Axons and synapses mediating startle-like responses evoked by electrical stimulation of the reticular formation in rats: symmetric and asymmetric collision effects

A new method for determining the locations, directions of transmission and transmission times of synapses mediating electrically evoked responses is proposed here. Electrical stimulation of pontine or medullary reticular formation with one 0.1-ms pulse evokes a short-latency startle-like response. Two pulses were delivered to single sites at various interpulse intervals and the currents required to evoke a criterion startle response were measured. The results suggest that the startle-evoking substrates have absolute refractory periods that range from 0.25–0.6 ms. When one pulse was delivered to a caudal pontine site and a second pulse was delivered to a an ipsilateral medulla site, decreases in required current were observed as interpulse interval increased from +0.4 to +0.8 ms or as interpulse interval decreased from −0.4 to −0.8 ms. These collision-like effects, being symmetric around an interpulse interval of 0, suggest that electrically evoked startle is mediated by fast axons that pass longitudinally through medulla. When one pulse was delivered to the rostral pons and a second pulse to the ipsilateral medulla, however, required currents decreased sharply as interpulse intervals increased from +0.4 to 1.0 ms and as interpulse intervals decreased from +0.2 to −0.2 ms. These asymmetric collision-like effects suggest that strong synapses in the caudal pons, transmitting from pons to medulla, mediate electrically evoked startle. The 0.3-ms asymmetry suggests that the transmission time (i.e., from presynaptic stimulus to postsynaptic action potential) averaged 0.3 ms via monosynaptic connections. The short duration of collision (0.7 ms) suggests that only one postsynaptic action potential was produced with high probability for each presynaptic action potential. From the localization of these effects and the short refractory periods, we estimate that < 60 giant cells on each side of the ventral pontine reticular formation mediate the startle reflex in the rat.     

Effects of self- and cross-reinnervation on the numbers of motoneurons regenerating to forearm muscles in young and adult rats

The present study was carried out to compare the ability of motoneurons to regenerate to functionally appropriate and inappropriate muscles, following axotomy at different stages of postnatal development. Five-, 10-, 21-day-old and adult rats of both sexes were used. In one group, the right median and radial nerves were cut and reunited. In a second group, the cut nerves were cross reunited and, in a third group the nerves were merely exposed. Following survival periods of up to one year, the extent of motoneuron regeneration through the repaired nerves was determined by injecting the retrogradely transported tracers horseradish peroxidase (HRP) and Fast Blue into the flexor and extensor muscles of the right forearm. The results were expressed in terms of the difference between the number of labelled motoneurons on the experimental side of the spinal cord and the number on the control side, the latter having been labelled by injection of HRP and Fast Blue into the muscles of the left forearm. Comparisons were then made between the groups with respect to the age at which axotomy occurred, and the target of regeneration. The results showed that when axotomy was performed in 5- and 10-day-old rats, significantly fewer motoneurons were labelled, irrespective of whether or not the target was functionally appropriate, than when axotomy was performed in adulthood. The difference was most likely due to a lower survival rate of motoneurons following axotomy in neonates. No difference was found, however, between the numbers of labelled median and radial nerve motoneurons following self- versus cross-reinnervation in any age group. This suggests that, in both adult and neonatal rats, motoneurons which survive axotomy are able to regenerate equally well to functionally appropriate or inappropriate muscles.     

Increased delayed type hypersensitivity in rats subjected to unilateral mononeuropathy is mediated by neurokinin-1 receptors

An animal model of peripheral mononeuropathy was utilized in the present study to investigate the potential role of substance P (SP) in modifying immune responses associated with chronic pain conditions. Animals subjected to unilateral sciatic ligation and sham-operated animals were sensitized with keyhole limpet hemocyanin (KLH) and subsequently challenged in the ipsilateral or contralateral hind paw to produce a delayed-type hypersensitivity (DTK) response. Subcutaneous microdialysis and radioimmunoassay were used to measure interstitial fluid SP levels in the challenged tissue prior to and following immune challenge in control and neuropathic animals. Following immune challenge, there was a significant increase in the concentration of SP in tissue dialysate samples from the challenged paw of both sham-operated and neuropathic animals. However, tissue SP levels in neuropathic animals were more than two-fold higher than those obtained from sham-operated controls following challenge. SP concentration remained elevated for 2.5 h following immune challenge in neuropathic animals compared to 90 min in sham-operated animals. Compared with controls, neuropathic animals also exhibited an increased DTH response that was reversed, in a dose-related fashion, by the non-peptide NK-1 receptor blocker L-703,606. The same antagonist had no effect in sham-operated animals. These data suggest that the increased DTH response in animals subjected to unilateral mononeuropathy involves SP and NK-1 receptors present in the challenged tissue.     

Developmental changes in short-term facilitation are opposite at temporoammonic synapses compared to Schaffer collateral synapses onto CA1 pyramidal cells

CA1 pyramidal neurons receive two distinct excitatory inputs that are each capable of influencing hippocampal output and learning and memory. The Schaffer collateral (SC) input from CA3 axons onto the more proximal dendrites of CA1 is part of the trisynaptic circuit, which originates in Layer II of the entorhinal cortex (EC). The temporoammonic (TA) pathway to CA1 provides input directly from Layer III of the EC onto the most distal dendrites of CA1 pyramidal cells, and is involved in spatial memory and memory consolidation. We have previously described a developmental decrease in short-term facilitation from juvenile (P13-18) to young adult (P28-42) rats at SC synapses that is due to feedback inhibition via synaptically activated mGluR1 on CA1 interneurons. It is not known how short-term changes in synaptic strength are regulated at TA synapses, nor is it known how short-term plasticity is balanced at SC and TA inputs during development. Here we describe a novel developmental increase in short-term facilitation at TA synapses, which is the opposite of the decrease in facilitation occurring at SC synapses. Although short-term facilitation is much lower at TA synapses when compared with SC synapses in juveniles, short-term plasticity at SC and TA synapses converges at similar levels of paired-pulse facilitation in the young adult rat. However, in young adults CA3-CA1 synapses still exhibit more facilitation than TA-CA1 synapses during physiologically-relevant activity, suggesting that the two pathways are each poised to uniquely modulate CA1 output in an activity-dependent manner. Finally, we show that there is a developmental decrease in the initial release probability at TA synapses that underlies their developmental decrease in facilitation, but no developmental change in release probability at SC synapses. This represents a fundamental difference in the presynaptic function of the two major inputs to CA1, which could alter the flow of information in hippocampus during development.     

Changes of sensory conduction velocity and refractory periods with decreasing tissue temperature in man

Summary Changes with temperature of maximum sensory nerve conduction velocity as well as absolute and relative refractory periods were tested in 14 human subjects. Corresponding to previously published findings maximum conduction velocity decreased with cooling following a Q₁₀ of +1.4. The absolute and relative refractory periods were increased by cooling, the Q₁₀ being –3.1 and –3.35 respectively. There was a tendency showing a more pronounced temperature effect at low temperatures. The Q₁₀ and the steepness of the regressionline changed at the level of 26.9°C, but were significant for the relative refractory period only.Dedicated to Prof. Fritz Buchthal on the occasion of his seventyth birthday     

M4 muscarinic receptors are involved in modulation of neurotransmission at synapses of Schaffer collaterals on CA1 hippocampal neurons in rats

All five subtypes of muscarinic acetylcholine receptors (mAChR; M(1)-M(5)) are expressed in the hippocampus, where they are involved both in cognitive functions and in synaptic plasticity, such as long-term potentiation (LTP). Muscarinic toxins (MTs) are small proteins from mamba snake venoms that display exquisite discrimination between mAChRs. MT1 acts as an agonist at M(1) and an antagonist at M(4) receptors, with similar affinities for both. MT3, the most selective antagonist available for M(4) receptors, infused into the CA1 region immediately after training caused amnesia in the rat, indicating the participation of M(4) receptors in memory consolidation. Our goal was to investigate the participation of M(4) receptor in neurotransmission at the hippocampal Schaffer collaterals-CA1 synapses. Two different preparations were used: 1) field potential recordings in freshly prepared rat hippocampal slices with high-frequency stimulation to induce potentiation and 2) whole-cell voltage clamp in cultured hippocampal organotypic slices with paired stimuli. In preparation 1, a dose of MT3 that was previously shown to cause amnesia blocked LTP; the nonselective antagonist scopolamine blocked LTP without affecting basal transmission, although it was depressed with higher concentration. In preparation 2, basal transmission was decreased and LTP induction was prevented by an MT3 concentration that would bind mainly to M(4) receptors. Although M(1) receptors appeared to modulate transmission positively at these excitatory synapses, M(1) activation concomitant with M(4) blockade (by MT1) only allowed a brief, short-term potentiation. Accordingly, M(4) blockade by MT3 strongly supports a permissive role of M(4) receptors and suggests their necessary participation in synaptic plasticity at these synapses.     

Change in bi-directional plasticity at CA1 synapses in hippocampal slices taken from 6-hydroxydopamine-treated rats: the role of endogenous norepinephrine

The object of the present study is to investigate the role of endogenous adrenergic innervation in regulating bi-directional synaptic plasticity in rat hippocampal CA1 synapses. The endogenous adrenergic system was eliminated by giving subcutaneous injection of 6-hydroxydopamine (6-OHDA) to rats immediately after birth, and the animals were killed for experiments at postnatal ages of 25-35 days. In hippocampal slices taken from 6-OHDA-treated animals, theta-burst stimulation at 100 Hz failed to induce long-term potentiation (LTP) at CA1 synapses. However, the induction of long-term depression (LTD) by prolonged low frequency stimulation at 1 Hz was unaffected in slices from 6-OHDA-treated animals. Bath application of norepinephrine (NE) restored LTP to control levels and blocked LTD. This effect was mimicked by beta- but not alpha-adrenergic receptor agonists, i.e. by isoproterenol but not phenylephrine. The activators of adenylyl cyclase and protein kinase A (PKA), i.e. forskolin and 8-bromoadenosine-3', 5'-cyclic monophosphate, respectively, restored LTP in slices from 6-OHDA-treated animals. In addition, application of the D1/D5 receptor agonist, dihydrexidine, also restored LTP in slices from 6-OHDA-treated animals. These results suggest that physiologically the recruitment of catecholamine innervation may be important for induction of LTP at hippocampal CA1 synapses during tetanic stimulation, while it may not be essential for LTD induction by prolonged 1 Hz stimulation. The released NE and dopamine exert their role in modulating synaptic plasticity via activation of beta-adrenergic and D1/D5 receptors, respectively, which in turn increase the levels of cytoplasm adenosine-3',5'-cyclic monophosphate and PKA.     

Specific inhibitory synapses shift the balance from feedforward to feedback inhibition of hippocampal CA1 pyramidal cells

Feedforward and feedback inhibition are two fundamental modes of operation widespread in the nervous system. We have functionally identified synaptic connections between rat CA1 hippocampal interneurons of the stratum oriens (SO) and interneurons of the stratum lacunosum moleculare (SLM), which can act as feedback and feedforward interneurons, respectively. The unitary inhibitory postsynaptic currents (uIPSCs) detected with K-gluconate-based patch solution at −50 mV had an amplitude of 20.0 ± 2.0 pA, rise time 2.2 ± 0.2 ms, decay time 25 ± 2.2 ms, jitter 1.4 ± 0.2 ms (average ± SEM, n  = 39), and were abolished by the γ-aminobutyric acid (GABA)_A receptor antagonist 2-(3-carboxypropyl)-3-amino-6-methoxyphenyl-pyridazinium bromide (SR 95531). Post hoc anatomical characterization revealed that all but one of the identified presynaptic neurons were oriens-lacunosum moleculare (O-LM) cells, whereas the postsynaptic neurons were highly heterogeneous, including neurogliaform ( n  = 4), basket ( n  = 4), Schaffer collateral-associated ( n  = 10) and perforant path-associated ( n  = 9) cells. We investigated the short-term plasticity expressed at these synapses, and found that stimulation at 10–40 Hz resulted in short-term depression of uIPSCs. This short-term plasticity was determined by presynaptic factors and was not target-cell specific. We found that the feedforward inhibition elicited by the direct cortical input including the perforant path onto CA1 pyramidal cells was modulated through the inhibitory synapses we have characterized. Our data show that the inhibitory synapses between interneurons of the SO and SLM shift the balance between feedback and feedforward inhibition onto CA1 pyramidal neurons.     

Deficit of NMDA receptor activation in CA1 hippocampal area of aged rats is rescued by D-cycloserine

Activation of the glycine modulatory site of the N-methyl-D-aspartate glutamate receptor (NMDAR) may reduce cognitive impairments associated with normal ageing. In order to test this hypothesis, we assessed the effects of the partial agonist D-cycloserine (DCS) on cellular activities involved in memory formation. This was performed in CA1 cellular networks of adult and aged Sprague-Dawley rat hippocampal slices using extracellular field excitatory postsynaptic potential recordings. Synaptic potentials specifically mediated by NMDAR were significantly reduced in aged animals. DCS increased the magnitude of these responses in both adult and old rats but this effect was significantly higher in the latter, thus reversing the age-related decrease in NMDAR synaptic potentials. NMDAR-mediated theta burst long-term potentiation (TBS-LTP) as well as long-term depression (LTD) of synaptic transmission, prominent models for the cellular basis of learning and memory, were also weakened in aged animals. Age-related alterations of both forms of synaptic plasticity were rescued by DCS. In addition, the DCS-induced decrease in basal fast glutamatergic neurotransmission involving the activation of inhibitory glycinergic receptors, previously reported in young rats (Rouaud & Billard, 2003), was severely attenuated in aged animals. In summary, our results indicate that the facilitation of NMDAR activation through its glycine-binding site rescues the age-related deficit of cellular mechanisms of learning and memory. Such physiological evidences suggest that this modulation site of NMDAR represents an important target to alleviate cognitive deficits associated with normal ageing.     

Blood-brain barrier is impaired in the hippocampus of young adult spontaneously hypertensive rats

A causative role of blood-brain barrier (BBB) impairment is suggested in the pathogenesis of vascular dementia with leakage of serum components from small vessels leading to neuronal and glial damage. We examined the BBB function of young adult spontaneously hypertensive rats (SHR) in order to determine earlier changes in the BBB in chronic hypertension. SHR and stroke-prone SHR (SHRSP) were injected with horseradish peroxidase (HRP) as an indicator of BBB function and compared with Wistar Kyoto rats (WKY). The brain tissues were further examined with cationized ferritin, a marker for evaluating glycocalyx. The staining for HRP was distributed around the vessels in the hippocampal fissure of SHR and SHRSP, but not in WKY. With electron microscopy, the extravasated reaction product of HRP appeared in abluminal pits of the endothelial cells of arterioles and within the basal lamina in the hippocampus, but not the cerebral cortex, of SHR and SHRSP. On the contrary, the reaction product of HRP was never seen in the abluminal pits of the endothelial cells or the basal lamina of vessels in WKY. The number of cationized ferritin particles binding to the endothelial cells of capillaries was decreased in the hippocampus of SHR and SHRSP, while the number decreased in the cerebral cortex of SHRSP compared with those in WKY. However, the cationized ferritin binding was preserved in the endothelial cells of the arterioles with an increased vascular permeability. These findings suggest that the chronic hypertensive state induces BBB dysfunction in the hippocampus at an early stage.     

Thresholds to electrical stimulation of nerves in cat canine tooth-pulp with Aβ-, Aδ- and C-fibre conduction velocities

The thresholds to electrical stimulation and the conduction velocities of nerve fibres supplying the pulp of cat canine teeth have been determined. Compound action potentials and the responses of 80 single units were recorded from the inferior alveolar nerve. The properties of 4 types of coronal stimulating electrode were compared.In the single unit studies separate estimates of intradental and extradental conduction velocity of the fibres were obtained by stimulating the pulp in the crown and in the root of the tooth. The units had extradental conduction velocities ranging from 57.7 to 0.9 m·s⁻¹ and therefore included Aβ-, Aδ- and C-fibres. The thresholds of the units to coronal stimulation ranged from 7 μA, 0.1 ms to 805 μA, 1.0 ms.     

Tenascin-R-deficient mice show structural alterations of symmetric perisomatic synapses in the CA1 region of the hippocampus

Accumulating evidence suggests that extracellular matrix (ECM) molecules play important roles in formation of synapses. Our previous electrophysiologic study of mice deficient in the extracellular matrix glycoprotein tenascin-R (TN-R) showed an impaired gamma-aminobutyric acid release at perisomatic inhibitory synapses in the CA1 pyramidal cell layer of the hippocampus. The present study investigated possible ultrastructural correlates of abnormal perisomatic inhibition. Topographic, morphometric, and stereologic methods were applied at the light and electron microscopic levels to quantify the density and spatial arrangement of cell bodies of CA1 pyramidal neurons and density and architecture of symmetric synapses formed on them in TN-R(-/-) and wild-type mice of different ages. The spatial arrangement of neuronal cell bodies in the CA1 pyramidal cell layer was found more diffuse and disordered in TN-R(-/-) mice than in wild-type animals. The coverage of the plasma membrane of pyramidal cell bodies by active zones of symmetric synapses was reduced by at least 40% in TN-R(-/-) animals compared with control animals. Further, the length of active zone profiles of perisomatic inhibitory synapses in the CA1 pyramidal cell layer was 8-14% smaller, whereas the number of active zones calculated per length unit of cell body profile was 30-40% smaller in TN-R mutants than in wild-type animals. The density and spatial arrangement of synaptic vesicles in the synaptic terminals provided ultrastructural evidence for reduced synaptic activity in TN-R mutants. Thus, TN-R appears to play an important role in the regulation of the number and architecture of perisomatic inhibitory synapses, which play crucial roles in the synchronization of neuronal activity and modulation of synaptic plasticity in the hippocampus.     

Baclofen-induced disinhibition in area CA1 of rat hippocampus is resistant to extracellular Ba

The mechanism of disinhibition produced by (±)-baclofen was studied using intracellular recording in area CA1 of rat hippocampal slices. Baclofen reversibly depressed monosynaptic IPSPs evoked by direct activation of interneurons in the presence of the excitatory amino acid receptor antagonists 6,7-dinitroquinoxaline-2,3-dione (DNQX) andd,l-2amino-5-phosphonovalerate (APV). Ba²⁺ prevented baclofen-induced hyperpolarization of pyramidal neurons but not depression of monosynaptic IPSPs by baclofen. Baclofen reversibly depressed monosynaptic IPSPs when applied close to the recording site, but was ineffective when applied close to the stimulating site in stratum radiatum. These results suggest that baclofen disinhibits pyramidal neurons in area CA1 of the rat hippocampus by activating receptors on the terminals of inhibitory neurons that are coupled to a Ba²⁺-insensitive effector mechanism.     

Contribution of ionotropic glutamate receptors and voltage-dependent calcium channels to the potentiation phenomenon induced by transient pentylenetetrazol in the CA1 region of rat hippocampal slices

The role of ionotropic glutamate receptors and voltage-dependent calcium channels (VDCCs) in potentiation phenomenon and epileptic activity induced by a transient pentylenetetrazol (PTZ) application in the CA1 region of rat hippocampal slices was investigated. Also we examined whether adenosine as an inhibitory neuromodulator would interact with expression of the long-lasting effect of transient PTZ. Population spikes (PS) were recorded in the CA1 cell body layer of the hippocampal slices following stratum radiatum stimulation. Changes in the PS amplitude potentiation and number of extra PS, which induced by transient PTZ were used as indices to quantify the effects of drugs. PS input-output curve was significantly increased 10 min after PTZ application and persisted at least for 60 min after PTZ washout. Polyspikes also appeared, but did not persist. Both ketamine and APV reduced the extent of potentiation of PS amplitude but had no effect on number of extra PS. The selective non-NMDA receptor antagonist CNQX prevented the amplitude potentiation and the generation of extra PS. The blocker of VDCCs, verapamil, prevented the amplitude potentiation and inhibited polyspike activity. Co-application of adenosine and PTZ produced a rapid and reversible decrease in the PS amplitude, but PTZ-induced potentiation phenomenon was observed after washout. It is concluded that ionotropic glutamate receptors as well as VDCCs involve in the PTZ-induced LTP of PS amplitude. PTZ-induced LTP is also insensitive to adenosine. The epileptiform activity induced by a transient PTZ application could be attributed to VDCCs. The polyspikes mediated by VDCCs are dependent on prior activation of AMPA receptors.     

Pathway specificity of dendritic spine morphology in identified synapses onto rat hippocampal CA1 neurons in organotypic slices

The output of the hippocampus is largely determined by interaction of the three excitatory pathways that impinge on CA1 pyramidal neurons. These synapses, formed by axons of: (1) CA3 pyramidal neurons; (2) neurons of the entorhinal cortex (EC); and (3) neighboring CA1 neurons, are all potentially plastic. Here, we take advantage of the accessibility of the organotypic slice preparation to identify the type of spines with which each of these pathways forms synapses, at different developmental stages. Recent reports have shown that morphology of dendritic spines is activity-dependent with large mushroom spines being thought to represent stronger synaptic connections than thin or stubby spines. Although in a wide range of preparations, mushroom spines represent only 15% of spines across the whole dendritic tree, we find that this proportion is highly pathway specific. Thus in organotypic slices, the axons of CA3 neurons form synapses with mushroom spines on CA1 neurons in approximately 50% of cases, whereas this spine type is rare (<10%) in either of the other two pathways. This high proportion of mushroom spines only occurs after spontaneous excitatory activity in the CA1 cells increases over the second week in vitro. Previous studies suggest that pathway specificity also occurs in vivo. In tissue fixed in vivo, it is the synapses of distal apical dendrites thought to be formed by axons originating in the EC that are richer in mushroom spines. Hence, contrary to previous suggestions, the proportion of mushroom spines is clearly not an intrinsic property of the pathway but rather a characteristic dependent on the environment. We suggest that this is most likely a result of the previous activity of the synapses. The fact that, despite the large differences in pathway specificity between preparations, the overall proportion of different spine types remains unchanged, suggests a strong influence of homeostasis across the network.     

Neonatal exposure to monosodium L-glutamate induces loss of neurons and cytoarchitectural alterations in hippocampal CA1 pyramidal neurons of adult rats

Glutamatergic post-synaptic receptors are closely related to the known excitotoxic effects of high doses of L-glutamate. Several behavioral abnormalities, glial reaction, and an increase of expression of the NMDA receptor sub-units have been observed in the rat hippocampus after early monosodium glutamate exposure. Thus, a quantitative morphological study was carried out to determine the effects of early exposure to monosodium glutamate on post-synaptic structures that mediate glutamate excitatory neurotransmission in the hippocampal CA1 field. Four milligrams per gram body weight of monosodium glutamate was subcutaneously injected into neonatal Wistar rats, at 1, 3, 5, and 7 days. Cell loss and several cytoarchitectonic parameters were evaluated in pyramidal cells from the hippocampal CA1 field in the treated rats at 60 days of age. An untreated group of rats were used as controls. Cell number in the hippocampus of experimental rats was 11.5% less than that in control animals. In addition, both dendritic arborization and dendritic spine density were adversely affected, and thin and mushroom-shaped spines became proportionally more numerous, while the opposite occurred to stubby spines. These results strongly suggest the occurrence of cell death and also show some cytoarchitectural modifications in the surviving neurons. These could lead to functional alterations in the hippocampal integrative activity, due to an early cytoexcitotoxic effect of monosodium glutamate.     

Differential sensitivity to Zolpidem of IPSPs activated by morphologically identified CA1 interneurons in slices of rat hippocampus

Hippocampal pyramidal cells express several alpha-subunits, which determine the affinity of GABAA (gamma-aminobutyric acid) receptors for benzodiazepine site ligands. This study asked whether inhibitory postsynaptic potentials (IPSPs) elicited by specific interneuronal subclasses were differentially sensitive to the alpha1-preferring agonist Zolpidem, i.e. whether different receptors mediate different inhibitory connections. Paired intracellular recordings in which the presynaptic cell was an interneuron and the postsynaptic cell a CA1 pyramid were performed in slices of adult rat hippocampus. Resultant IPSPs were challenged with Zolpidem, cells filled with biocytin and identified morphologically. IPSPs elicited by fast spiking (FS) basket cells (n = 9) were enhanced more than IPSPs elicited by regular spiking (RS) basket cells (n = 10). At FS basket cell synapses the efficacy of Zolpidem was equivalent to that of Diazepam, while RS basket cell IPSPs are enhanced 50% less by Zolpidem than by Diazepam. Thus, while alpha1 subunits may dominate at synapses supplied by FS basket cells, RS basket cell synapses also involve alpha2/3 subunits. Two bistratified cell IPSPs tested with Zolpidem did not increase in amplitude, despite powerful enhancements of bistratified cell IPSPs by Diazepam, consistent with previous indications that these synapses utilize alpha5-containing receptors. Enhancements of basket cell IPSPs by Zolpidem and Diazepam were bi- or triphasic with steep amplitude increases separated by plateaux, occurring 10-15, 25-30 and 45-55 min after adding the drug to the bath. The entire enhancement was, however, blocked by the antagonist Flumazenil (n = 7). Flumazenil, either alone (n = 3), or after Zolpidem, reduced IPSP amplitude to approximately 90% of control, suggesting that alpha4-containing receptors were not involved.     

Epileptogenic actions of xanthines in relation to their affinities for adenosine A1 receptors in CA3 neurons of hippocampal slices (guinea pig)

In order to analyze the epileptogenic mechanisms of caffaine and related xanthines, putative effects of these drugs were studied on adenosine receptors of CA3 neurons in hippocampal slices. Epileptogenic concentrations of different xanthine derivatives strongly correlated with their affinities for the inhibitory A₁ adenosine receptor subtype. The A₁ receptor agonists adenosine and R-PIA reversibly depressed xanthine-induced epileptic activity without effects on the resting membrane potential or on spontaneously occuring action potentials. These findings suggest that the epileptogenic potency of xanthines is primarily due to the blockade of the A₁ receptors through an abnormal rise of intracellular cAMP and to the excessive transmembrane calcium fluxes underlying paroxysmal depolarization shifts.     

Post-weaning social isolation of rats leads to a diminution of LTP in the CA1 to subiculum pathway

Post-weaning social isolation of rats produces psychological and physiological changes that are relevant to schizophrenia. Here, we report that long-term potentiation (LTP) in the CA1 to subiculum pathway is lower by 34%, (P<0.0001) in brain slices from isolates compared with those from socially housed rats. We also report that LTP in this pathway is NMDA receptor-dependent.