piperidines and cyclothiazide

Ion channels gated by neurotransmitters are present across metazoans, in which they are essential for brain function, sensation and locomotion; closely related homologs are also found in bacteria. Structures of eukaryotic pentameric cysteine-loop (Cys-loop) receptors and tetrameric ionotropic glutamate receptors in multiple functional states have recently become available. Here, I describe how these studies relate to established ideas regarding receptor activation and how they have enabled decades' worth of functional work to be pieced together, thus allowing previously puzzling aspects of receptor activity to be understood.

Topics: Animals; Bacteria; Benzothiadiazines; Cognition; Cysteine Loop Ligand-Gated Ion Channel Receptors; Gene Expression; Humans; Ion Channel Gating; Ion Channels; Ivermectin; Locomotion; Models, Molecular; Neurotransmitter Agents; Perception; Piperidines; Receptors, Glutamate; Synapses; Synaptic Transmission

The endocannabinoid (eCB) system and the cannabinoid CB1 receptor (CB1R) play key roles in the modulation of brain functions. Although actions of eCBs and CB1Rs are well described at the synaptic level, little is known of their modulation of neural activity at the network level. Using microelectrode arrays, we have examined the role of CB1R activation in the modulation of the electrical activity of rat and mice cortical neural networks in vitro. We find that exogenous activation of CB1Rs expressed on glutamatergic neurons decreases the spontaneous activity of cortical neural networks. Moreover, we observe that the net effect of the CB1R antagonist AM251 inversely correlates with the initial level of activity in the network: blocking CB1Rs increases network activity when basal network activity is low, whereas it depresses spontaneous activity when its initial level is high. Our results reveal a complex role of CB1Rs in shaping spontaneous network activity, and suggest that the outcome of endogenous neuromodulation on network function might be state dependent.

Topics: 4-Aminopyridine; Action Potentials; Animals; Animals, Newborn; Benzothiadiazines; Brain; Cannabinoid Receptor Modulators; Cells, Cultured; Electric Stimulation; Endocannabinoids; Excitatory Amino Acid Antagonists; GABA Antagonists; In Vitro Techniques; Mice; Mice, Transgenic; Nerve Net; Neural Inhibition; Neurons; Organophosphorus Compounds; Picrotoxin; Piperidines; Potassium Channel Blockers; Pyrazoles; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Sodium Channel Blockers; Tetrodotoxin; Valine

The phosphorylation state of the glutamate receptor subtype 1 (GluR1) subunit of the AMPA receptor (AMPAR) plays a critical role in synaptic expression of the receptor, channel properties, and synaptic plasticity. Several Gs-coupled receptors that couple to protein kinase A (PKA) readily recruit phosphorylation of GluR1 at S845. Conversely, activation of the ionotropic glutamate NMDA receptor (NMDAR) readily recruits dephosphorylation of the same GluR1 site through Ca2+-mediated recruitment of phosphatase activity. In a physiological setting, receptor activation often overlaps and crosstalk between coactivation of multiple signaling cascades can result in differential regulation of a given substrate. After investigating the effect of coactivation of the NMDAR and the Gs-coupled beta-adrenergic receptor on GluR1 phosphorylation state, we have observed a novel signal that prevents PKA-mediated phosphorylation of GluR1 at serine site 845. This blockade of GluR1 phosphorylation is dependent on cellular depolarization recruited by either NMDAR or AMPAR activation, independent of Ca2+ and independent of calcineurin, protein phosphatase 1, and/or protein phosphatase 2A activity. Thus, in addition to the typical kinase-phosphatase rivalry mediating protein phosphorylation state, we have identified a novel form of phospho-protein regulation that occurs at GluR1 and may also occur at several other PKA substrates.

Topics: 2-Amino-5-phosphonovalerate; Adrenergic beta-Antagonists; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Benzothiadiazines; Calcineurin Inhibitors; Calcium; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclosporine; Egtazic Acid; Excitatory Amino Acid Antagonists; Glutamic Acid; GTP-Binding Protein alpha Subunits, Gs; Hippocampus; Isoproterenol; Long-Term Potentiation; Male; Marine Toxins; Mice; Mice, Inbred C57BL; N-Methylaspartate; Oxazoles; Phenols; Phosphoprotein Phosphatases; Phosphorylation; Phosphoserine; Piperidines; Protein Phosphatase 1; Protein Phosphatase 2; Protein Processing, Post-Translational; Receptors, Adrenergic, beta-1; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Signal Transduction

Earlier studies showed that positive modulators of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors enhance synaptic responses and facilitate synaptic plasticity. Those studies focused mainly on hippocampal functions. However, AMPA receptors have regionally distinct subunit compositions and thus potencies and efficacies of modulators may vary across the brain. The present study compared the effects of CX546 [1-(1,4-benzodioxan-6-ylcarbonyl) piperidine], a benzamide-type modulator, on synaptic transmission in neurons of the reticular thalamic nucleus (RTN), which regulates the firing mode of relay cells in other thalamic nuclei, and on hippocampal CA1 pyramidal cells. CX546 greatly prolonged synaptic responses in CA1 pyramidal cells, but at the same concentration it had only weak modulatory effects in RTN neurons. Effects on miniature excitatory postsynaptic currents (EPSCs) were similar to those on EPSCs in both regions, suggesting that variations in neuronal morphology and transmitter release kinetics do not account for the differences. Relay cells in the ventrobasal thalamus also exhibited weak modulatory effects that were comparable with those in RTN neurons. Regionally different effects on response duration were also observed with CX516 [BDP-12, 1-(quinoxalin-6-ylcarbonyl)piperidine], a second benzamide drug. In contrast, 100 microM cyclothiazide produced comparable synaptic enhancements in hippocampus and RTN. The regional selectivity of benzamide drugs (ampakines) may be explained, at least in part, by a lower potency at thalamic AMPA receptors, perhaps due to the prevalence of the subunits GluR3 and 4. Although regional preferences of the ampakines were modest in their extent, they may be sufficient to be of relevance when considering future therapeutic applications of such compounds.

Topics: Animals; Benzothiadiazines; Dioxoles; Excitatory Postsynaptic Potentials; Hippocampus; In Vitro Techniques; Male; Membrane Potentials; Patch-Clamp Techniques; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Synaptic Transmission; Thalamus

Glutamate was previously shown to enhance aerobic glycolysis i.e. increase glucose utilization and lactate production with no change in oxygen levels, in mouse cortical astrocytes by a mechanism involving glutamate uptake. It is reported here that a similar response is produced in both hippocampal and cerebellar astrocytes. Application of the cognitive-enhancing drug CX546 promoted further enhancement of glucose utilization by astrocytes from each brain area following glutamate exposure. alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors represent the purported molecular target of cognitive-enhancing drugs such as CX546, and the presence of AMPA receptor subunits GluR1-4 was evidenced in astrocytes from all three regions by immunocytochemistry. AMPA itself did not stimulate aerobic glycolysis, but in the presence of CX546, a strong enhancement of glucose utilization and lactate production was obtained in cortical, hippocampal and cerebellar astrocytes. The effect of CX546 was concentration-dependent, with an EC(50) of 93.2 microm in cortical astrocytes. AMPA-induced glucose utilization in the presence of CX546 was prevented by the AMPA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and the negative modulator GYKI 52466. In addition, the metabolic effect of CX546 in the presence of AMPA was mimicked by the AMPA receptor modulator cyclothiazide. Our data suggest that astrocyte energetics represents a novel target for cognitive-enhancing drugs acting as AMPA receptor modulators.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Astrocytes; Benzothiadiazines; Cell Separation; Cells, Cultured; Cerebellum; Cerebral Cortex; Dioxoles; Dose-Response Relationship, Drug; Energy Metabolism; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Glucose; Glutamic Acid; Hippocampus; Lactic Acid; Mice; Nootropic Agents; Piperidines; Receptors, AMPA

Prior studies showed that positive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor modulators facilitate long-term potentiation (LTP) and improve the formation of several types of memory in animals and humans. However, these modulators are highly diverse in their effects on receptor kinetics and synaptic transmission and thus may differ also in their efficacy to promote changes in synaptic strength. The present study examined three of these modulators for their effects on synaptic plasticity in field CA1 of hippocampal slices, two of them being the benzamide drugs 1-(quinoxalin-6-ylcarbonyl)piperidine (CX516) and 1-(1,4-benzodioxan-6-ylcarbonyl)piperidine (CX546) which prominently enhance synaptic transmission yet differ in their relative impact on amplitude versus duration of the synaptic response. The third drug was cyclothiazide which potently blocks AMPA receptor desensitization. Effects on plasticity were assessed by measuring (i) the likelihood of obtaining stable potentiation when using theta-burst stimulation with three instead of four pulses per burst, (ii) the maximum amount of potentiation under optimal stimulation conditions, and (iii) the effect on long-term depression (LTD). Both benzamides facilitated the formation of stable potentiation induced with three-pulse burst stimulation which is normally ineffective. CX546 in addition increased maximally inducible potentiation after four-pulse burst stimulation from about 50% to 100%. Burst response analysis revealed that CX546 greatly prolonged the duration of depolarization by slowing the decay of the response which thus presumably leads to a more continuous N-methyl-D-aspartate (NMDA) receptor activation. Cyclothiazide was ineffective in increasing maximal potentiation in either field or whole-cell recordings. CX546, but not CX516, also enhanced nearly two-fold the NMDA receptor-dependent long-term depression induced by heterosynaptic 2 Hz stimulation. Tests with recombinant NMDA receptors (NR1/NR2A) showed that CX516 and CX546 have no direct effects on currents mediated by these receptors. These results suggest that (1) modulation of AMPA receptors which increases either response amplitude or duration can facilitate LTP formation, (2) modulators that effectively slow response deactivation augment the maximum magnitude of LTP and LTD, and (3) receptor desensitization may have a minor impact on synaptic plasticity in the hippocampus. Taken together, our data indicate tha

Topics: Animals; Animals, Newborn; Benzothiadiazines; Cell Line; Central Nervous System Stimulants; Dioxoles; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Electric Stimulation; Embryo, Mammalian; Glutamic Acid; Hippocampus; Humans; In Vitro Techniques; Kidney; Long-Term Potentiation; Neuronal Plasticity; Patch-Clamp Techniques; Picrotoxin; Piperidines; Pyramidal Cells; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Synapses; Time Factors; Transfection

A major subtype of glutamate receptors, AMPA receptors (AMPARs), are generally thought to mediate excitation at mammalian central synapses via the ionotropic action of ligand-gated channel opening. It has recently emerged, however, that synaptic activation of AMPARs by glutamate released from the climbing fibre input elicits not only postsynaptic excitation but also presynaptic inhibition of GABAergic transmission onto Purkinje cells in the cerebellar cortex. Although presynaptic inhibition is critical for information processing at central synapses, the molecular mechanisms by which AMPARs take part in such actions are not known. This study therefore aimed at further examining the properties of AMPAR-mediated presynaptic inhibition at GABAergic synapses in the rat cerebellum. Our data provide evidence that the climbing fibre-induced inhibition of GABA release from interneurons depends on AMPAR-mediated activation of GTP-binding proteins coupled with down-regulation of presynaptic voltage-dependent Ca(2+) channels. A G(i/o)-protein inhibitor, N-ethylmaleimide, selectively abolished the AMPAR-mediated presynaptic inhibition at cerebellar GABAergic synapses but did not affect AMPAR-mediated excitatory actions on Purkinje cells. Furthermore, both G(i/o)-coupled receptor agonists, baclofen and DCG-IV, and the P/Q-type calcium channel blocker omega-agatoxin IVA markedly occluded the AMPAR-mediated inhibition of GABAergic transmission. Conversely, AMPAR activation inhibited action potential-triggered Ca(2+) influx into individual axonal boutons of cerebellar GABAergic interneurons. By suppressing the inhibitory inputs to Purkinje cells, the AMPAR-mediated presynaptic inhibition could thus provide a feed-forward mechanism for the information flow from the cerebellar cortex.

Topics: Action Potentials; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Benzothiadiazines; Benzoxazines; Calcium; Calcium Channel Blockers; Cerebellum; Chelating Agents; Colforsin; Cyclopropanes; Drug Interactions; Egtazic Acid; Enzyme Inhibitors; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; GABA Antagonists; gamma-Aminobutyric Acid; Glycine; In Vitro Techniques; Morpholines; Naphthalenes; Neural Inhibition; Neurons; Piperidines; Presynaptic Terminals; Pyrazoles; Rats; Rats, Wistar; Receptors, AMPA; Ryanodine; Synapses; Triazines; Triazoles

The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid subtype of ionotropic glutamate receptors consists of rapidly gating ion channels. Positive modulation of channel gating may slow gating kinetics through at least two distinct mechanisms, evidenced by the predominant slowing of either the rate of receptor desensitization or the rate of offset after agonist withdrawal (deactivation). This study compares the actions of two positive allosteric modulators [cyclothiazide, which modulates desensitization, and 1-(1,4-benzodioxan-6-ylcarbonyl)piperidine (CX546), which modulates deactivation] in a mutant shown previously to impede modulation by cyclothiazide. These experiments test the hypothesis that the point mutation, GluR1(S493T), would also cause a loss of modulation by CX546. Wild-type GluR1 through -4 receptors were modulated by CX546, as assayed by the potentiation of steady-state currents in the Xenopus laevis oocyte expression system. CX546 potentiated steady-state currents of both splice isoforms of GluR1. Modulation by CX546 was completely abolished in GluR1(S493T) and its homolog, GluR2(S497T), although this mutation did not affect apparent agonist affinity in the absence of CX546. Thus, the GluR1(S493T) mutation has a similar impairment of modulation by either cyclothiazide or CX546, indicating that some residues at the subunit interface of glutamate receptors play an important role in channel deactivation and desensitization.

Topics: Amino Acid Substitution; Animals; Benzothiadiazines; Binding Sites; Dioxoles; Glutamic Acid; Kinetics; Models, Molecular; Oocytes; Piperidines; Point Mutation; Receptors, AMPA; Serine; Threonine; Transfection; Xenopus laevis

The present study describes the activity of two novel potent and selective AMPA receptor potentiator molecules LY392098 and LY404187. LY392098 and LY404187 enhance glutamate (100 microM) stimulated ion influx through recombinant homomeric human AMPA receptor ion channels, GluR1-4, with estimated EC(50) values of 1.77 microM (GluR1(i)), 0.22 microM (GluR2(i)), 0.56 microM (GluR2(o)), 1.89 microM (GluR3(i)) and 0.20 microM (GluR4(i)) for LY392098 and EC(50) values of 5.65 microM (GluR1(i)), 0.15 microM (GluR2(i)), 1.44 microM (GluR2(o)), 1.66 microM (GluR3(i)) and 0.21 microM (GluR4(i)) for LY404187. Neither compound affected ion influx in untransfected HEK293 cells or GluR transfected cells in the absence of glutamate. Both compounds were selective for activity at AMPA receptors, with no activity at human recombinant kainate receptors. Electrophysiological recordings demonstrated that glutamate (1 mM)-evoked inward currents in human GluR4 transfected HEK293 cells were potentiated by LY392098 and LY404187 at low concentrations (3-10 nM). In addition, both compounds removed glutamate-dependent desensitization of recombinant GluR4 AMPA receptors. These studies demonstrate that LY392098 and LY404187 allosterically potentiate responses mediated by human AMPA receptor ion channels expressed in HEK 293 cells in vitro.

Topics: Allosteric Regulation; Antihypertensive Agents; Benzothiadiazines; Calcium; Cell Line; Dioxoles; Dose-Response Relationship, Drug; Drug Synergism; Electrophysiology; Excitatory Amino Acid Agonists; Humans; Piperidines; Receptors, AMPA; Receptors, Glutamate; Recombinant Proteins; Sulfonamides; Thiophenes

The effects of various (S)-alpha-amino-3-hydroxy-5-methyl-4-izoxazole-propionate (AMPA) receptor modulators on AMPA-induced whole-cell currents were compared in isolated rat cerebellar Purkinje cells. The positive modulators, aniracetam, cyclothiazide, 1-(1, 3-benzodioxol-5-ylcarbonyl)-piperidine (1-BCP), and 1-(quinoxaline-6-ylcarbonyl)-piperidine (BDP-12), dose-dependently potentiated the steady-state component of AMPA currents. The negative modulator, (-)1-(4-aminophenyl)-4-methyl-7, 8-methylenedioxy-4,5-dihydro-3-methylcarbamoyl-2,3-benzodiazepine (GYKI 53784), dose-dependently suppressed AMPA responses. Its concentration-response curve was shifted to the right in a parallel fashion by all positive modulators, indicating a competitive type of interaction. However, the relative potencies of the positive modulators were different with regard to the enhancement of AMPA responses and the reversal of GYKI 53784-induced inhibition, respectively. It is supposed that positive modulators act at multiple allosteric sites and that they interact with GYKI 53784 at only one of these sites.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Benzodiazepines; Benzothiadiazines; Cells, Cultured; Cerebellum; Dioxoles; Dose-Response Relationship, Drug; Drug Synergism; Excitatory Amino Acid Antagonists; Membrane Potentials; Piperidines; Purkinje Cells; Pyrrolidinones; Rats; Receptors, AMPA

Aniracetam, 1-(1,3-benzodioxol-5-yl-carbonyl)piperidine (1-BCP) and cyclothiazide, three compounds considered to enhance cognition through modulation of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors, were evaluated in the 'kynurenate test', a biochemical assay in which some nootropics have been shown to prevent the antagonism by kynurenic acid of the N-methyl-D-aspartate (NMDA)-evoked [3H]noradrenaline ([3H]NA) release from rat hippocampal slices. Aniracetam attenuated the kynurenate (100 microM) antagonism of the [3H]NA release elicited by 100 microM NMDA with high potency (EC50< or =0.1 microM). Cyclothiazide and 1-BCP were about 10 and 100 times less potent than aniracetam, respectively. The effect of aniracetam persisted in the presence of the AMPA receptor antagonist 6-nitro-7-sulphamoyl-benzo[f]quinoxaline-2,3-dione (NBQX) added at 5 microM, a concentration that did not affect NMDA receptors; in contrast, NBQX reduced the effect of 1-BCP and abolished that of cyclothiazide. The AMPA-evoked release of [3H]NA from hippocampal slices or synaptosomes was enhanced by cyclothiazide, less potently by 1-BCP and weakly by aniracetam. High concentrations of kynurenate (1 mM) antagonized the AMPA-evoked [3H]NA release in slices; this antagonism was attenuated by 1 microM cyclothiazide and reversed to an enhancement of AMPA-evoked [3H]NA release by 10 microM of the drug, but was insensitive to 1-BCP or aniracetam. It is concluded that aniracetam exerts a dual effect on glutamatergic transmission: modulation of NMDA receptor function at nanomolar concentrations, and modulation of AMPA receptors at high micromolar concentrations. As to cyclothiazide and 1-BCP, our data concur with the idea that both compounds largely act through AMPA receptors, although an NMDA component may be involved in the effect of 1-BCP.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Antihypertensive Agents; Benzothiadiazines; Dioxoles; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Heterocyclic Compounds; Hippocampus; In Vitro Techniques; Kynurenic Acid; Male; N-Methylaspartate; Nootropic Agents; Norepinephrine; Piperidines; Pyrrolidinones; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Tritium

Relationships between the kinetic properties of AMPA receptors and the decay phase of fast excitatory transmission were investigated using modulatory drugs. The benzothiadiazide compound cyclothiazide blocked receptor desensitization in patches excised from hippocampus but had only a weak influence on receptor deactivation, i.e., on the decay of responses produced by a 1-ms pulse of glutamate. The ampakine drug CX516 (BDP-12) produced an opposite pattern of effects: a fourfold slowing of deactivation with little change in desensitization. A structurally related drug (CX554 or BDP-20) had prominent effects on both desensitization and deactivation. The halfwidth of field EPSPs measured in the CA1 region of hippocampal slices increased 50-100% in the presence of CX516 or CX554 but by less than 15% at concentrations of cyclothiazide that fully blocked desensitization in patch experiments. These results indicate that receptor deactivation plays a substantially greater role than receptor desensitization in determining the duration of synaptic responses.

Topics: Animals; Benzothiadiazines; Dioxoles; Excitatory Postsynaptic Potentials; Hippocampus; In Vitro Techniques; Piperidines; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Synapses; Synaptic Transmission

The benzoylpiperidine 1-(1,3-benzodioxol-5-ylcarbonyl)-piperidine (1-BCP), and related compounds, potentiate alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acidergic (AMPAergic) synaptic currents in central neurons, and improve performance of rodents and humans on learning and memory tasks. Their physiological actions are similar but not identical to thiazides, which also enhance AMPAergic synaptic responses and improve performance of rats in water-maze and passive-avoidance tests. Thiazides also dramatically increase AMPA receptor-mediated neuronal death in vitro and in vivo. Here it was evaluated whether 1-BCP potentiated AMPA receptor-mediated excitotoxicity in hippocampal neuron cultures. Glutamate + MK 801 (to block NMDA receptors) + 1 mM 1-BCP produced neuronal death that was reversed by 10 microM 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)quinoxaline (NBQX), a selective AMPA receptor antagonist. 1-BCP and drugs with similar activities can facilitate AMPA receptor-mediated excitotoxicity.

Topics: Animals; Benzothiadiazines; Cell Survival; Cells, Cultured; Dioxoles; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Glutamic Acid; Hippocampus; Neurons; Neurotoxins; Piperidines; Quinoxalines; Rats; Receptors, AMPA

It is now clear that the AMPA subtype of ionotropic glutamate receptors (iGluRs) undergoes a rapid desensitization in response to activation by AMPA receptor agonists. This desensitization is inhibited by compounds such as aniracetam and cyclothiazide, which act at a distinct site on the AMPA receptor complex. In particular, cyclothiazide greatly potentiates AMPA receptor-mediated depolarizing responses in the hippocampus. We have recently shown cyclothiazide also increases AMPA-induced release of [3H]norepinephrine ([3H]NE). More, recently, a benzamide compound, 1-(1,3-benzodioxol-5-ylcarbonyl)-piperidine (1-BCP), has been reported to enhance AMPA-induced currents and to facilitate memory retention in rats in a number of memory tasks. In this study, the effects of 1-BCP on excitatory amino acid agonist-induced [3H]NE release in rat hippocampal slices were determined. We report that 1-BCP, like cyclothiazide, selectively potentiates AMPA-induced [3H]NE release. However, cyclothiazide was more potent and efficacious than 1-BCP. Nevertheless, these data suggest a role for AMPA receptor-mediated enhancement of norepinephrine release as a mechanism of action for nootropic compounds such as 1-BCP.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Benzothiadiazines; Dioxoles; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists; Hippocampus; Kainic Acid; Male; Memory; N-Methylaspartate; Norepinephrine; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, AMPA