Neck Location on the Outer Convexity is a Predictor of Incomplete Occlusion in Treatment with the Pipeline Embolization Device: Clinical and Angiographic Outcomes.

BACKGROUND AND PURPOSE: With the increasing use of the Pipeline Embolization Device for the treatment of aneurysms, predictors of clinical and angiographic outcomes are needed. This study aimed to identify predictors of incomplete occlusion at last angiographic follow-up. MATERIALS AND METHODS: In our retrospective, single-center cohort study, 105 ICA aneurysms in 89 subjects were treated with Pipeline Embolization Devices. Patients were followed per standardized protocol. Clinical and angiographic outcomes were analyzed. We introduced a new morphologic classification based on the included angle of the parent artery against the neck location: outer convexity type (included angle, <160°), inner convexity type (included angle, >200°), and lateral wall type (160° ≤ included angle ≤200°). This classification reflects the metal coverage rate and flow dynamics. RESULTS: Imaging data were acquired in 95.3% of aneurysms persistent at 6 months. Complete occlusion was achieved in 70.5%, and incomplete occlusion, in 29.5% at last follow-up. Multivariable regression analysis revealed that 60 years of age or older (OR, 5.70; P = .001), aneurysms with the branching artery from the dome (OR, 10.56; P = .002), fusiform aneurysms (OR, 10.2; P = .009), and outer convexity-type saccular aneurysms (versus inner convexity type: OR, 30.3; P < .001; versus lateral wall type: OR, 9.71; P = .001) were independently associated with a higher rate of incomplete occlusion at the last follow-up. No permanent neurologic deficits or rupture were observed in the follow-up period. CONCLUSIONS: The aneurysm neck located on the outer convexity is a new, incomplete occlusion predictor, joining older age, fusiform aneurysms, and aneurysms with the branching artery from the dome. No permanent neurologic deficits or rupture was observed in the follow-up, even with incomplete occlusion.

Mechanism of the rapid effect of 17 beta-estradiol on medial amygdala neurons.

The mechanism by which sex steroids rapidly modulate the excitability of neurons was investigated by intracellular recording of neurons in rat medial amygdala brain slices. Brief hyperpolarization and increased potassium conductance were produced by 17 beta-estradiol. This effect persisted after elimination of synaptic input and after suppression of protein synthesis. Thus, 17 beta-estradiol directly changes the ionic conductance of the postsynaptic membrane of medial amygdala neurons. In addition, a greater proportion of the neurons from females than from males responded to 17 beta-estradiol.

Leptin facilitates learning and memory performance and enhances hippocampal CA1 long-term potentiation and CaMK II phosphorylation in rats.

Leptin, an adipocytokine encoded by an obesity gene and expressed in adipose tissue, affects feeding behavior, thermogenesis, and neuroendocrine status via leptin receptors distributed in the brain, especially in the hypothalamus. Leptin may also modulate the synaptic plasticity and behavioral performance related to learning and memory since: leptin receptors are found in the hippocampus, and both leptin and its receptor share structural and functional similarities with the interleukin-6 family of cytokines that modulate long-term potentiation (LTP) in the hippocampus. We therefore examined the effect of leptin on (1) behavioral performance in emotional and spatial learning tasks, (2) LTP at Schaffer collateral-CA1 synapses, (3) presynaptic and postsynaptic activities in hippocampal CA1 neurons, (4) the intracellular Ca(2+) concentration ([Ca(2+)](i)) in CA1 neurons, and (5) the activity of Ca(2+)/calmodulin protein kinase II (CaMK II) in the hippocampal CA1 tissue that exhibits LTP. Intravenous injection of 5 and/or 50mug/kg, but not of 500mug/kg leptin, facilitated behavioral performance in passive avoidance and Morris water-maze tasks. Bath application of 10(-12)M leptin in slice experiments enhanced LTP and increased the presynaptic transmitter release, whereas 10(-10)M leptin suppressed LTP and reduced the postsynaptic receptor sensitivity to N-methyl-d-aspartic acid. The increase in the [Ca(2+)](i) induced by 10(-10)M leptin was two times greater than that induced by 10(-12)M leptin. In addition, the facilitation (10(-12)M) and suppression (10(-10)M) of LTP by leptin was closely associated with an increase and decrease in Ca(2+)-independent activity of CaMK II. Our results show that leptin not only affects hypothalamic functions (such as feeding, thermogenesis, and neuroendocrine status), but also modulates higher nervous functions, such as the behavioral performance related to learning and memory and hippocampal synaptic plasticity.

Insulin acting as a modulator of feeding through the hypothalamus.

To understand the functional role of insulin in the control of feeding, biochemical and physiological studies were performed in the rat. 1) Insulin content in the brain was much higher than that in the blood, and was extremely variable from animal to animal. 2) Specific binding sites of insulin in the brain were most abundant in the hypothalamus and olfactory bulb. 3) Neither insulin content nor binding sites in the brain was significantly affected by peripheral insulin concentration. 4) Activity of glucoreceptor neurons in the ventromedial hypothalamus (VMH) was facilitated by simultaneous application of insulin and glucose, but inhibited by insulin alone. 5) Activity of the glucose-sensitive neurons in the lateral hypothalamus (LHA) was facilitated by insulin in a dose-dependent manner. 6) Stimulation of the ventral part of the LHA accelerated pancreatic vagal nerve activity. Stimulation of the dorsal part of the LHA and the VMH was inhibitory. 7) Pancreatic splanchnic nerve activity during LHA stimulation tended to show inhibition, but sometimes was modulated by the stimulus frequency. Both inhibition and facilitation were observed in the activity in response to VMH stimulation.

Induction of outward current by orexin-B in mouse peritoneal macrophages.

To define effects of novel feeding regulating peptides, orexins, in immunocompetent cells, ion channel activity in mouse peritoneal macrophages was analyzed by the perforated patch-clamp method. Orexin-B (OX-B) induced an outward current at smaller holding potentials than K+ equilibrium potentials. Reversal potentials of OX-B induced current were dependent on external K+ concentrations but not on external Cl- concentration. Orexin-A is less effective than OX-B. Quinine blocked the outward current and tetraethylammonium partially suppressed the current. These results suggest that OX-B can modulate macrophage functions through the activation of Ca2+-dependent K2+ channels.

A new brain glucosensor and its physiological significance.

The concentration of fibroblast growth factor (FGF), which is found in cerebrospinal fluid (CSF), markedly increases after the start of feeding. Food intake was dose-dependently suppressed by picomole doses of FGF and facilitated by anti-FGF antibody. This suppression was caused by activation of protein kinase C in glucose-sensitive neurons in the lateral hypothalamus. In situ hybridization by use of cDNA showed that acidic (a)FGF was produced in ependymal cells. The ependymal cells released aFGF by responding to glucose increase in CSF after feeding. Released aFGF diffused into the brain parenchyma and was taken by neurons. Passive avoidance was significantly more reliable after aFGF infusion into CSF. Clamping cerebral arteries in the gerbil induced ischemia, which damaged neurons in the CA1 layer of the hippocampus. Pretreatment with aFGF prevented this damage. Thus, aFGF is not only the most potent substance yet found for the suppression of feeding, but it is also extremely effective as a neurotrophic and memory facilitating substance.

Effects of an acidic fibroblast growth factor fragment analog on learning and memory and on medial septum cholinergic neurons in senescence-accelerated mice.

We examined the effects of repeated subcutaneous injections of an acidic fibroblast growth factor fragment analog, [Ala16] acidic fibroblast growth factor (1-29), on learning and memory and on the choline acetyltransferase immunoreactivity of forebrain neurons in senescence-accelerated mice. One group of accelerated senescence-prone mice (accelerated senescence-prone-8) received [Ala16] acidic fibroblast growth factor (1-29), whereas the other group of accelerated senescence-prone-8 mice and a group of accelerated senescence-resistant mice (control) received vehicle solution. Injections began at three weeks after birth and were given weekly for 10 months. In a passive avoidance test, the mean retention latency at three, six and nine months of age was significantly longer in controls (vehicle-treated accelerated senescence-resistant-1) and acidic fibroblast growth factor fragment-treated accelerated senescence-prone-8 than in vehicle-treated accelerated senescence-prone-8 mice, and the latency in acidic fibroblast growth factor fragment-treated accelerated senescence-prone-8 mice was significantly shorter than that in controls only at nine months of age. In the Morris water maze task, the mean latency to climb onto the platform was significantly longer in acidic fibroblast growth factor fragment- and vehicle-treated accelerated senescence-prone-8 mice than in controls. However, the mean latency in the third and fourth trial blocks was significantly shorter for acidic fibroblast growth factor fragment-treated accelerated senescence-prone-8 than for vehicle-treated accelerated senescence-prone-8 mice. In the probe trials, controls and acidic fibroblast growth factor fragment-treated accelerated senescence-prone-8 mice spent significantly more time in the quadrant in which the platform had previously been located than in the other three quadrants. In acidic fibroblast growth factor fragment-treated accelerated senescence-prone-8 mice, the density of medial septum neurons intensely stained for choline acetyltransferase was significantly greater than that in vehicle-treated accelerated senescence-prone-8 mice, but significantly less than that in controls. The results indicate that the beneficial effect of [Ala16] acidic fibroblast growth factor (1-29) on learning and memory function in accelerated senescence-prone-8 mice may be related to a preservation of function in medial septum cholinergic neurons.

Immunohistochemical localization in the rat brain of an epitope corresponding to the fibroblast growth factor receptor-1.

The localization of fibroblast growth factor receptor-1 was investigated in rat brain by immunohistochemistry using a polyclonal antibody against an acidic peptide sequence of chicken fibroblast growth factor receptor-1. For raising the antisera in rabbits, we synthesized the oligopeptide EDDDDEDDSSSEEKEAD which is a highly acidic region of chicken fibroblast growth factor receptor-1. The oligopeptide was used as a haptenic antigen by conjugating with poly-L-glutamate as a carrier protein. On immunospot assay, the best antiserum was capable of detecting 15.7 pmols of both the chicken and its analogous human oligopeptides but failed to react even with up to 1 nmol of poly-L-glutamate. When rat brain homogenate was examined by Western blots, the antiserum revealed two bands with molecular weights of 145,000 and 75,000 corresponding to known sizes of the membrane-bound and secreted forms of the rat receptor, respectively. Immunohistochemistry in rat brain demonstrated that putative fibroblast growth factor receptor-1 immunoreactivity sites were present mainly in neurons but also in tanycytes and ependymal cells. Positive neurons were distributed widely in various brain regions, but were particularly abundant in such regions as the lateral hypothalamus, substantia nigra, locus coeruleus and raphe nuclei. The present study suggests that fibroblast growth factor receptor-1 is expressed preferentially in certain neuronal systems that appear to be under the influence of fibroblast growth factors in the normal brain. The result should facilitate study of the functional significance of fibroblast growth factors in these brain neurons.

Increased expression of hippocampal cholinergic neurostimulating peptide-related components and their messenger RNAs in the hippocampus of aged senescence-accelerated mice.

Hippocampal cholinergic neurostimulating peptide stimulates cholinergic phenotype development by inducing choline acetyltransferase in the rat medial septal nucleus in vitro. Adult senescence-accelerated-prone mice/8, a substrain of the senescence-accelerated-prone mouse, show a remarkable age-accelerated deterioration in learning and memory. We cloned mouse hippocampal cholinergic neurostimulating peptide precursor protein complementary DNA. The deduced amino acid sequence showed that the neurostimulating peptide itself is the same as that found in the rat. In situ hybridization revealed that the highest expression of the precursor protein messenger RNA was in hippocampal pyramidal neurons. Compared with a strain of senescence-accelerated-resistant mouse (control mouse), adult senescence-accelerated-prone mice/8 showed increased expression of both the precursor messenger RNA and the neurostimulating peptide-related immunodeposits in the hippocampal CA1 field. The deposits were intensely and diffusely precipitated in neuropils throughout the strata oriens and radiatum in senescence-accelerated-prone mice/8, but not in control mice. The neurostimulating peptide content in the hippocampus was higher in senescence-accelerated-prone mice/8 than in control mice, while its precursor protein itself was not different between the two strains. Furthermore, our previous and present data show that the medial septal and hippocampal choline acetyltransferase activity was significantly lower in senescence-accelerated-prone mice/8 than in control mice. The data suggest that, in hippocampal neurons in adult senescence-accelerated-prone mice/8, the production of hippocampal cholinergic neurostimulating peptide precursor protein in neuronal somata, which is associated with an increased expression of its messenger RNA in the CA1 field, occurs as a consequence of low activity in their presynaptic cholinergic neurons. This is followed by accelerated processing to generate bioactive peptide and transport to its functional fields. However, certain mechanisms reduce the release of the peptide and lead to its accumulation in the neuropil. These disturbances of the septohippocampal cholinergic system might be the biochemical mechanism underlying the characteristic deterioration of senescence-accelerated-prone mice/8.

Impairment of long-term potentiation and spatial memory in leptin receptor-deficient rodents.

Leptin is well known to be involved in the control of feeding, reproduction and neuroendocrine functions through its action on the hypothalamus. However, leptin receptors are found in brain regions other than the hypothalamus (including the hippocampus and cerebral cortex) suggesting extrahypothalamic functions. We investigated hippocampal long-term potentiation (LTP) and long-term depression (LTD), and the spatial-memory function in two leptin receptor-deficient rodents (Zucker rats and db/db mice). In brain slices, the CA1 hippocampal region of both strains showed impairments of LTP and LTD; leptin (10(-12) M) did not improve these impairments in either strain. These strains also showed lower basal levels of Ca(2+)/calmodulin-dependent protein kinase II activity in the CA1 region than the respective controls, and the levels did not respond to tetanic stimulation. These strains also showed impaired spatial memory in the Morris water-maze test (i.e. longer swim-path lengths during training sessions and less frequent crossings of the platform's original location in the probe test. From these results we suggest that the leptin receptor-deficient animals show impaired LTP in CA1 and poor spatial memory due, at least in part, to a deficiency in leptin receptors in the hippocampus.

A single pre-training glucose injection induces memory facilitation in rodents performing various tasks: contribution of acidic fibroblast growth factor.

Effects of a pre-training intraperitoneal glucose injection on learning and memory were tested using two tasks: passive avoidance and Morris water maze. In the former task, mice that had received glucose 2 h prior (but not 1, 3, or 5 h prior) to a trial that combined acquisition with passive avoidance of foot shock showed a significantly increased retention latency when tested 24 h later. Thus, this effect was time-dependent, and it was also found to be dose-dependent by further experiment. In contrast, 2-deoxy-D-glucose and fructose had no such effect. In the Morris water maze task, glucose injection 2 or 3 h before a block of trials enhanced the spatial memory performance of mice. These glucose-induced memory-facilitation effects were abolished by an intracerebroventricular injection of anti-acidic fibroblast growth factor antibody 30 min before the glucose injection, suggesting a critical role for endogenous acidic fibroblast growth factor in this facilitatory effect. Furthermore, continuous intracerebroventricular infusion of acidic fibroblast growth factor in rats significantly increased retention latency (when tested repeatedly on successive days using a passive avoidance task). Our earlier studies demonstrated that brain acidic fibroblast growth factor is produced in the ependymal cells of the cerebroventricular system, and is released into the cerebrospinal fluid following either a meal or a (intraperitoneal or intracerebroventricular) glucose injection. This released acidic fibroblast growth factor also diffuses into the brain parenchyma, and is taken up by neurons in the hippocampus, hypothalamus, and elsewhere in the brain some 2 h after the meal or glucose injection. These and the present findings indicate (i) that pre-training glucose injection improves memory performance, and (ii) that acidic fibroblast growth factor, especially by its action within the hippocampus, is involved in this enhancement process.

Production of antisera to acidic fibroblast growth factor and their application to immunohistochemical study in rat brain.

Antisera against acidic fibroblast growth factor purified from bovine brain were produced in rabbits and used for immunohistochemical study of the rat brain. When examined in an immunospot assay using a nitrocellulose membrane, the best antibody was capable of detecting 80 fmol of acidic fibroblast growth factor but failed to react even with up to 5 pmol of basic fibroblast growth factor. Using this antiserum, the immunohistochemical distribution of acidic fibroblast growth factor was examined in rat brain. Acidic fibroblast growth factor-like immunoreactivity was localized mainly in a subpopulation of ependymal cells and tanycytes, as well as in some glial cells. Positive ependymal cells were observed throughout the walls of ventricles, including the third ventricle and cerebral aqueduct. Immunoreactive processes of tanycytes were found extending from the ventral wall of the third ventricle to the brain parenchyma and surface. The most intense immunostaining was observed in circumventricular organs such as the organum vasculosum laminalis terminalis and the subfornical organ. Particularly in the latter organ, there was an extremely dense plexus of immunoreactive fibers and processes around the wall of capillaries. The present results suggest that the effects of acidic fibroblast growth factor on brain functions may be exerted through the circumventricular organs and/or ependymal cells.

Orexin-A (hypocretin-1) impairs Morris water maze performance and CA1-Schaffer collateral long-term potentiation in rats.

Glucose-sensitive neurons in the lateral hypothalamic area produce orexin-A (hypocretin-1) and orexin-B (hypocretin-2) and send their axons to the hippocampus, which predominantly expresses orexin receptor 1 showing a higher sensitivity to orexin-A. The purpose of the present study was to assess the effects of orexin-A on the performance of Wistar rats during the Morris water maze test and then to determine the effects of orexin-A on both the long-term potentiation and long-term depression in Schaffer collateral/commissural-CA1 synapses in hippocampal slices. The results of the Morris water maze test show that 1.0 and 10 nmol of orexin-A, when administered intracerebroventricularly, retarded spatial learning. A probe test examined after training of water maze task also showed an impairment in spatial memory. The results of an electrophysiological study using hippocampal slices demonstrated that 1.0 to 30 nM of orexin-A applied to the perfusate produces a dose-dependent and time dependent suppression of the long-term potentiation. In addition, the long-term depression was not affected by orexin-A. The results of a paired-pulse facilitation experiment indicated that the effects of orexin-A were post-synaptic and not due to presynaptic transmitter release. These results show that orexin-A impairs spatial performance and these impairments can be attributed to a suppression of long-term potentiation in the Schaffer collateral-CA1 hippocampal synapses.

Effect of acidic fibroblast growth factor on basal forebrain cholinergic neurons in senescence-accelerated mice.

We examined the effects of chronic administration of acidic fibroblast growth factor (aFGF) on memory and choline acetyltransferase (ChAT) immunoreactivity in the forebrain of senescence-accelerated mice (SAMP8 strain). Subcutaneous injection of aFGF (aFGF group) or saline vehicle (saline group) once a week into SAMP8 was begun at three weeks after birth and continued for nine months. In the passive avoidance test, the retained latency was significantly longer in the aFGF group than in the saline group. In the Morris test, the mean latency to climb on a platform was significantly shorter in the aFGF group than in the saline group. The number of ChAT-positive neurons in the forebrain septum was greater in the aFGF group than in the saline group, and was at the level of that in the control mouse strain (SAMR1). The intensity of ChAT staining in the aFGF group appeared slightly weaker than in SAMR1 but significantly stronger than in the saline group. The results indicate that the effect of aFGF on memory function in SAMP8 may be related to the preservation of function in septal cholinergic cells.

Acidic fibroblast growth factor delays in vitro ischemia-induced intracellular calcium elevation in gerbil hippocampal slices: a sign of neuroprotection.

Using microfluorometry, effects of acidic fibroblast growth factor (aFGF) on the in vitro ischemia-induced intracellular calcium elevation were investigated in gerbil hippocampal slices at 35 degrees C. When slices were superfused with hypoxic and glucose-free medium, the mean latency of the in vitro ischemia-induced calcium elevation was 209 +/- 51 s. The addition of aFGF in medium (25 micrograms/l) delayed the calcium elevation throughout the experiments: the mean latency was 541 +/- 94 s. This retardation in calcium elevation may be indicative of neuroprotective nature of aFGF.

Acidic fibroblast growth factor prevents death of hippocampal CA1 pyramidal cells following ischemia.

Ischemic insult induces neuronal death in the CA1 subfields of the hippocampus which are designated generally as the most vulnerable brain region. Recent studies have shown that acidic and basic fibroblast growth factors are potent trophic factors that support the survival of neurons in many brain regions including the hippocampus. Here we demonstrate that continuous infusion of acidic fibroblast growth factor into the lateral cerebral ventricles beginning 2 days before ischemia prevents the death of the CA1 pyramidal cells in the hippocampus of gerbils. Furthermore, delayed continuous administration of acidic fibroblast growth factor starting 5 min after ischemia is equally protective. The results suggest a possible physiological function for acidic fibroblast growth factor in the normal support of hippocampal CA1 pyramidal cells and neurons in some other brain regions in considering the broad spectrum of responsive neurons.

Complex functional attributes of amygdaloid gustatory neurons in the rhesus monkey.

To reveal specific functions of glucose-sensitive (GS) and glucose-insensitive (GIS) cells in chemical information processing, single neuron activity was recorded in the amygdaloid body (AMY) of macaques during: 1) gustatory stimulations and 2) micro-electrophoretic administration of chemicals. Of the 629 neurons tested, 56 (8.9%) responded to, usually two or more, taste qualities. Hedonically distinct tastants usually elicited opposite firing rate changes of the gustatory cells. Seventy percent of the gustatory responses were recorded from GS neurons (17% of all AMY cells). Catecholamines (CAs) induced discharge rate changes in a majority of taste-responsive neurons: The GS gustatory cells were suppressed by norepinephrine (in the form of noradrenaline HCl, NA), whereas the GIS taste-responsive neurons were facilitated by dopamine (DA). Furthermore, NA- and/or DA-antagonists were able to attenuate or suppress taste-elicited responses of several of these cells. These and previous data indicate a specific functional organization of AMY gustatory cells: The GS and GIS taste neurons appear to be involved in differential integration of feeding-associated humoral-metabolic, motivational and exogenous chemical information.

Protection against impairment of memory and immunoreactivity in senescence-accelerated mice by acidic fibroblast growth factor.

Subcutaneous injection of aFGF once a week into senescence-accelerated mice (SAM)P8 was begun at 3 weeks after birth and continued for 10 months. Saline was injected as a control. Learning and memory and cellular immunological functions in the aFGF group were enhanced significantly, while those of the saline group deteriorated. 1. The number of cholinergic neurons was decreased by less than 20% and choline acetyltransferase activity in individual neurons in the medical septum which send monosynaptic terminals to the hippocampus was significantly decreased in the saline group, but not so much in the aFGF group. 2. The respective densities of muscarinic and NMDA receptors and the aFGF receptor, i.e., FGFR-1 on the hippocampal neurons were also significantly higher in the aFGF group than in the saline group. 3. The long-term potentiation in the hippocampal slice preparations after a brief tetanic stimulation at the Schaffer collateral/commissural afferents was significantly facilitated in the aFGF group, but not in the saline group. 4. These data indicate the normalization caused by aFGF of the medial septohippocampal circuit, which is necessary for learning and memory. 5. The delayed type hypersensitivity reactions (DTH) in the footpad caused by challenge with trinitrophenyl or sheep red blood cells as measured at the end of the 2nd and 7th months, indicated the T cell immune response. Both types of DTHs were reduced in the 7th month as compared with the 2nd month in the saline group, but the aFGF group was protected against this reduction in accordance with age. 6. These results show that aFGF provides protection against impairment of not only learning and memory but also DTH immunoreactivity in SAMP8. They also indicate a close relationship between learning and memory and T cell immune function.

Senescence-accelerated mouse. Neurochemical studies on aging.

Senescence-accelerated mouse (SAMP8) is known as a murine model of accelerated aging and memory dysfunction. The binding activity of [3H] 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxam ide (PK-11195) as a neurochemical marker of gliosis markedly increased with aging in the cerebral cortex and hippocampus of SAMP8. Immunoreactivity for glial fibrillary acidic protein (GFAP) was also enhanced. A beta-amyloid precursor protein (APP)-like immunoreactivity and 27-kDa-carboxyl terminal fragments of APP increased in SAMP8 brain. In addition, anti-APP antibody stained reactive astrocytes surrounding spongy degeneration in brain stern of SAMP8. These results suggest that astrocytosis and production of APP-derived fragments occur markedly in SAMP8 brains.

Orexin-A (Hypocretin-1) and leptin enhance LTP in the dentate gyrus of rats in vivo.

Orexin-A (Hypocretin-1) has been localized in the posterior and lateral hypothalamic perifornical region. Orexin containing axon terminals have been found in hypothalamic nuclei and many other parts of the brain; for example, the hippocampus. Two types of orexin receptors have been discovered. Orexin 1 type of receptors have been described and been shown to be widely distributed in the rat brain including the hippocampus. Subsequently Orexin-A was found to impair both water maze performance and hippocampal long term potentiation (LTP). Leptin is expressed in adipose tissue and released into the blood where it affects food intake and can also produce widespread physiological changes mediated via autonomic preganglionic neurons, pituitary gland, and cerebral cortex. Immunoreactivity for leptin receptors has been found in various hypothalamic nuclei including the lateral hypothalamic area as well as the hippocampus especially in the dentate gyrus and CA1. Leptin receptor deficient rats and mice also show impaired LTP in CA1 and poor performance in the water maze. The present study was conducted to determine the effects of 0.0, 30, 60, 90, and 100 nM, orexin-A, and leptin, 0.0, 1.0, 100 nM, 1, and 10 microM, in 1.0 microl of ACSF, applied directly into the dentate gyrus, on LTP in medial perforant path dentate granule cell synapses in urethane anesthetized rats. Orexin-A specifically enhanced LTP at the 90 nM dose; and it was possible to block the enhancement by pretreating the animals with SB-334867, a specific orexin 1 receptor antagonist. Leptin enhanced normal LTP at 1.0 microM but inhibited LTP at lower and higher doses. These results and previous data indicate that the same peptide could possibly have different modulatory post synaptic effects in different hippocampal synapses dependent upon different types of post synaptic receptors.