. Maximal decrements were found in the terminal fields of the septohippocampal projection after medial septal lesions, while maximal deficits after atropine treatment correlated with muscarinic receptor binding. Electrical stimulation of the medial septum resulted in increased glucose utilization in some terminal fields of the septohippocampal projection and decreased utilization in the terminal fields of the perforant pathway. Our data clearly indicate that acute alterations in cholinergic activity can affect hippocampal glucose metabolism but the distribution, direction and degree of these changes is dependent on the specific treatment.

Animals↗