Magnetic resonance imaging of PLP-induced experimental allergic encephalomyelitis in Lewis rats

Despite epidemiological studies indicating a positive relationship between alcohol and stroke, little is known with regard to effect of chronic alcohol on neuronal injury after stroke. In this study, we examined the effect of chronic ethanol on mRNA levels of sarcoplasmic or endoplasmic Ca2+-ATPase (SERCA2b) and inositol 1,4, 5-triphosphate receptor (IP3R1) in gerbils subjected to global cerebral ischemia induced by ligation of both common carotid arteries. Gerbils were given daily by intragastric intubation either a liquid diet containing ethanol (4 g/kg) or the same diet with an isocaloric amount of sucrose for 35 days. They were subsequently subjected to a 5 min ischemic insult followed by reperfusion for 48 h. In agreement with other studies, ischemic insult caused significant decreases (P<0.05) in mRNA levels of both IP3R1 and SERCA2b in the hippocampal CA1 region but not in the dentate gyrus. Nevertheless, despite a significant (P<0.05) decrease in SERCA2b mRNA in the Purkinje neurons, chronic ethanol did not alter the expression of this mRNA species in the hippocampal CA1 neurons nor did it alter the decrease in SERCA2b mRNA due to cerebral ischemic insult. Since IP3R1 and SERCA2b are key mediators for regulation of intracellular Ca2+ stores, the decrease in SERCA2b mRNA but not IP3R1 mRNA in cerebellar neurons may be an important mechanism underlying alteration of calcium homeostasis and cerebellar degeneration upon chronic ethanol consumption.     

Anxiolytic 5-hydroxytryptamine1A agonists suppress firing activity of dorsal hippocampus CA1 pyramidal neurons through a postsynaptic mechanism: single-unit study in unanesthetized, unrestrained rats

Recent behavioral studies indicate that conditioned fear response to contextual stimuli is reduced effectively by anxiolytic 5-hydroxytryptame (5-HT)1A agonists. Since the hippocampus seems to play an essential role in associative fear memories evoked by context, it is important to assess the effect of 5-HT1A agonists on pyramidal cell activity in the hippocampus. We examined the effects of 5-HT1A agonists on the spontaneous firing rate of hippocampal CA1 pyramidal neurons in unanesthetized, unrestrained rats. Systemic administration of selective 5-HT1A agonists, 8-hydroxy-2-(di-n-propylamino)tetralin, buspirone, ipsapirone, and flesinoxan produced a dose-dependent inhibition of neuronal activity. Putative 5-HT1A antagonists NAN-190 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine and (-)-pindolol did not change neuronal activity of CA1 pyramidal neurons. The suppression of neuronal activity by buspirone was antagonized by NAN-190 but not by (-)-pindolol. Lack of antagonistic activity of (-)-pindolol for the suppression of pyramidal neurons via a postsynaptic mechanism is consistent with the results of recent electrophysiological experiments in anesthetized rats. Pretreatment with parachlorphenylalanine did not change the spontaneous firing rates of hippocampal CA1 pyramidal neurons or abolish the suppressant effects of buspirone on these neurons. Taken together, the present results strongly suggest that suppression of the hippocampal CA1 pyramidal neuronal activity by anxiolytic 5-HT1A agonists in awake rats is mediated by postsynaptic 5-HT1A receptors located on pyramidal neurons.     

The reaction of astrocytes and neurons in the hippocampus of adult rats during chronic ethanol treatment and correlations to behavioral impairments

Chronic ethanol treatment of Wistar rats to 10% (v/v) ethanol over a period of 4, 12, and 36 weeks produced distinct alterations of the glial fibrillary acidic protein immunoreactivity (GFAP-IR) of dorsal hippocampal astrocytes. Ethanol consumption over a period of 4 weeks caused an increase in the total GFAP-IR of the astrocytes. Down-regulation of the total GFAP-IR was measured in all examined brain regions after 36 weeks of ethanol treatment. Prolonged ethanol treatment induced a significant loss of the total number of hippocampal pyramidal and dentate gyrus granule cells. Regional differences in the vulnerability to the neurotoxic effects of chronic ethanol intake over 36 weeks were found: CA3 > CA1 + CA2 > > CA4 > GD. In agreement with the degree of neuronal cell loss, ethanol-induced behavioral impairments were found. The acquisition of maze performance using a complex elevated labyrinth was deteriorated after 36 weeks of ethanol treatment, suggesting a deficit in learning and memory. These findings illustrate the importance of time-response analysis when determining the structural and functional changes produced by chronic ethanol treatment.     

Ethanol, stroke, brain damage, and excitotoxicity

The N-methyl-d-aspartate (NMDA)-glutamate receptor could contribute to stroke, trauma, and alcohol-induced brain damage through activation of nitric oxide formation and excitotoxicity. In rat primary cortical cultures NMDA was more potent at activating nitric oxide formation than triggering excitotoxicity. Ethanol dose dependently inhibited both responses. In contrast, treatment of neuronal cultures with ethanol (100 mM) for 4 days significantly increased NMDA stimulated nitric oxide formation and excitotoxicity. These findings suggest that ethanol acutely inhibits but chronically causes supersensitivity to NMDA-induced excitotoxicity in neuronal cultures. To investigate ethanol's interaction with stroke induced damage models of global cerebral ischemia were studied. Transient global ischemia resulted in a loss of hippocampal CA1 pyramidal neurons over a 3- to 5-day period. Determinations of the NMDA receptor ligand binding stoichiometry or postischemic receptor binding changes did not show differences between neurons that undergo delayed neuronal death following ischemia and those that show no toxicity, for example, CA1 and dentate gyrus, respectively. Acute ethanol (3 g/kg) was found to protect against ischemia-induced CA1 hippocampal damage by lowering body temperature, but not under temperature controled conditions. These studies indicate that the factors contributing to stroke-induced brain damage are complex, although they are consistent with chronic ethanol increasing stroke-induced brain damage by increasing NMDA excitotoxicity.     

Behavioral and neuroanatomical effects of prenatal, postnatal, or combined exposure to ethanol in weanling rats.

Separate and combined effects of prenatal and postnatal exposure to ethanol on activity, emotionality, learning, and hippocampal neuroanatomy were examined in infant rats. Neonatal rats from mothers that were fed either a liquid ethanol (E) or control (C) diet were artificially reared on either 3% ethanol (E) or isocaloric maltose/dextrin (C). Pups in 4 treatment groups (EE, EC, CE, and CC) were compared. Differences in activity and emotionality were slight. Ethanol affected both the partial reinforcement acquisition effect and the partial reinforcement extinction effect. Hippocampal cell density (compared with Group CC) showed a 12% reduction in CA1 pyramidal cells and an 11% reduction in mature granule cells in Groups EC and EE; the CA4 area (compared with Group CC) was significantly larger after postnatal exposure (Groups CE and EE). Significant positive correlations were found between rate of extinction after partial reinforcement (PRF) training and CA1 pyramidal cell density in Groups CC and CE. A significant negative correlation was found between extinction rate after PRF training and CA4 area in Group EE. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Development of long-distance efferent projections from fetal hippocampal grafts depends upon pathway specificity and graft location in kainate-lesioned adult hippocampus

Fetal hippocampal cells grafted into the excitotoxically lesioned hippocampus of adult rats are capable of extending axonal projections into the host brain. We hypothesize that the axonal growth of grafted fetal cells into specific host targets, and the establishment of robust long-distance efferent graft projections, require placement of fetal cells in close proximity to appropriate axon guidance pathways. Intracerebroventricular administration of kainic acid in adult rats leads to a specific loss of hippocampal CA3 pyramidal neurons. We grafted 5'-bromodeoxyuridine-labeled embryonic day 19 hippocampal cells into adult hippocampus at four days post-kainic acid lesion, and quantitatively measured the projection of grafted cells into the contralateral hippocampus and the septum after three to four months survival using Fluoro-Gold and 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine (Dil) tracing. Grafts located in or near the degenerated CA3 cell layer exhibited numerous neurons which established commissural projections with the contralateral hippocampus. However, such projection did not occur in intrahippocampal grafts located away from the CA3 cell layer. In contrast, neurons in all grafts established robust projections into the septum regardless of location within hippocampus although grafts located near the degenerated CA3 cell layer displayed more neurons with such projections. Location of grafted cells clearly influences the development of efferent graft projections into distant targets in the adult host brain, particularly access to axon guidance pathways to facilitate the formation of projections. The establishment of robust long-distance commissural projections of fetal hippocampal grafts is clearly dependent on their placement in or near the degenerated CA3 cell layer, suggesting that appropriate axon guidance pathways for commissural pathways are tightly focussed near this cell layer. However, the establishment of septal projections of these grafts was not dependent on specific location within the CA3 cell layer, suggesting that axonal guidance mechanisms to the septum are more diffuse and not limited to the CA3 dendritic layers. The results underscore that fetal hippocampal grafts are capable of partly restoring lesioned hippocampal circuitry in adult animals when appropriately placed in the host hippocampus.     

A novel calcium-independent enzyme capable of incorporating putrescine into proteins

Chronic reductions in cerebral blood flow associated with aging and progressive neurodegenerative disorders can precipitate cognitive failure. To assess whether chronic cerebrovascular insufficiency elicits neuronal apoptosis, apoptotic cell death in the hippocampus was quantitated in a rat model of permanent carotid occlusion. Bilateral carotid artery occlusion (2VO) was shown to induce apoptotic morphology and DNA strand breaks in hippocampal neurons 2 and 27 weeks after ligation. The rate of pyramidal cell apoptosis was higher at chronic (27 weeks) compared to sub-chronic (2 weeks) time points. 2VO-induced apoptosis resulted in a decrease in total pyramidal cell number at 27 weeks but not at earlier time points, indicating progressive neuronal loss. Working and reference memory errors in the radial arm maze were strongly correlated with the number of apoptotic neurons in CA1 but not CA3 pyramidal cell fields. These data provide the first indication that apoptotic loss of pyramidal neurons may play a role in memory impairment associated with clinical conditions of chronic cerebrovascular insufficiency.     

Identification of 45 kD antigen in immune complexes of patients of allergic bronchopulmonary aspergillosis

The hippocampus is a major target of alpha-bungarotoxin (alpha-BTX) binding. This ligand binds to the alpha 7 nicotinic, cholinergic receptor, which has been implicated in hippocampal habituation to repetitive auditory stimulation, a phenomenon thought to involve inhibitory neurons. This study examined whether alpha-BTX binds to neurons containing nitric oxide synthase (NOS), a marker of one subgroup of inhibitory hippocampal neurons. Rat hippocampal sections were processed for NOS immunohistochemistry, photographed and then processed for [125I]alpha-BTX autoradiography. Comparison between the distribution of neurons immunoreactive for NOS and those positive for alpha-BTX binding in the same regions of the hippocampal formation revealed a variable degree of colocalization of NOS and alpha-BTX. Of the cells labeled with alpha-BTX, 2% in the dentate gyrus and 40% in the hippocampus proper were also immunoreactive for NOS. These NOS/alpha-BTX neurons were most prevalent in CA1 stratum oriens. The results suggest a possible role for NOS-containing neurons in alpha 7-mediated inhibition to repetitive auditory stimulation in rat hippocampus.     

Effects of prenatal ethanol exposure on parvalbumin-expressing GABAergic neurons in the adult rat medial septum

Exposure of human fetuses to ethanol often results in the fetal alcohol syndrome. Animal models of fetal alcohol syndrome have been developed and used to examine the consequences of prenatal ethanol exposure on the central nervous system. The objective of this study was to determine the long-term effects of prenatal ethanol exposure on parvalbumin-expressing (PA+) GABAergic neurons of the rat medial septum. Pregnant Long-Evans rats were maintained on 1 of 3 diets from gestational day 0 to 21: an ethanol-containing liquid diet in which ethanol accounted for 35% of the total calories, a similar diet with the isocaloric substitution of sucrose for ethanol, or a lab chow control diet. Offspring were killed on postnatal day 60, and their brains were prepared for parvalbumin immunocytochemistry. Female rats exposed to the ethanol-containing diet during gestation had 42% fewer PA+ neurons in the medial septum and reduced PA+ cell density when compared with female rats exposed to the sucrose diet. Ethanol females also had fewer PA+ neurons per unit volume than sucrose females. Male rats exposed to ethanol did not display a similar reduction in PA+ neurons or density. No effect of prenatal diet was found on the area or volume of the medial septum, nor were cell diameters affected. As such, prenatal exposure to ethanol seems to reduce permanently the number of PA+ neurons in the female rat medical septum without affecting area, volume, or neuronal size. Functional implications and possible relations to the fetal alcohol syndrome are discussed.     

Postischemic enhancements of N-methyl-D-aspartic acid (NMDA) and non-NMDA receptor-mediated responses in hippocampal CA1 pyramidal neurons

Glutamate receptor-mediated responses were investigated by using a whole-cell recording and an intracellular calcium ion ([Ca2+]i) imaging in gerbil postischemic hippocampal slices prepared at 1, 3, 6, 9, 12, and 24 hours after 5-minute ischemia. Bath application of N-methyl-D-aspartic acid (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), and kainate showed that NMDA-, AMPA- and kainate-induced currents were enhanced in postischemic CA1 pyramidal neurons at 1 to 12 hours after 5-minute ischemia. NMDA and non-NMDA receptor-mediated excitatory postsynaptic currents (EPSC) were examined in postischemic CA1 pyramidal neurons at 3 hours after 5-minute ischemia to confirm whether synaptic responses are enhanced in the postischemic CA1 pyramidal neurons. The amplitudes of NMDA- and non-NMDA-receptor-mediated EPSC were enhanced in the postischemic CA1 pyramidal neurons. NMDA-, AMPA-, and kainate-induced [Ca2+]i elevations were also examined to determine whether the enhancement of currents is accompanied by the enhancement of [Ca2+]i elevation. The enhancements of NMDA-, AMPA-, and kainate-induced [Ca2+]i elevations were shown in the postischemic CA1. These results indicate that NMDA and non-NMDA receptor-mediated responses are persistently enhanced in the CA1 pyramidal neurons 1 to 12 hours after transient ischemia, and suggest that the enhancement of glutamate receptor-mediated responses may act as one of crucial factors in the pathologic mechanism responsible for leading postischemic CA1 pyramidal neurons to irreversible neuronal injury.     

Low ethanol concentrations enhance GABAergic inhibitory postsynaptic potentials in hippocampal pyramidal neurons only after block of GABAB receptors

Despite considerable evidence that ethanol can enhance chloride flux through the gamma-aminobutyric acid type A (GABA/A/) receptor-channel complex in several central neuron types, the effect of ethanol on hippocampal GABAergic systems is still controversial. Therefore, we have reevaluated this interaction in hippocampal pyramidal neurons subjected to local monosynaptic activation combined with pharmacological isolation of the various components of excitatory and inhibitory synaptic potentials, using intracellular current- and voltage-clamp recording methods in the hippocampal slice. In accord with our previous findings, we found that ethanol had little effect on compound inhibitory postsynaptic potentials/currents (IPSP/Cs) containing both GABA/A/ and GABA/B/ components. However, after selective pharmacological blockade of the GABA/B/ component of the IPSP (GABA/B/-IPSP/C) by CGP-35348, low concentrations of ethanol (22-66 mM) markedly enhanced the peak amplitude, and especially the area, of the GABA/A/ component (GABA/A/-IPSP/C) in most CA1 pyramidal neurons. Ethanol had no significant effect on the peak amplitude or area of the pharmacologically isolated GABA/B/-inhibitory postsynaptic current (IPSC). These results provide new data showing that activation of GABAB receptors can obscure ethanol enhancement of GABA/A/ receptor function in hippocampus and suggest that similar methods of pharmacological isolation might be applied to other brain regions showing negative or mixed ethanol-GABA interactions.     

Altered hippocampal kainate-receptor mRNA levels in temporal lobe epilepsy patients

This study determined whether hippocampal kainate (KA) receptor mRNA levels were increased or decreased in temporal lobe epilepsy patients compared with nonseizure autopsies. Hippocampal sclerosis (HS; n = 17), nonsclerosis (non-HS; n = 11), and autopsy hippocampi (n = 9) were studied for KA1-2 and GluR5-7 mRNA levels using semiquantitative in situ hybridization techniques, along with neuron densities. Compared with autopsy hippocampi, HS and non-HS cases showed decreased GluR5 and GluR6 hybridization densities per CA2 and/or CA3 pyramid. Furthermore, HS patients demonstrated increased KA2 and GluR5 hybridization densities per granule cell compared with autopsy hippocampi. These findings indicate that chronic temporal lobe seizures were associated with differential changes in hippocampal KA1-2 and GluR5-7 hybridization densities that vary by subfield and pathology group. In temporal lobe epilepsy patients, these results support the hypothesis that pyramidal cell GluR5 and GluR6 mRNA levels are decreased as a consequence of seizures, and in HS patients granule cell KA2 and GluR5 mRNA levels are increased in association with aberrant fascia dentata mossy fiber sprouting and/or hippocampal neuronal loss.     

Usefulness of redux properties in acid-resistant bacilli for rapid detection of their growth in culture

The mechanism by which (-) deprenyl enhances cognitive function in Alzheimer's disease (AD) is not yet understood. (-) Deprenyl (0.2 mg/kg/day) was administered intramuscularly to adult male monkeys (n = 6) for 25 days. Control monkeys (n = 6) received physiological saline by the same route. The activity of acetylcholinesterase (AChE) in different brain regions and the dendritic arborization in CA3 pyramidal neurons of hippocampus were analysed. (-) Deprenyl-treated monkeys showed a significant increase in the AChE activity by 43% (p < 0.001) in the frontal cortex, by 39% (p < 0.025) in the motor cortex, by 66% (p < 0.001) in the hippocampus and by 26% (p < 0.05) in the striatum compared to controls. The branching points and the intersections of both apical and basal dendrites of CA3 hippocampal pyramidal neurons were also significantly increased in (-) deprenyl-treated monkeys. Enhanced AChE activity may increase dendritic arborization in the hippocampus and it may also play a role in improving cognitive functions observed in AD, following (-) deprenyl treatment.     

Increasing threshold of the epileptiform activity in the CA1 field of hippocampal slices of Krushinski?-Molodkina rats as protective adaptation mechanism

The Krushinsky-Molodkina rat CA1 hippocampal slices revealed an increased threshold of the epileptiform activity development, a depressed signal transmission in the presynaptic glutamatergic fibres, no long-term increase in excitability of the CA1 pyramidal neurons characteristic of Wistar rats following Mg2+ removal and K+ increase. These events suggest a protective adaptive mechanism preventing propagation of seizure activity into limbic structures of the rats.     

Monosynaptic GABA-mediated inhibitory postsynaptic potentials in CA1 pyramidal cells of hyperexcitable hippocampal slices from kainic acid-treated rats

To examine the mechanisms underlying chronic epileptiform activity, field potentials were first recorded to identify hyperexcitable hippocampal slices from kainic acid-treated rats. Intracellular recordings were then obtained from CA1 pyramidal cells in the hyperexcitable areas. Twenty-two of the 47 cells responded to electrical stimulation of the stratum radiatum with a burst of two or more action potentials and reduced early inhibitory postsynaptic potentials, and were considered hyperexcitable. The remaining 25 cells were not hyperexcitable, displaying a single action potential and biphasic inhibitory postsynaptic potentials after stimulation, like control cells (n = 20). A long duration, voltage-sensitive component was associated with subthreshold excitatory postsynaptic potentials in the majority of hyperexcitable (12/15) and non-hyperexcitable (3/5) cells examined from kainic acid-treated animals, but not from cells (1/10) of control animals. Stimulation of stratum radiatum during pharmacological blockade of ionotropic excitatory amino acid synaptic transmission elicited biphasic monosynaptic inhibitory postsynaptic potentials in all hyperexcitable (n = 9) and non-hyperexcitable (n = 9) cells tested from kainate-treated animals, as well as in control cells (n = 8). The mean amplitude, latency to peak, equilibrium potential, and conductance changes of early and late monosynaptic inhibitory postsynaptic potentials were not different between cells of kainic acid-treated and control animals. In seven hyperexcitable cells tested, the early component of monosynaptic inhibitory postsynaptic potentials was significantly reduced by the GABAA receptor antagonist bicuculline (100-200 microM). The late component was significantly decreased by the GABAB receptor antagonist 2-hydroxysaclofen (1-2 mM; n = 3). Comparable effects were observed on early and late monosynaptic inhibitory postsynaptic potentials in non-hyperexcitable cells (n = 4) from kainic acid-treated animals and control cells (n = 5). These results suggest that GABAergic synapses on hyperexcitable hippocampal pyramidal cells of kainate-treated rats are intact and functional. Therefore, epileptiform activity in the kainate-lesioned hippocampus may not arise from a disconnection of GABAergic synapses made by inhibitory interneurons on pyramidal cells. The hyperexcitability may be due to underactivation of inhibitory interneurons and/or reorganization of excitatory inputs to pyramidal cells since, in kainate-treated animals, pyramidal cells appear to express additional excitatory mechanisms.     

Morphological changes in the hippocampal CA3 region induced by non-invasive glucocorticoid administration: a paradox

Repeated stress induces atrophy, or remodeling, of apical dendrites in hippocampal CA3 pyramidal neurons. In rats, the stress effect is blocked by adrenal steroid synthesis inhibitors, and mimicked by daily injection of corticosterone. We report that non-invasive administration of corticosterone in the drinking water (400 micrograms/ml) also produced atrophy of apical dendrites in CA3. Unexpectedly, the combination of daily stress and oral corticosterone negated the effects of either treatment alone, and no changes in the apical dendritic length or branching pattern of CA3 pyramidal neurons were observed compared to control unstressed rats.     

Direct administration of insulin-like growth factor to fetal rhesus monkeys (Macaca mulatta)

A potential treatment for the amelioration of fetal growth failure is insulin-like growth factor-I (IGF-I). To address concerns of safety and efficacy, IGF-I (80 microg/kg; GroPep Pty.) was administered i.p. to healthy rhesus monkey fetuses via ultrasound guidance every other day between gestational days (GD) 110-120 and 130-140 (third trimester; term = approximately GD 165 +/- 10; n = 6). Pregnancies were monitored sonographically, and fetal/maternal blood samples were collected for complete blood counts, immunophenotyping, and biochemical analyses. Blood samples, external measures of the fetus and newborn, and tissue and organ weights were collected at fetal necropsy (GD 150; n = 2) or at term delivery of neonates (GD 160; n = 4). The results of these investigations have shown no evidence of hypoglycemia in the fetus or dam during the course of treatment. Circulating concentrations of fetal, but not maternal, IGF-I increased with treatment (approximately 80 to approximately 1015 ng/ml), and there was no evidence of a change in serum IGF-II or an increase in IGF binding protein-3 compared with historical control values. Fetal lymphocytes and select red cell parameters increased, and a significant elevation in circulating B cells and CD4/CD8 ratios in fetal lymph nodes was shown. Although no changes were detected in body weights, increases in thymic, splenic, and kidney weights and small intestine lengths occurred. Thus, administration of IGF-I to the fetal monkey is safe and results in 1) transient increases in circulating IGF-I, 2) a significant effect on fetal hematopoietic and lymphoid tissues, and 3) an increase in select fetal organ weights and measures. These data suggest that IGF-I may represent a potential candidate for therapeutic treatment of growth-compromised human fetuses in utero.     

Differential activation of adenosine receptors decreases N-type but potentiates P-type Ca2+ current in hippocampal CA3 neurons

Adenosine is released in the brain in significant quantities in response to increased cellular activity. Adenosine has been shown either to decrease synaptic transmission or to produce an excitatory response in hippocampal synapses, resulting in increased glutamate release. Previous reports have shown that adenosine or its analogs reduced Ca2+ current in dorsal root ganglion and hippocampal neurons. Here we show that the selective activation of adenosine receptor subtypes has different effects on Ca2+ channels from acutely isolated pyramidal neurons from the CA3 region of guinea pig hippocampus. Activation of A1 receptors inhibited primarily N-type Ca2+ current. In contrast, activation of A2b receptors resulted in significant potentiation of P-type but not N-type Ca2+ current. This potentiation could be inhibited by blocking the cAMP-dependent protein kinase. Because of the ubiquity of adenosine, the differential effects on Ca2+ channels of adenosine receptor subtype activation may have significant implications for neuronal excitability.     

Electron microscopic immunocytological profiles in chronic fatigue syndrome

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.