Biomedical subjects

S G Beck

Publications and source records attributed to S G Beck.

At least 19 recordsLinked to original sources

PubMed1999

Corticosteroids alter G protein inwardly rectifying potassium channels protein levels in hippocampal subfields.

Corticosterone or cortisol, stress hormones in rat and human, respectively, alter neurotransmitter receptor-mediated responses in the brain. Corticosterone could alter these responses by modifying any component of the receptor-effector pathway. Many of these receptors are linked to guanine nucleotide regulatory proteins (G proteins) which, in turn, can activate second messenger systems and/or ion channels, such as G protein inwardly rectifying potassium channels (GIRK). The aim of these experiments was to determine whether corticosterone treatment altered the levels of GIRK proteins in rat hippocampus. Corticosterone treatment selectively altered the levels of GIRK1 and GIRK2 (measured on immunoblots) depending on the subfield of the hippocampus examined. These data lend credence to the hypothesis that corticosterone differentially alters neurotransmitter receptor-mediated responses dependent on the brain area.

Adrenalectomy↗

PubMed1998

Corticosteroids influence the action potential firing pattern of hippocampal subfield CA3 pyramidal cells.

Corticosteroids regulate gene expression through the activation of mineralocorticoid and glucocorticoid receptors. The hippocampus contains the highest density of mineralocorticoid and glucocorticoid receptors in the central nervous system. The modulation of neuron excitability by corticosteroids in hippocampal subfield CA1 is well documented. However, it is not known whether corticosteroids produce different effects across the various hippocampal subfields. Therefore, we used intracellular recording techniques to examine the actions of chronic corticosteroid treatment (2 weeks) on the electrophysiological properties of rat hippocampal subfield CA3 pyramidal cells. The treatment groups used in this investigation were: adrenalectomy (ADX), selective mineralocorticoid receptor activation with aldosterone (ALD), mineralocorticoid and glucocorticoid receptor activation with high levels of corticosterone (HCT), and SHAM. Corticosteroid treatment altered the percentage of nonburst and burst firing neurons. The percentages of nonbursting cells were 74 and 62% in tissue from ADX and HCT animals compared to 42 and 41% in ALD and SHAM animals, respectively. The corticosteroid-induced effect on the ratio of nonbursting to bursting cells does not appear to be secondary to changes in the cell's membrane input resistance, resting potential, time constant, action potential, slow-or fast-afterhyperpolarizing potential properties. Based on these results we conclude that corticosteroids are important for maintaining the ratio of nonburst and burst firing pyramidal neurons in subfield CA3. These novel results are distinct from those previously reported for subfield CA1, suggesting that corticosteroids have different effects across hippocampal subfields.

Action Potentials↗

PubMed1998

Corticosteroids alter 5-hydroxytryptamine1A receptor-effector pathway in hippocampal subfield CA3 pyramidal cells.

Corticosteroids influence neuron activity in the hippocampus through the activation of mineralocorticoid and glucocorticoid receptors. For example, corticosteroids modulate the responses elicited by the activation of several different neurotransmitter receptors on hippocampal pyramidal cells. However, the effects of corticosteroids on the serotonin (5-HT) receptors systems in subfield CA3 are not completely known. Therefore, we used single-electrode voltage clamp techniques to examine the actions of chronic corticosteroid treatment on the 5-HT1A receptor-effector pathway in rat hippocampal subfield CA3 pyramidal cells. Activation of the 5-HT1A receptor increases the conductance of an inward rectifying potassium channel, increasing outward current. The treatment groups used in this investigation were: adrenalectomy, selective mineralcorticoid receptor activation with aldosterone, mineralcorticoid receptor and glucocorticoid receptor activation with high levels of corticosterone and SHAM. Corticosteroids altered the characteristics of the 5-HT concentration-response curve for the 5-HT1A receptor. The effective concentration at 50% of maximum value was smaller in cells from the adrenalectomy treatment group compared to the other treatment groups. The maximum response was smaller in cells from the high corticosterone treatment group compared to SHAM and adrenalectomy treatment group animals. G protein function was also altered by corticosterone treatment. Less current was elicited by guanosine 5'-0-13-thiotriphosphate in cells from the high corticosterone treatment group compared to the other treatment groups and in cells from the SHAM treatment group compared to adrenalectomy treatment group animals. Corticosteroid treatment did not alter the current-voltage relationship, the conductance or the reversal potential of the potassium current linked to the 5-HT1A receptor. We conclude that corticosteroids alter the 5-HT1A receptor-mediated-response in hippocampal subfield CA3 neurons at site(s) downstream of the receptor.

Adrenal Cortex Hormones↗

PubMed1997

Molecular cloning and characterization of human podocalyxin-like protein. Orthologous relationship to rabbit PCLP1 and rat podocalyxin.

Human renal cortex and heart cDNA libraries were screened for a human homolog of rabbit PCLP1 using the rabbit PCLP1 cDNA as a probe. Clones spanning 5869 base pairs with an open reading frame coding for a 528-amino acid peptide were obtained. The putative peptide contains a potential signal peptide and a single membrane-spanning region. The extracellular domain contains multiple potential sites for N- and O-linked glycosylation and 4 cysteines for potential disulfide bonding similar to rabbit PCLP1. On Northern blot a major transcript is seen at 5.9 kilobases. Antibodies to this protein show a doublet at 160/165 kDa on Western blots of human glomerular extract and a pattern of intense glomerular staining and vascular endothelial staining on immunofluorescence of human kidney sections. Comparison of the rabbit and human peptide sequences shows a high degree of identity in the transmembrane and intracellular domains (96%) with a lower degree of identity in the extracellular domain (36%). An antibody to the intracellular domain reacted across species (human, rabbit, and rat) and recognized both rabbit PCLP1 and rat podocalyxin. An interspecies Southern blot probed with a cDNA coding for the intracellular domain showed strong hybridization to all vertebrates tested in a pattern suggesting a single copy gene. We conclude that this cDNA and putative peptide represent the human homolog of rabbit PCLP1 and rat podocalyxin.

Amino Acid Sequence↗

PubMed1997

Corticosterone alters G protein alpha-subunit levels in the rat hippocampus.

The hypothalamic-pituitary-adrenal axis regulates the synthesis and secretion of corticosteroid hormones. The hippocampus, a component of the limbic system, contains the highest concentration of corticosteroid receptors in the brain and may play an important role in regulating hypothalamic-pituitary-adrenal axis activity and mediating physiological responses to stress. The corticosteroid hormone corticosterone alters the response elicited by activation of several different G protein-linked neurotransmitter receptors in the hippocampus. In the present study we used Western blot and immunohistochemical techniques to determine the effects of chronic adrenalectomy (ADX), low basal (CT) and high (HCT) corticosterone treatments on Gs, Gi1 and 2 and Go alpha-subunit levels and intracellular location in the rat hippocampus. CT treatment increased Gs alpha-subunit levels and HCT treatment increased the levels of Gs, Gi1 and 2 and Go alpha-subunits when compared to sham as detected on Western blots. No change in the intracellular location of the G protein alpha-subunits was detected using immunohistochemistry. Based on our results, we conclude that corticosterone alters G protein alpha-subunit levels in the rat hippocampus without altering their intracellular location. These results provide an important piece of information towards understanding how corticosteroids alter G protein-linked neurotransmitter receptor-mediated responses.

Adrenalectomy↗

PubMed1997

Levetiracetam (ucb LO59) affects in vitro models of epilepsy in CA3 pyramidal neurons without altering normal synaptic transmission.

Previous behavioural and electrophysiological studies have indicated that levetiracetam (ucb LO59) acts as an anticonvulsant drug in vivo. The purpose of the present study was to investigate the effects of levetiracetam on normal synaptic transmission and epileptiform activity in vitro. Intracellular recordings were obtained from the CA3 subfield of the rat hippocampal slice preparation. Levetiracetam in a concentration of 10 microM did not influence basic cell properties or normal synaptic transmission evoked by subthreshold and suprathreshold stimuli to the commissural pathway. However, it strongly inhibited the development of epileptiform bursting by the gamma-aminobutyric acid (GABA)A-receptor antagonist bicuculline (1-30 microM). Levetiracetam also decreased the size of bursts previously established by bicuculline. In experiments in which the glutamate-receptor agonist N-Methyl-D-Aspartate (NMDA) was used to generate spontaneous bursting, levetiracetam had no effect on the size of the bursts but decreased bursting frequency. The difference in effects of levetiracetam on bicuculline- and NMDA-induced bursting appeared to be dependent on the convulsant used, since in the presence of 10 microM bicuculline, levetiracetam decreased the size of NMDA-bursts to the same extent as the size of synaptically evoked bicuculline-bursts but had little effect on bursting frequency. The results show that under our experimental conditions, levetiracetam did not alter the components of normal synaptic transmission. However, levetiracetam at the concentrations studied inhibited epileptiform bursting induced by bicuculline and NMDA in vitro in a manner consistent with the profile of an antiepileptogenic drug.

Animals↗

PubMed1997

Fluoxetine selectively alters 5-hydroxytryptamine1A and gamma-aminobutyric acidB receptor-mediated hyperpolarization in area CA1, but not area CA3, hippocampal pyramidal cells.

Fluoxetine is a 5-hydroxytryptamine (5-HT, serotonin)-selective reuptake inhibitor (SSRI) and is one of the main drugs used for the treatment of depression. Because it takes 2 to 3 weeks of treatment before clinical efficacy is manifest, the acute actions of fluoxetine cannot account for the clinical actions of the drug. The chronic effects of fluoxetine have not been completely delineated. The experiments detailed here investigate the chronic effects of fluoxetine on 5-HT and gamma-aminobutyric acid (GABA) receptor-mediated actions using intracellular recording techniques in hippocampal brain slices. Rats were treated with fluoxetine for 3 weeks via osmotic minipumps implanted s.c. Fluoxetine and norfluoxetine plasma levels were determined. The hippocampal pyramidal cell characteristics and the 5-HT1A and GABA(B) receptor-mediated hyperpolarization were measured in the CA1 and the CA3 subfields. The 5-HT4 receptor-mediated decrease in the slow afterhyperpolarization amplitude was also recorded in area CA1. The time constant, magnitude of the change in resistance during 300-ms hyperpolarizing current pulses and half-decay time of the sAHP were altered by chronic fluoxetine treatment in area CA1 pyramidal cells. No changes were seen in any of the active or passive membrane properties of the CA3 hippocampal pyramidal cells. Fluoxetine treatment increased the potency of 5-HT for the 5-HT1A receptor-mediated hyperpolarization in area CA1, but not area CA3, and decreased the potency of baclofen for the GABA(B) receptor-mediated hyperpolarization in area CA1, but not area CA3. The characteristics of the concentration-response curve for the 5-HT-mediated decrease in sAHP amplitude in area CA1 were not altered by fluoxetine treatment. Chronic fluoxetine selectively and differentially altered the cell characteristics and the 5-HT1A and GABA(B) receptor-mediated responses in area CA1 of the hippocampus, which forms the final common output of the hippocampus.

Animals↗

PubMed1996

Androgen modulates N-methyl-D-aspartate-mediated depolarization in CA1 hippocampal pyramidal cells.

Previously, research elucidating steroid hormone actions in the central nervous system has focused on their role in sexual reproduction and maintaining homeostasis. The hippocampus is a target of steroid modulation and is involved in the development of emotional behavior and memory storage. Area CA1 of the hippocampus contains a high density of androgen receptor (AR) and N-methyl-D-aspartate (NMDA) receptors. NMDA receptors underlie excitatory synaptic transmission and excitotoxicity in CA1 neurons. The effects of AR activation on the neurophysiology of hippocampal pyramidal neurons is unknown. Standard intracellular recording techniques in hippocampal slices were used to investigate the effects of the non-aromatizable androgen, 5-alpha-dihydrotestos-terone-proprionate (DHTP), on CA1 pyramidal cell characteristics and NMDA receptor-mediated responses. Male Sprague-Dawley rats were unoperated, sham-operated (SHAM), gonadectomized (GDX), or gonadectomized with DHTP replacement therapy (GDX + DHTP). Neuronal AR was saturated by DHTP treatment as determined by binding studies and immunocytochemistry. Chronic DHTP treatment increased the action potential duration and decreased the fast afterhyperpolarization (fAHP) amplitude. To test the effect of DHTP on glutamate receptor-mediated responses, hippocampal slices were exposed to increasing concentrations of NMDA. In pyramidal cells from SHAM and GDX-treated animals, 30 microM NMDA induced an irreversible depolarization; the membrane potential of pyramidal cells from GDX + DHTP-treated animals recovered to baseline. The effect of DHTP was time dependent, implicating protein synthetic mechanisms. Our findings demonstrate that androgens can influence pyramidal cell characteristics and neurotransmitter-evoked actions in hippocampal CA1 pyramidal cells.

Androgens↗

PubMed1996

Differential immunohistochemical labeling of Gs, G(il) and 2, and G(o) alpha-subunits in rat forebrain.

The anatomical and morphological distribution of the G proteins G(o), G(i1) and 2, and Gs alpha-subunits in rat forebrain sections was determined using immunohistochemical techniques. Diffuse G(o) labeling occurred in the neuropil throughout the cortex, superficial layers of the entorhinal cortex, thalamus, several white matter fiber tracts, and hippocampus. G(i1) and 2 immunoreactivity was also located in the neuropil but produced a more fibrous pattern. Fibrous labeling of G(i1) and 2 was observed in the cortex, amygdala, hippocampal subfield CA3, and several white matter fiber tracts. Both G(o) and G(i1) and 2 labeling was present in the pencil fibers within the striatum and lateral geniculate nucleus. Gs labeling, in contrast to G(o) and G(i1) and 2, was generally cytoplasmic. Cytoplasmic Gs labeling was observed in the thalamus, habenula, dentate, geniculate nucleus, hypothalamus, and hippocampus. Intense Gs labeling was observed in the striatum parenchyma, choroid plexus, and infundibular stem. Based on our results, we conclude that the G proteins G(o), G(i1) and 2, and Gs are anatomically distributed differently throughout the brain. The diffuse neuropil labeling of G(o), fibrous neuropil labeling of G(i1) and 2, and cytoplasmic labeling of Gs strongly suggests that the G proteins are also differentially distributed morphologically within a neuron. The differential anatomical and cellular location of G proteins in the CNS may contribute to the coupling specificity between neurotransmitter receptors and G proteins.

Animals↗

PubMed1996

Androgens selectively modulate C-fos messenger RNA induction in the rat hippocampus following novelty.

We have previously shown that androgen receptors are found in high concentrations in hippocampal CA1 pyramidal cells. To begin to explore the possible roles for androgen receptors in this area of the brain, we studied the effects of endogenous and exogenous androgen on the behaviourally induced expression of cellular immediate early gene messenger RNAs. Adult male Fischer 344 rats were either gonadectomized, gonadectomized and given two Silastic capsules of dihydrotestosterone propionate at the time of surgery, or left intact. Three weeks later, animals were placed into a novel open field for 20 min. This behavioural paradigm caused region- and gene-specific increases of c-fos, jun-B, c-jun and zif268 messenger RNA in the hippocampus as determined by semi-quantitative in situ hybridization histochemistry. The removal of circulating androgen by gonadectomy potentiated, whereas dihydrotestosterone treatment of castrates attenuated, the behaviourally induced expression of c-fos messenger RNA in the CA1 region of the hippocampus. No changes in c-fos messenger RNA expression were detected in the CA3 or dentate gyrus regions where androgen receptor levels are low. Androgen status did not affect either the basal or stimulated expression of Jun-B, c-Jun or zif268 messenger RNA in any of the three cellular regions of the hippocampus examined. These results implicate androgen receptors in modulating the active response of hippocampal neurons to a behaviourally relevant stimulus. Since the products of cellular immediate genes can function to alter an array of downstream genes, the modulation of these genes in the hippocampus by gonadal hormones may have important ramifications for hippocampal function.

Animals↗

PubMed1996

Corticosterone alters 5-HT1A receptor-mediated hyperpolarization in area CA1 hippocampal pyramidal neurons.

The 5-hydroxytryptamine1A (5-HT1A) receptor in the CA1 region of the hippocampus is linked through a G protein to an inwardly rectifying potassium conductance. Activation of the 5-HT1A receptor results in a membrane hyperpolarization and decreases neuronal firing rate. The hippocampus contains a high concentration of the mineralocorticoid (MR) and glucocorticoid (GR) corticosterone (CT) receptor subtypes. Some laboratories have reported that CT modulates 5-HT1A receptor binding density and mRNA levels in area CA1 of the hippocampus; however, others have reported no change. Previous electrophysiological studies have demonstrated that acute (1 to 4 hour) MR activation in slices from adrenalectomized (ADX) rats attenuates the 5-HT1A receptor-mediated hyperpolarization, while acute MR+ GR or GR activation alone did not alter the 5-HT1A response. Our results confirm that the 5-HT1A response was attenuated 2 to 8 hours following MR activation. However, we found that GR activation alone decreased the potency, but not the maximal response to 5-HT. Chronic (2-week) treatment with basal levels of CT did not alter the 5-HT1A response. Administration of high concentrations of CT in vitro to neurons from chronically treated ADX rats decreased the magnitude of the 5-HT1A receptor-mediated hyperpolarization. We conclude that the 5-HT1A receptor-effector system in CA1 hippocampal pyramidal neurons is modulated by CT in a dose- and time-dependent manner.

Analysis of Variance↗

PubMed1996

Androgens modulate glucocorticoid receptor mRNA, but not mineralocorticoid receptor mRNA levels, in the rat hippocampus.

Androgen, mineralocorticoid and glucocorticoid receptors (AR, MR and GR, respectively) are ligand-activated transcription factors that alter gene expression and have a wide variety of effects in the central nervous system. High levels of AR, MR and GR mRNA have been found in the CA1 pyramidal cell region of the rat hippocampus and all 3 of these proteins bind to a similar hormone response element in DNA suggesting the possibility of common receptor function or cross-talk between these receptors at the level of transcription. To begin to investigate this hypothesis, we examined the regulation of AR, MR and GR mRNA expression in the rat hippocampus following treatment with androgens in combination with gonadectomy and/or adrenalectomy. Three-month-old male Sprague-Dawley rats were either castrated for 3 weeks, castrated and immediately implanted with 2 Silastic capsules filled with the non-aromatizable androgen, dihydrotestosterone, or left gonadally intact. Four days prior to sacrifice, these animals were either adrenalectomized or sham operated. GR, MR and AR mRNA were measured in the hippocampal subfields using in situ hybridization. In the CA1 region, dihydrotestosterone treatment of castrates decreased GR mRNA levels to 69 percent of levels found in gonadally intact rats and prevented the adrenalectomy-induced increases in GR mRNA observed in the gonadally intact and castrated animals. No changes in GR mRNA were observed in the CA3 region or dentate gyrus, where AR expression is low or absent. There was no effect of androgen treatment on MR mRNA levels nor did gonadectomy or androgen replacement alter the increases in MR mRNA following adrenalectomy. AR mRNA levels in the CA1 region were unchanged across all treatment groups. In vitro binding studies revealed almost complete nuclear occupancy of hippocampal AR in dihydrotestosterone-treated castrates. No appreciable in vitro binding of dihydrotestosterone to hippocampal MR or GR (Ki approximately 1500 nM) was observed which suggests that androgen regulation of GR mRNA in the hippocampus is occurring through AR binding. These data demonstrate a functional similarity of androgens and glucocorticoids in the regulation of GR mRNA levels in an area where AR and GR are colocalized. Androgen-mediated downregulation of GR expression may prove to be an important event in the adaptive responses of CA1 pyramidal cells to hormonal stimuli.

Adrenalectomy↗

PubMed1995

Baclofen concentration-response curves differ between hippocampal subfields.

The hippocampus contains interneurons that release gamma-aminobutyric acid (GABA). GABA hyperpolarizes hippocampal CA1 and CA3 pyramidal cells through activation of GABAB postsynaptic receptors. GABAB and 5-hydroxytryptamine1A (5-HT1A) receptors share effector mechanism(s). Agonist potency and the maximal hyperpolarization produced by 5-HT1A receptor activation is different between the CA1 and CA3 subfields. We determined that baclofen, a selective GABAB agonist, was more potent and produced a greater maximal response in area CA3 than in CA1. The larger magnitude of the response can be attributed partly to the larger input resistance of CA3 neurons. GABAB receptor-effector coupling differences between area CA1 and CA3 are proposed as the mechanism underlying the baclofen response incongruities.

Animals↗

PubMed1995

Chronic corticosterone treatment maintains synaptic activity of CA1 hippocampal pyramidal cells: acute high corticosterone administration increases action potential number.

The hypothalamic-pituitary-adrenocortical (HPA) axis controls the levels of plasma corticosterone (CT) in the rat and the levels of cortisol in man. CT is important in maintaining homeostasis and regulating energy production. Homeostasis is maintained by basal activation of the hippocampal-HPA axis. In response to stress CT secretion is increased. CT activation of receptors in the hippocampus provides feedback inhibition of the HPA axis to return the system to basal activity. There are two types of CT receptors: the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). CT has a 10-fold higher affinity for MR than GR. Normal basal levels of CT occupy the majority of the MR. During the diurnal surge of CT and following the presentation of a stressful stimulus, the MR and GR are both maximally occupied. To begin to understand how CT influences the hippocampal-HPA axis, intracellular recording techniques in the hippocampal brain slice preparation were used to determine how high concentrations of CT may alter cell characteristics and/or evoked synaptic activity. Two treatment groups were used, i.e., adrenalectomized (ADX) and ADX with CT pellet replacement (ADX+CT) that produced plasma blood levels equal to that seen in a normal rat in the morning. Acute administration of 100 nM CT decreased action potential threshold and the number of action potentials elicited by a depolarizing current pulse in cells from both the ADX and ADX+CT treated rats. The amplitude of the evoked excitatory postsynaptic potentials (EPSP) or inhibitory postsynaptic potentials (IPSP) declined in cells recorded from ADX animals and ADX rats acutely treated with high concentrations of CT (ADX/CT).(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗

PubMed1995

Distribution and hormonal regulation of androgen receptor (AR) and AR messenger ribonucleic acid in the rat hippocampus.

The actions of androgens in both peripheral and central tissues are linked in part to their ability to specifically bind and activate androgen receptors (ARs). ARs have been well studied in the rat hypothalamus and peripheral reproductive tissues, where they are directly involved in endocrine feedback mechanisms and reproduction. Previous studies revealed relatively high levels of AR and AR messenger RNA (mRNA) in the rat hippocampus; however, the action of androgen in this brain region remains unclear. To begin to address this issue, we used a multidisciplinary approach to quantitate hippocampal AR and AR mRNA levels and investigate their regulation after various hormonal manipulations. In vitro binding assays revealed a single, saturable, high affinity binding site for androgen in hippocampal cytosols. The expression of AR mRNA in the intact adult male rat hypothalamus and hippocampus was demonstrated using reverse transcription-polymerase chain reaction and quantified using a ribonuclease protection assay. Comparable levels of AR mRNA were found in the hippocampus and hypothalamus. In addition, in situ hybridization analysis revealed a unique distribution of AR mRNA in the hippocampus. AR mRNA was found predominately in the CA1 pyramidal cells, which form the major signal output of the hippocampal trisynaptic circuit. Reverse transcription-polymerase chain reaction of total RNA from microdissected hippocampal regions confirmed this distribution. Ribonuclease protection assay demonstrated a significant decrease in the AR mRNA content of the hippocampus in animals killed 4 days after castration or in intact rats after four daily injections of the AR antagonist, flutamide (15 mg/animal), compared to that in intact controls (P < 0.01). In contrast, a 35% increase (P < 0.05) in the hippocampal AR mRNA content was found in old (22-month-old) compared to young (5-month-old) male rats. In both cases, [3H]dihydrotestosterone binding to the cytosolic preparation did not parallel the changes observed in the AR mRNA content. Taken together, these data demonstrate that hippocampal cells containing AR can respond to circulating androgen to alter AR gene expression. Furthermore, AR mRNA autoregulation appears to be both age and tissue specific and does not directly follow the regulatory patterns described for other steroid hormone receptors found in the hippocampus.

Aging↗

PubMed1995

Modulation of the 5-hydroxytryptamine4 receptor-mediated response by short-term and long-term administration of corticosterone in rat CA1 hippocampal pyramidal neurons.

Corticosterone (CT) treatment decreases the magnitude of the 5-hydroxytryptamine (5-HT)1A receptor-mediated hyperpolarization in rat CA1 hippocampal pyramidal neurons. In the present study, we examined the short- and long-term effects of CT on the functionally excitatory 5-HT4 receptor-mediated decrease in the amplitude of the slow afterhyperpolarization (sAHP) that follows a calcium spike and the concomitant decrease in sAHP half decay time. Rats were adrenalectomized (ADX) 2 weeks before the experiment. Data for concentration-response curves were obtained with sharp electrode current clamp recordings in the CA1 pyramidal cell layer of hippocampal slices. Significant changes were found in the 5-HT4 receptor-mediated decrease in sAHP amplitude. The Emax of the 5-HT4 response was significantly increased in cells from ADX rats when the superfusion medium contained 1 nM CT. Short-term administration of 100 nM CT did not alter the 5-HT4 response. Chronic treatment with low concentrations of CT decreased the Emax of the 5-HT4 response. Treatment with CT concentrations that mimic conditions of chronic stress decreased the Emax of the 5-HT4 response and shifted the EC50 to the right. Based on these results we conclude that the magnitude and the potency of the 5-HT4 receptor-mediated decrease in sAHP amplitude is altered by CT. Because the short- and long-term effects of CT treatment are not the same, the actions of CT are time and concentration dependent. CT modulation of the 5-HT4 response is different from its modulation of the 5-HT1A response.

Action Potentials↗

PubMed1994

Serotonergic suppression of interhemispheric cortical synaptic potentials.

The inhibitory effects of 5-hydroxytryptamine (5-HT) on interhemispheric and intracortical synaptic potentials in layer V neurons of the rat medial prefrontal (MFC) cortex were examined. Low concentrations (1-3 microM) of 5-HT selectively attenuated polysynaptic potentials that were similarly evoked by callosal or white matter stimulation. Maximally effective concentrations of 5-HT blocked interhemispheric transmission by 50-90%, as evidenced by an attention of the short latency callosal depolarizing synaptic potential (e-DPSP). These effects of 5-HT were not associated with a change in membrane potential or input resistance. The e-DPSP was characterized as having an N-methyl-D-aspartate (NMDA) and a non-NMDA component; the non-NMDA component was attenuated by 5-HT. Attenuation of the synaptic potential was accompanied by an attenuation of a postsynaptic glutamate potential. Suppression of both the e-DPSP and the glutamate potential was concentration dependent with 10-100 microM being maximally effective. The 5-HT1A/2 antagonist, spiperone, antagonized the effects of 5-HT on synaptic and glutamate potentials. Spiperone (1 microM) shifted the concentration-effect curves for suppression of the e-DPSP and the glutamate potential to the right; however, the Kb for the glutamate potential concentration-effect curve was 10 times that for the e-DPSP curve. The differential antagonist sensitivity of synaptic and glutamate potentials was an indication that serotonin acted on more than one receptor subtype to reduce interhemispheric transmission.

2-Amino-5-phosphonovalerate↗

PubMed1994

5-HT1A receptor linked to inward-rectifying potassium current in hippocampal CA3 pyramidal cells.

1. Voltage- and current-clamp intracellular recordings were performed on rat CA3 hippocampal pyramidal cells in a slice preparation. 2. Under current-clamp conditions, 5-hydroxytryptamine (5-HT) or baclofen (BAC) perfusion hyperpolarized CA3 cells. 3. Under single-electrode voltage-clamp conditions, 5-HT perfusion elicited an outward current flow that was blocked by 2 mM BaCl2 but not by 100 microM CdCl2. 4. The Emax of the current response in CA3 was larger than that elicited in CA1 and the potency was less in CA3 than CA1. 5. Increasing the external potassium concentration shifted the reversal potential for the 5-HT-mediated response. 6. The potassium current exhibited inward rectification. 7. The BAC- and 5-HT-mediated currents were not additive. 8. Pertussis-toxin (PTX) treatment blocked both 5-HT- and BAC-elicited hyperpolarizations. 9. On the basis of these results, we conclude that 5-HT hyperpolarized hippocampal CA3 pyramidal cells by increasing an inward-rectifying potassium conductance. Furthermore both the 5-HT1A and gamma-aminobutyric acidB (GABAB) receptors are linked to potassium channels via a PTX-sensitive G protein.

Animals↗