Hippocampal Release Research Articles

Detection of seizure-associated high-frequency oscillations above 500 Hz

High-frequency oscillations (HFOs) of up to 500Hz in EEG are considered to have close relation with ictogenesis. We had the unique opportunity to record a seizure in EEG with intracerebral macroelectrodes and a sampling frequency of 10kHz. Considering the notion that faster HFOs are likely more ictogenic, we investigated this ictal EEG data to find if even faster HFOs were present. HFOs were investigated in interictal spikes and seizure activity using time-frequency spectra: t values corresponding to frequencies from 100 to 1000Hz were obtained by comparison to the background and controlled by the false discovery rate (FDR). The seizure had a right hippocampal onset. HFOs up to 800Hz as well as HFOs below 500Hz built up in the hippocampal discharges more at the beginning of the seizure and during the preictal period than in the interictal period. These HFOs were visually confirmed in temporally expanded EEG traces. We demonstrated for the first time the existence of HFOs above 500Hz and up to 800Hz with intracerebral macroelectrodes in an epileptic patient; they occurred primarily in association with the seizure discharge. HFOs above 500Hz possibly reflect facilitation of ictogenic neuronal hypersynchronization.

Nicotine's Allure

Both conscious and unconscious memory mechanisms contribute to the rewarding effects of nicotine and other drugs of abuse. In this issue of Neuron, Tang and Dani use in vivo measures of synaptic plasticity in freely moving mice to link nicotine-induced dopamine release in hippocampus to LTP induction and behavioral reinforcement.

Persistent zinc depletion in the mossy fiber terminals in the intrahippocampal kainate mouse model of mesial temporal lobe epilepsy

Zinc is released in synaptic vesicles with glutamate, and modulates glutamatergic neurotransmission. In brain, the highest amount of zinc, detected by Timm staining, is in the mossy fiber (MF) system in the hippocampus. In the intrahippocampal kainate (KA) mouse model of mesial temporal lobe epilepsy, which is elicited by intrahippocampal KA, prominent MF sprouting develops rapidly within 2 weeks post-KA. However, the intensity of Timm staining is reduced gradually thereafter. The present study is designed to determine the mechanisms underlying this reduction of Timm staining. The changes in Timm staining, and VGluT1, Synapsin-1, and zinc transporter 3 (ZnT3) immunoreactivity (IR) were examined from 4-56 days post-KA. An analysis of glutamate release in the KA-injected hippocampus was conducted by microdialysis before and during the continuous injection of midazolam (MDZ). At 56 days post-KA, Timm staining disappeared completely, whereas VGluT-1-, Synapsin-1-, and ZnT3-IR were increased in the sprouted MF boutons. However, when the seizures were suppressed by a continuous perfusion of MDZ, the glutamate release in the hippocampus decreased and Timm staining was recovered. This study showed that the reduction of Timm staining is the result of decreased zinc content but not the loss of MF itself. The reduction is the result of the enhanced release of zinc relative to storage, and it should facilitate the glutamate excitation that might be related to the epileptogenesis and rapid advancement of the morphologic changes in this model.

Acetylcholine-Stimulated [3H]GABA Release from Mouse Brain Synaptosomes is Modulated by α4β2 and α4α5β2 Nicotinic Receptor Subtypes

Nicotinic acetylcholine receptor (nAChR) agonists stimulate the release of GABA from GABAergic nerve terminals, but the nAChR subtypes that mediate this effect have not been elucidated. The studies reported here used synaptosomes derived from the cortex, hippocampus, striatum, and thalamus of wild-type and alpha4-, alpha5-, alpha7-, beta2-, and beta4-null mutant mice to identify nAChR subtypes involved in acetylcholine (ACh)-evoked GABA release. Null mutation of genes encoding the alpha4 or beta2 subunits resulted in complete loss of ACh-stimulated [(3)H]GABA release in all four brain regions. In contrast, alpha5 gene deletion exerted a small but significant decrease in maximal ACh-evoked [(3)H]GABA release in hippocampus and striatum, with a more profound effect in cortex. Acetylcholine-stimulated [(3)H]GABA release from thalamic synaptosomes was not significantly affected by alpha5 gene deletion. No effect was detected in the four brain regions examined in alpha7- or beta4-null mutant mice. Further analysis of ACh-evoked [(3)H]GABA release revealed biphasic concentration-response relationships in the four brain regions examined from all wild-type animals and in alpha5 null mutant mice. Moreover, a selective reduction in the maximum response of the high-affinity component was apparent in alpha5-null mutant mice. The results demonstrate that alpha4beta2-type nAChRs are critical for ACh-stimulated [(3)H]GABA release from all four brain regions examined. In addition, the results suggest that alpha5-containing receptors on GABAergic nerve terminals comprise a fraction of the high ACh-sensitivity component of the concentration-response curve and contribute directly to the ability of nicotinic agonists to evoke GABA release in these regions.

Prenatal choline supplementation in rats increases the expression of IGF2 and its receptor IGF2R and enhances IGF2-induced acetylcholine release in hippocampus and frontal cortex

Choline is an essential nutrient whose availability during the second half of gestation produces long-lasting cognitive effects. Rats that obtain supplemental choline during embryonic day (E) 11–17 have enhanced depolarization-evoked acetylcholine (ACh) release from hippocampal slices, whereas choline deficiency during this time reduces this release. Previously we reported that rats whose mothers consumed a choline-supplemented diet during E11–17 have higher levels of insulin-like growth factor II (IGF2) mRNA and protein in the frontal cortex compared to control and prenatally choline-deficient animals. Since IGF2 has been shown to stimulate endogenous ACh release, we measured the release of ACh from hippocampal and frontal cortical slices from rats on postnatal day (P) 18, P24, P34 and P80 in response to a depolarizing concentration of potassium (45 mM or 25 mM) or to IGF2 treatment in the absence or presence of a depolarizing concentration of potassium (25 mM). On P18, IGF2/depolarization-evoked ACh release from hippocampal slices was enhanced by prenatal choline supplementation. In the frontal cortex on P80, prenatal choline supplementation dramatically potentiated ACh release induced by depolarization, IGF2 or the combination of the two. On P18 and P90 and in both brain regions, IGF2 mRNA and protein levels, as well as protein levels of the IGF2 receptor (IGF2R), were higher in prenatally choline-supplemented rats. Choline supplementation also increased IGF2R mRNA levels in the septum. In summary, prenatal choline supplementation produced alterations in IGF2 signaling, via increased levels of IGF2 and IGF2R, which may enhance cholinergic neurotransmission and confer neuroprotection against insult.

Minimal latency to hippocampal epileptogenesis and clinical epilepsy after perforant pathway stimulation‐induced status epilepticus in awake rats

Hippocampal epileptogenesis is hypothesized to involve secondary mechanisms triggered by initial brain injury. Chemoconvulsant-induced status epilepticus has been used to identify secondary epileptogenic mechanisms under the assumption that a seizure-free, preepileptic "latent period" exists that is long enough to accommodate delayed mechanisms. The latent period is difficult to assess experimentally because early spontaneous seizures may be caused or influenced by residual chemoconvulsant that masks the true duration of the epileptogenic process. To avoid the use of chemoconvulsants and determine the latency to hippocampal epileptogenesis and clinical epilepsy, we developed an electrical stimulation-based method to evoke hippocampal discharges in awake rats and produce hippocampal injury and hippocampal-onset epilepsy reliably. Continuous video monitoring and granule cell layer recording determined whether hippocampal epileptogenesis develops immediately or long after injury. Bilateral perforant pathway stimulation for 3 hours evoked granule cell epileptiform discharges and convulsive status epilepticus with minimal lethality. Spontaneous stage 3-5 behavioral seizures reliably developed within 3 days poststimulation, and all 72 spontaneous behavioral seizures recorded in 10 animals were preceded by spontaneous granule cell epileptiform discharges. Histological analysis confirmed a reproducible pattern of limited hippocampal and extrahippocampal injury, including an extensive bilateral loss of hilar neurons throughout the hippocampal longitudinal axis. These results indicate that hippocampal epileptogenesis after convulsive status epilepticus is an immediate network defect coincident with neuron loss or other early changes. We hypothesize that the latent period is directly related and inversely proportional to the extent of neuron loss in brain regions involved in seizure initiation, spread, and clinical expression.

Involvement of the cAMP-dependent pathway in the reduction of epileptiform bursting caused by somatostatin in the mouse hippocampus

The cyclic AMP pathway is major signal transduction system involved in hippocampal neurotransmission. Recently, the peptide somatostatin-14 (SRIF) has emerged as a key signal that, by activating its receptors, inhibits epileptiform bursting in the mouse hippocampus. Little is known on transduction mechanisms, which may mediate SRIF function in native cell/tissues. Using a well-established model of epileptiform activity induced by Mg(2+)-free medium with 4-aminopyridine [0 Mg(2+)/4-aminopyridine (4-AP)] in mouse hippocampal slices, we demonstrated that protein kinase A (PKA)-related signaling is upregulated by hippocampal bursting and that treatment with SRIF normalizes this upregulation. We also demonstrated that the SRIF-induced inhibition of PKA impairs phosphorylation of the NMDA receptor subunit NR1. Extracellular recordings of the 0 Mg(2+)/4-AP-induced hippocampal discharge from the CA3 region demonstrated that treating slices with compounds, which interfere with PKA activity, prevent SRIF inhibition of epileptiform bursting. Our results suggest that SRIF modulation of hippocampal activity may involve PKA-related signaling.

Serotonergic involvement in the effects of chronic cold stress on reversal learning in the rats

Chronic stress is a risk factor and an antecedent to depression and to dysregulation of brain modulatory systems. Chronic intermittent cold (CIC) stress sensitized the increase in norepinephrine (NE) release in hippocampus and medial prefrontal cortex (mPFC) in response to acute stress (Mana & Grace, 1997. Neuroscience 81:1055). Cognitive performance in an attentional set‐shifting task (AST) can be enhanced by tonic NE transmission in mPFC (Lapiz & Morilak, 2006. Neuroscience 137:1039), and is disrupted by chronic unpredictable stress (Bondi et al. 2007. Neuropsychopharmacol. e‐pub). This study addressed the effects of CIC stress on performance of rats in the AST. Male Sprague‐Dawley rats exposed to a 4°C cold room (6 hr/day × 14 days) were tested in the AST. Analyses showed a significant effect of Stress (P = 0.043), Task (P < 0.0001) and a Stress × Task interaction (P = 0.001), with CIC‐stressed rats requiring more trials during reversal 1. The orbitofrontal cortex (OFC) has previously been implicated in reversal tasks, possibly modulated by serotonin (5‐HT). We showed that 5‐HT depletion with Para‐chlorophenylalanine (200 mg/kg/day, i.p.) induced a similar selective deficit in reversal, while the CIC‐induced impairment in reversal learning was attenuated by the 5‐HT reuptake inhibitor (SSRI) Citalopram (5 mg/kg, i.p.). These results indicate that the CIC stress‐induced impairment in cognitive flexibility may involve an alteration in 5‐HT function in OFC. These deficits may be relevant to the symptoms of neuropsychiatric disorders that respond to SSRI treatment, i.e., depression and anxiety disorders.Support: NIMH grant MH72672 & NARSAD Award to MDLB

EFFECT OF DURATION OF STATUS CONVULSION ON NEURONAL APOPTOSIS AND EARLY APOPTOTIC EVENTS IN HIPPOCAMPUS OF RATS

OBJECTIVE: Our goal was to explore the influence of duration of status epilepticus on neuronal apoptosis, mitochondrial membrane potential, and cytochrome c release in hippocampus in Wistar rats after status epilepticus (SE). METHODS: SE that lasted for 30 minutes or 3 hours was induced by intraperitoneal injection with lithium chloride and pilocarpine. Rats were killed at different time points. The apoptosis, mitochondrial membrane potential, and intracellular cytochrome c level were investigated by flow cytometry. RESULTS: The proportion of apoptotic cells, the decrease of mitochondrial membrane potential, and the release of intracellular cytochrome c significantly changed 30 minutes after 30-minute SE. The peak level was at the 12th hour after SE and 6th hour after SE in apoptosis and the 2 early apoptotic events, respectively. Compared with the same time point after 30-minute SE, the levels of apoptosis and the 2 early apoptotic events after 3-hour SE were much higher. The neuronal apoptosis and the 2 early apoptotic events in hippocampus after SE had a positive correlation with the duration of SE in partial correlation analysis. CONCLUSIONS: Severe seizures could induce the changes of neuronal apoptosis and the early apoptotic events in hippocampus after SE; the longer the duration of SE, the more serious the change of apoptosis and early apoptotic events were.

Antidepressant treatments and function of glutamate ionotropic receptors mediating amine release in hippocampus

Previous evidences showed that, besides noradrenaline (NA) and 5-hydroxytryptamine (5-HT), glutamate transmission is involved in the mechanism of action of antidepressants (ADs), although the relations between aminergic and glutamatergic systems are poorly understood. The aims of this investigation were to evaluate changes in the function of glutamate AMPA and NMDA receptors produced by acute and chronic administration of the two ADs reboxetine and fluoxetine, selective inhibitors of NA and 5-HT uptake, respectively. Rats were treated acutely (intraperitoneal injection) or chronically (osmotic minipump infusion) with reboxetine or fluoxetine. Isolated hippocampal nerve endings (synaptosomes) prepared following acute/chronic treatments were labelled with [ 3H]NA or [ 3H]5-HT and [ 3H]amine release was monitored during exposure in superfusion to NMDA/glycine, AMPA or K +-depolarization. Acute and chronic reboxetine reduced the release of [ 3H]NA evoked by NMDA/glycine or by AMPA. The NMDA/glycine-evoked release of [ 3H]NA was also down-regulated by chronic fluoxetine. Only acute, but not chronic, fluoxetine inhibited the AMPA-evoked release of [ 3H]5-HT. The release of [ 3H]NA and [ 3H]5-HT elicited by K +-depolarization was almost abolished by acute reboxetine or fluoxetine, respectively, but recovered during chronic ADs administration. ADs reduced NMDA receptor-mediated releasing effects in noradrenergic terminals after acute and chronic administration, although by different mechanisms. Chronic treatments markedly reduced the expression level of NR1 subunit in synaptic membranes. The noradrenergic and serotonergic release systems seem to be partly functionally interconnected and interact with glutamatergic transmission to down-regulate its function. The results obtained support the view that glutamate plays a major role in AD activity.

Chronic Prenatal Ethanol Exposure Increases Glucocorticoid‐Induced Glutamate Release in the Hippocampus of the Near‐Term Foetal Guinea Pig

Exposure to high cortisol concentration can injure the developing brain, possibly via an excitotoxic mechanism involving glutamate (Glu). The present study tested the hypothesis that chronic prenatal ethanol exposure (CPEE) activates the foetal hypothalamic-pituitary-adrenal axis to produce high cortisol exposure in the foetal compartment and alters sensitivity to glucocorticoid-induced Glu release in the foetal hippocampus. Pregnant guinea pigs received daily oral administration of ethanol (4 g/kg maternal body weight/day) or isocaloric-sucrose/pair-feeding from gestational day (GD) 2 until GD 63 (term, approximately GD 68) at which time they were euthanised, 1 h after their final treatment. Adrenocorticotrophic hormone (ACTH) and cortisol concentrations were determined in foetal plasma. Basal and electrically stimulated Glu and gamma-aminobutyric acid (GABA) efflux in the presence or absence of dexamethasone (DEX), a selective glucocorticoid-receptor agonist, were determined ex vivo in foetal hippocampal slices. Glucocorticoid receptor (GR), mineralocorticoid receptor (MR) and N-methyl-D-aspartate (NMDA) receptor NR1 subunit mRNA expression were determined in situ in the hippocampus and dentate gyrus. In the near-term foetus, CPEE increased foetal plasma ACTH and cortisol concentrations. Electrically stimulated glutamate, but not GABA, release was increased in CPEE foetal hippocampal slices. Low DEX concentration (0.3 microM) decreased stimulated glutamate, but not GABA, release in both CPEE and control foetal hippocampal slices. High DEX concentration (3.0 microM) increased basal release of Glu, but not GABA, in CPEE foetal hippocampal slices. GR, but not MR, mRNA expression was elevated in the hippocampus and dentate gyrus, whereas NR1 mRNA expression was increased in the CA1 and CA3 fields of the foetal hippocampus. These data demonstrate that CPEE increases high glucocorticoid concentration-induced Glu release in the foetal hippocampus, presumably as a consequence of increased GR expression. These effects of CPEE, coupled with increased glutamate release and increased NMDA receptor expression, may predispose the near-term foetal hippocampus to GR and Glu-NMDA receptor-mediated neurodevelopmental toxicity.

Interaction Between P2X and Nicotinic Acetylcholine Receptors in Glutamate Nerve Terminals of the Rat Hippocampus

Nicotinic acetylcholine receptors (nAChRs [constituted by pentameric association of alpha2-10 and beta2-4 subunits]) and P2X receptors (P2XRs [activated by ATP and constituted by multimeric association of P2X1-7 subunits]) are both ionotropic receptors permeable to cations, which have in common the disparity between the wealth of data showing their presence in the brain and little evidence of their participation in mediating synaptic transmission. This has led to the proposal that both nAChRs and P2XRs might primarily modulate rather than directly mediate synaptic transmission, which is in accordance with the predominant presynaptic localization of both receptor subtypes (Role and Berg, 1996; Cunha and Ribeiro, 2000). Interestingly, both functional neurochemical (Allgaier et al., 1995; Salgado et al., 2000; Diáz-Hernández et al., 2002) and electrophysiological studies (Barajas-Lopez et al., 1998; Searl et al., 1998; Zhou and Calligan, 1998; Khakh et al., 2000) indicated a close interaction between nAChRs and P2XRs, which is paralleled by a co-release of ATPand ACh from central terminals (e.g., Richardson and Brown, 1987). Because glutamate release in the hippocampus is controlled by both nAChRs (e.g., McGehee et al., 1995) and P2XRs (Khakh et al., 2003; Rodrigues et al., 2005), we investigated if there was a functional interaction between these two presynaptic ionotropic receptors in the control of glutamate release in the rat hippocampus.

INFLUENCES OF AGE AND THE DURATION OF STATUS CONVULSION ON INTRACELLULAR CYTOCHROME C RELEASE IN HIPPOCAMPUS

Objectives: To explore the influences of age and duration of status convulsion SC on intracellular cytochrome C (cytC) release in hippocampus.

Neurochemical effects of exercise and neuromuscular electrical stimulation on brain after stroke: A microdialysis study using rat model

Treadmill exercise and neuromuscular electrical stimulation are common clinical approaches for stroke rehabilitation. Both animal and clinical studies have shown the functional improvements after these interventions. However, the neurochemical effects on the ischemic brain had not been well studied. This study aimed at evaluating the effects of treadmill exercise and neuromuscular electrical stimulation (NMES), and studying their effects during a 2-week training, on the levels of common neurotransmitters (aspartate, glutamate, taurine and gamma-aminobutyric acid (GABA)) in the hippocampus following transient focal cerebral ischemia. Either treadmill exercise or neuromuscular electrical stimulation was prescribed to the rats 24 h after cerebral ischemia whereas Control group remained in cages for 2 weeks. Microdialysis technique was used to collect dialysates from ipsilesional hippocampus in vivo. It was found that the glutamate level was increased significantly during treadmill exercise and then returned to baseline level. Both interventions did not trigger significant effects on aspartate and glutamate basal levels during the 2 weeks. The relatively high taurine level in Control groups may suggest that the interventions might suppress the taurine release in hippocampus. GABA and aspartate levels did not showed significant changes over the 2 weeks in all groups. These results provide insights to explain the neurochemical effects on the ischemic injured brain during the course of rehabilitation.

Behavioural and neurochemical responses evoked by repeated exposure to an elevated open platform

Increased psychophysiological resistance to chronic stress has been related to increased 5-HT release in the dorsal hippocampus. This study investigated the changes in 5-HT release and turnover in the hippocampus evoked by acute and repeated exposure to an inescapable stressor, an elevated open platform, and compared them to the changes evoked in the frontal cortex. Repeated exposure to this stressor results in habituation of the plasma corticosterone response to the test, with full habituation being observed after 20 trials. Repeated exposure to the stressor for 5 or 10 occasions increased 5-HT turnover in the hippocampus. By contrast, 5-HT turnover in frontal cortex was increased by acute exposure to the stressor. Microdialysis studies showed that acute stress increased 5-HT overflow in prefrontal cortex but not dorsal hippocampus whereas repeated daily (10 days) exposure to the stressor increased basal extracellular 5-HT in the dorsal hippocampus, but not the prefrontal cortex. Prior exposure to the stressor on up to 10 occasions enhanced the plasma corticosterone response to a challenge in an elevated plus-maze performed 24 h later whereas repeated, but not acute, exposure to the stressor, elicited anxiolytic-like behavioural responses in this test. It is concluded that acute exposure to this form of inescapable stress selectively stimulates the 5-HT projections to the frontal cortex; repeated stress elicits a sustained increase in 5-HT release and turnover in the hippocampus. The data are consistent with the hypothesis that increased 5-HT release in the hippocampus may be implicated in the mechanisms underlying habituation to inescapable stress.

Modification of the synaptic glutamate turnover in the hippocampal tissue exposed to low-frequency, pulsed magnetic fields

The influence of pulsed magnetic fields (PMF) on the release and uptake of glutamate was investigated. While the release was examined using hippocampal slices, synaptosomes were chosen to characterize the uptake process. 3 H- d-aspartate was used as a marker of glutamergic transmission. The pulsed magnetic fields (9–15 mT) applied according to the pattern which induced epileptic discharges in hippocampus amplified and attenuated the release and uptake of glutamate, respectively. However, the magnetic fields which induced an increase in neuronal excitability without concomitant seizures amplified both processes. These results confirm our previous reports and indicate that the glutamergic synapses are the target of magnetic fields action.

Acetylcholine release in hippocampus and striatum during testing on a rewarded spontaneous alternation task

The present experiment tested male Sprague–Dawley rats for spontaneous alternation performance in a food-rewarded Y-shaped maze. Microdialysis samples, later assessed for acetylcholine concentration, were collected from the hippocampus and striatum of each rat prior to and during testing; testing sessions lasted 20 min. Early in testing, rats alternated at a rate of 72%. Alternation scores increased throughout the 20-min testing session and reached 93% during the last 5 min. The behavioral findings suggest that, during testing, rats changed the basis for their performance from a spatial working memory strategy to a persistent turning strategy. ACh release in both hippocampus and striatum increased at the onset of testing. Increases in ACh release in the striatum began at 18% above baseline during the first 5 min of testing and steadily increased reaching 58% above baseline during the final 5 min. The progressive rise of striatum ACh release during testing occurred at about the time rats adopted a persistent turning strategy. In contrast, ACh release in the hippocampus increased by 50% with the onset of testing and remained at this level until declining slightly during the last 5 min of testing. The relative changes in ACh release in the striatum and hippocampus resulted in a close negative relationship between the ratio of ACh release in the hippocampus/striatum and alternation scores.

Post-synaptic N-methyl- d-aspartate signalling in hippocampal neurons of rat: spillover increases the impact of each spike in a short burst discharge

High-frequency burst discharges in hippocampus typically consist of less than ten spikes fired at frequencies too high to be followed by a post-synaptic neuron. How significant are these numbers for synaptic signalling? We have measured the N-methyl- d-aspartate (NMDA) component of the excitatory post-synaptic current (EPSC NMDA) in hippocampal CA1 neurons of rat after burst discharge of variable duration. The synaptic facilitation is accompanied by a slow-down of the EPSC NMDA which develops on a spike-to-spike basis. Consequently the charge transferred by the after-burst EPSC NMDA is increased with each spike. The phenomenon is most probably due to the spillover-mediated recruitment of extrasynaptic NMDA receptors. In terms of post-synaptic signalling it dramatically increases the impact of each spike in a short burst discharge.

Progression of temporal lobe epilepsy in the rat is associated with immunocytochemical changes in inhibitory interneurons in specific regions of the hippocampal formation

Immunocytochemical markers of specific rat hippocampal interneuron subpopulations, including the calcium binding proteins parvalbumin (PV), and calretinin (CR) were examined in relation to the evolution of spontaneous seizures after electrically induced status epilepticus (SE). PV/CR/NeuN immunoreactive neurons were counted in the hippocampal formation at different time intervals after SE and related to spontaneous hippocampal discharge activity. Decreased PV immunoreactivity was observed within 1 day after SE in the hilus, pre- and parasubiculum, and in the entorhinal cortex layers II and V/VI. In layer III, the density of detectable PV immunoreactive neurons did not decrease significantly, whereas the number of surrounding principal neurons was extensively decreased within a week in most post-SE rats, and after 3–4.5 months in all rats that had developed a progressive evolution of seizures. CR immunoreactive neuron number decreased in all hippocampal subregions except for the stratum lacunosum-moleculare and the EC layer II, in which the density did not decrease significantly. The apparent decrease in the number of PV and CR immunoreactive hilar neurons was correlated with the duration of the SE and was most extensive in rats with a progressive form of epilepsy. The loss of CR and PV expression or the loss of CR- and PV-containing neurons in specific regions of the hippocampal formation may play a role in the progressive nature of epilepsy possibly via increasing the entorhinal–hippocampal activity.

Effects of galantamine, a nicotinic allosteric potentiating ligand, on nicotine-induced catecholamine release in hippocampus and nucleus accumbens of rats.

Galantamine, a drug for treatment of Alzheimer's disease, is a novel cholinergic agent with a dual mode of action that inhibits acetylcholinesterase and allosterically modulates nicotinic cholinergic receptors (nAChRs). Nicotine stimulates catecholamine secretion, inducing hippocampal norepinephrine (NE) release, and improves memory consolidation. Thus, the effect of galantamine on nicotine-induced hippocampal NE secretion was investigated. This was compared with the effect of galantamine on nicotine-induced dopamine (DA) release within the nucleus accumbens of the same rat. Nicotine (0.025-0.09 mg/kg i.v.) dose dependently increased NE and DA levels in microdialysates from the hippocampus and nucleus accumbens, respectively, of freely moving rats. Pretreatment with galantamine (3.0 mg/kg s.c.) 3 h before nicotine either potentiated NE responses to doses of nicotine that were ineffective alone (0.025-0.045 mg/kg) or significantly enhanced (0.065 mg/kg) NE responses, whereas galantamine was ineffective when administered 2 or 4 h before nicotine. In contrast to its effects on NE, galantamine did not alter accumbal DA responses to any dose of nicotine. These selective effects of galantamine on nicotine-stimulated NE secretion may reflect differences in local neural circuits that use nAChRs to modulate hippocampal NE versus accumbal DA release.