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1.
Mol Pharmacol ; 73(3): 977-86, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18089837

ABSTRACT

KCNQ2 (Kv7.2) and KCNQ3 (Kv7.3) are voltage-gated K(+) channel subunits that underlie the neuronal M current. In humans, mutations in these genes lead to a rare form of neonatal epilepsy (Biervert et al., 1998; Singh et al., 1998), suggesting that KCNQ2/Q3 channels may be attractive targets for novel antiepileptic drugs. In the present study, we have identified the compound N-(6-chloro-pyridin-3-yl)-3,4-difluoro-benzamide (ICA-27243) as a selective activator of the neuronal M current and KCNQ2/Q3 channels. In SH-SY5Y human neuroblastoma cells, ICA-27243 produced membrane potential hyperpolarization that could be prevented by coadministration with the M-current inhibitors 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone dihydrochloride (XE-991) and linopirdine. ICA-27243 enhanced both (86)Rb(+) efflux (EC(50) = 0.2 microM) and whole-cell currents in Chinese hamster ovary cells stably expressing heteromultimeric KCNQ2/Q3 channels (EC(50) = 0.4 microM). Activation of KCNQ2/Q3 channels was associated with a hyperpolarizing shift of the voltage dependence of channel activation (V((1/2)) shift of -19 mV at 10 microM). In contrast, ICA-27243 was less effective at activating KCNQ4 and KCNQ3/Q5 and was selective over a wide range of neurotransmitter receptors and ion channels such as voltage-dependent sodium channels and GABA-gated chloride channels. ICA-27243 (1-10 microM) was found to reversibly suppress seizure-like activity in an ex vivo hippocampal slice model of epilepsy and demonstrated in vivo anticonvulsant activity (ED(50) = 8.4 mg/kg) in the mouse maximal electroshock epilepsy model. In conclusion, ICA-27243 represents the first member of a novel chemical class of selective KCNQ2/Q3 activators with anticonvulsant-like activity in experimental models of epilepsy.


Subject(s)
Benzamides/pharmacology , KCNQ2 Potassium Channel/drug effects , KCNQ3 Potassium Channel/drug effects , Pyridines/pharmacology , Animals , CHO Cells , Cell Culture Techniques , Cell Line , Cell Line, Tumor , Cricetinae , Cricetulus , Dose-Response Relationship, Drug , Electrophysiology , Hippocampus/metabolism , Humans , Inhibitory Concentration 50 , Kidney/cytology , Male , Membrane Potentials/drug effects , Microelectrodes , Neuroblastoma/pathology , Patch-Clamp Techniques , Plasmids , RNA, Messenger/analysis , Rats , Rats, Sprague-Dawley , Sensitivity and Specificity
2.
J Med Chem ; 39(24): 4692-703, 1996 Nov 22.
Article in English | MEDLINE | ID: mdl-8941382

ABSTRACT

Heterocyclic analogues of 1192U90, 2-amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)-butyl) benzamide hydrochloride (1), were prepared and evaluated as potential antipsychotic agents. These analogues were evaluated in vitro for their binding to the dopamine D2, serotonin 5-HT2, and serotonin 5-HT1a receptors and in vivo for their ability to antagonize the apomorphine-induced climbing response in mice. Nine different types of heterocyclic carboxamides were studied in this investigation (i.e., pyridine-, thiophene-, benzothiophene-, quinoline-, 1,2,3,4-tetrahydroquinoline-, 2,3-dihydroindole-, indole-, benzimidazole-, and indazolecarboxamides). Two derivatives exhibited potent in vivo activities comparable to 1: 3-amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-2 -pyridinecarboxamide (16) and 3-amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl) -2-thiophenecarboxamide (29). Furthermore, these derivatives were found to be much less active in behavioral models predictive of extrapyramidal side effects than in the mouse climbing assay, which predicts antipsychotic activity. Carboxamides 16 and 29 were selected for further evaluation as potential backup compounds to 1.


Subject(s)
Piperazines/chemical synthesis , Thiazoles/chemical synthesis , Animals , Antipsychotic Agents/chemical synthesis , Antipsychotic Agents/metabolism , Antipsychotic Agents/pharmacology , Apomorphine/pharmacology , Benzamides/pharmacology , Clozapine/pharmacology , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/pharmacology , Magnetic Resonance Spectroscopy , Mice , Molecular Structure , Piperazines/metabolism , Piperazines/pharmacology , Raclopride , Receptors, Dopamine/metabolism , Receptors, Serotonin/metabolism , Risperidone/pharmacology , Salicylamides/pharmacology , Thiazoles/metabolism , Thiazoles/pharmacology
3.
Neuropsychopharmacology ; 15(3): 231-42, 1996 Sep.
Article in English | MEDLINE | ID: mdl-8873106

ABSTRACT

1192U90 was developed on the assumption that antagonism of 5-HT2 receptors efficacy yields more potently than D2 receptors against positive and negative symptoms of schizophrenia with minimal liability for extrapyramidal side effects (EPSs), and that 5-HT1A agonism further reduces EPSs and provides anxiolytic and antidepressant activity. 1192U90 was submitted to four tests that predict antipsychotic efficacy (antagonism of apomorphine-induced climbing in mouse, antagonism of apomorphine-induced circling in rats with unilateral 6-OHDA lesions, antagonism of amphetamine-induced hyperlocomotion in rat, and inhibition of conditioned avoidance in rat), two tests of 5-HT2 function (antagonism of 5-MeODMT-induced head twitches in mouse and antagonism of 5-HTP-induced wet dog shakes in rat), and three tests that predict EPS liability (antagonism of apomorphine-induced stereotypy in mouse and rat and induction of catalepsy in mouse). ED50s (mg/kg PO) were as follows: climbing 10.1, circling 7.9, hyperlocomotion 6.6, and avoidance 5.7; head twitches 5 and wet dog shakes 4.6; stereotypy in mouse 91.1, stereotypy in rat 133.4, and catalepsy 192.4. The ratio of ED50 for stereotypy antagonism to ED50 for climbing antagonism was 9 (compared to 4, 3, and 4 for clozapine, risperidone, and haloperidol). The ratio of ED50 for catalepsy induction to ED50 for climbing antagonism was 19 (compared to 7, 2, and 17 for clozapine, risperidone, and haloperidol). 1192U90 was also submitted to three tests that predict anxiolysis: It produced only a small increase in punished lever pressing for food in rat (Geller-Seifter conflict test), which is specific for rapid-onset efficacy, but produced large increases in punished key pecking for food in pigeon and cork gnawing in rat, which identify the delayed onset 5-HT1A agonists such as buspirone. The results suggest that 1192U90 would be effective for positive and negative symptoms of schizophrenia, with minimal liability for EPSs, and may also have anxiolytic properties.


Subject(s)
Antipsychotic Agents/pharmacology , Behavior, Animal/drug effects , Piperazines/pharmacology , Schizophrenia/physiopathology , Thiazoles/pharmacology , Animals , Columbidae , Male , Mice , Rats , Rats, Wistar
4.
J Med Chem ; 39(5): 1172-88, 1996 Mar 01.
Article in English | MEDLINE | ID: mdl-8676355

ABSTRACT

A series of substituted (4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)benzamide derivatives was prepared and evaluated as potential atypical antipsychotic agents. The target compounds were readily prepared from their benzoyl chloride, benzoic acid, or isatoic anhydride precursors, and they were evaluated in vitro for their ability to bind to dopamine D2, serotonin 5-HT2, and serotonin 5-HT1a receptors. To assess the potential antipsychotic activity of these compounds, we investigated their ability to inhibit the apomorphine-induced climbing response in mice. Selected compounds were evaluated further to determine their side-effect potentials. Structure-activity relationships of both mono- and polysubstituted benzamides are discussed herein. While several analogues had potent in vitro and in vivo activities indicative of potential atypical antipsychotic activity, anthranilamide 77 (1192U90) ddemonstrated a superior pharmacological profile. As a result of this investigation, 1192U90 (2-amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)ben zamide hydrochloride) was selected for further evaluation and is currently in phase I clinical trials as a potential atypical antipsychotic agent.


Subject(s)
Antipsychotic Agents/chemical synthesis , Piperazines/chemical synthesis , Receptors, Dopamine D2/metabolism , Receptors, Serotonin/metabolism , Serotonin Receptor Agonists/chemical synthesis , Thiazoles/chemical synthesis , Animals , Antipsychotic Agents/metabolism , Antipsychotic Agents/pharmacology , Apomorphine/pharmacology , Mice , Molecular Structure , Motor Activity/drug effects , Piperazines/metabolism , Piperazines/pharmacology , Serotonin Receptor Agonists/metabolism , Serotonin Receptor Agonists/pharmacology , Structure-Activity Relationship , Thiazoles/metabolism , Thiazoles/pharmacology
5.
J Med Chem ; 39(1): 149-57, 1996 Jan 05.
Article in English | MEDLINE | ID: mdl-8568802

ABSTRACT

A series of phthalimide and isoindolinone derivatives bridged to 4-(1,2-benzisothiazol-3-yl)-1-piperazinyl was prepared. The compounds were evaluated in vitro at dopamine D2 and serotonin 5-HT1a and 5-HT2 receptors and in vivo for their ability to antagonize the apomorphine-induced climbing response in mice. The effects of bridge length and conformation on the biological activity of these potential antipsychotic agents are discussed. A four-carbon spacer provided optimal activity within the two homologous series. Conformational investigations of the lead compound, isoindolinone 2, were conducted in an attempt to account for the superior activity observed for the butyl derivatives. On the basis of NMR and molecular modeling studies, two types of folded structures were proposed and several conformationally restrained analogues were synthesized. In general, restrictions incorporated within the linking bridge were detrimental to activity.


Subject(s)
Antipsychotic Agents/pharmacology , Indoles/pharmacology , Phthalimides/pharmacology , Animals , Antipsychotic Agents/chemical synthesis , Antipsychotic Agents/chemistry , Antipsychotic Agents/metabolism , Apomorphine/pharmacology , Binding, Competitive , Brain/drug effects , Brain/metabolism , Clozapine/pharmacology , Haloperidol/pharmacology , Indoles/chemical synthesis , Indoles/chemistry , Indoles/metabolism , Ketanserin/pharmacology , Magnetic Resonance Spectroscopy , Male , Mice , Molecular Conformation , Phthalimides/chemical synthesis , Phthalimides/chemistry , Phthalimides/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Dopamine D2/metabolism , Receptors, Serotonin/metabolism , Serotonin/metabolism , Serotonin Antagonists/pharmacology
6.
J Pharm Pharmacol ; 47(9): 775-81, 1995 Sep.
Article in English | MEDLINE | ID: mdl-8583392

ABSTRACT

403U76 (5-chloro-[[2-[(dimethylamino)methyl]phenyl]thio]benzene- methanol hydrochloride) is a potent, competitive, inhibitor of 5-hydroxytryptamine (5-HT) and noradenaline reuptake into rat brain synaptosomes. Inhibition of 5-HT uptake in-vivo by 403U76 was demonstrated by potentiation of the behavioural effects of 5-hydroxytryptophan in rats and mice and blockade of p-induced depletion of 5-HT in rats. The firing of 5-HT-ergic dorsal raphe neurons in rats was decreased after intravenous administration of low doses of 403U76 as would be predicted for a 5-HT uptake inhibitor. 403U76 antagonized tetrabenazine-induced sedation, an effect associated with inhibitors of noradrenaline uptake, but not with inhibitors of 5-HT uptake. Thus 403U76 affects noradrenergic as well as 5-HT-ergic neurotransmission in-vivo. Potential anxiolytic activity was indicated by reductions in isolation-induced vocalizations in neonates after 403U76 treatment. Low intravenous doses of 403U76 were well tolerated and had no sustained cardiovascular effects. There were no deleterious behavioural side-effects at active doses. Effects observed on isolated tissues or transmitter receptors occurred only at very high concentrations and were pharmacologically unimportant. Thus 403U76 can be considered a potential antidepressant/anxiolytic agent that is a potent, selective inhibitor of 5-HT and noradrenaline reuptake.


Subject(s)
Adrenergic Uptake Inhibitors/pharmacology , Benzyl Alcohols/pharmacology , Hemodynamics/drug effects , Norepinephrine/pharmacology , Selective Serotonin Reuptake Inhibitors/pharmacology , 5-Hydroxytryptophan/administration & dosage , 5-Hydroxytryptophan/pharmacology , Animals , Animals, Newborn , Benzyl Alcohols/administration & dosage , Binding, Competitive , Dogs , Electrophysiology , Fluoxetine/pharmacology , Fluvoxamine/pharmacology , Imipramine/pharmacology , Male , Mice , Neurons/cytology , Neurons/drug effects , Norepinephrine/metabolism , Raphe Nuclei/drug effects , Raphe Nuclei/metabolism , Rats , Rats, Sprague-Dawley , Selective Serotonin Reuptake Inhibitors/metabolism , Species Specificity , Synaptic Transmission/drug effects , Tetrabenazine/administration & dosage , Tetrabenazine/antagonists & inhibitors , Tetrabenazine/pharmacology , Vocalization, Animal/drug effects
7.
Life Sci ; 57(18): PL275-83, 1995.
Article in English | MEDLINE | ID: mdl-7475902

ABSTRACT

Binding of 3H-spiperone and 3H-raclopride to membranes of cells stably-transfected with a human dopamine D2 receptor clone was investigated, as was that of 3H-spiperone to those stably-transfected with a human D4 receptor clone. 3H-spiperone and 3H-raclopride labeled the same number of sites in the D2 receptor preparation. The inhibition of binding by clozapine, spiperone, (-) eticlopride, haloperidol and the novel substituted benzamide 1192U90 was also investigated. Clozapine and 1192U90 showed greater inhibition of 3H-raclopride binding than 3H-spiperone binding to the D2 receptor. Comparison with inhibition of 3H-spiperone binding to the D4 receptor revealed that clozapine and 1192U90 displayed apparent selectivity (as assessed by Ki ratios) for the D4 receptor when compared with binding of 3H-spiperone, but not 3H-raclopride, to the D2 receptor.


Subject(s)
Clozapine/pharmacology , Receptors, Dopamine D2/drug effects , Binding Sites , Cell Membrane/drug effects , Dopamine Antagonists/pharmacology , Dose-Response Relationship, Drug , Humans , Raclopride , Salicylamides/pharmacology , Spiperone/pharmacology
8.
J Med Chem ; 37(16): 2552-63, 1994 Aug 05.
Article in English | MEDLINE | ID: mdl-7914539

ABSTRACT

A series of novel 4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl) cyclic amides was prepared and evaluated as potential antipsychotic agents. The target compounds were examined in vitro for their binding affinities to the dopamine D2, serotonin 5-HT2, and serotonin 5-HT1a receptors and in vivo for their ability to antagonize the apomorphine-induced climbing response in mice. Derivatives that exhibited good D2/5-HT2 selectivity in vitro and good potency in vivo were selected for further evaluation in tests designed to assess their potential extrapyramidal side effect liability. Structural modifications discussed herein focus on the bicyclic amide subunit leading to the preparation of a variety of heterocyclic ring systems (i.e., phthalimide, isoindolinone, isoquinolinone, benzazepinone, indazolone, phthalazinone, 4-methyl phthalazinone, benzisothiazolone 1,1-dioxide, benzotriazinone, homophthalimide, benzisothiazolone, phthalazinedione, quinazoline, and saturated phthalazinones). The potency and selectivity within this series was found to be dependent on ring size, nature of the covalent linking unit, relative position of the functional groups, degree of unsaturation, and relative stereochemistry. In general, the cyclic benzamides examined in this investigation exhibited receptor binding activities indicative of potential atypical antipsychotic agents. Several of these derivatives possessed in vivo activities that suggest they would be useful in the treatment of schizophrenia and would have a low propensity to induce extrapyramidal side effects. Two potent analogues were identified and selected for further evaluation: 2-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-1-isoind olinone (31) and (+-)-cis-2-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)-butyl)- 4a,5,6,7,8,8a-hexahydro-1(2H)-phthalazinone hydrochloride (52).


Subject(s)
Antipsychotic Agents/chemical synthesis , Dopamine D2 Receptor Antagonists , Indoles/chemical synthesis , Phthalazines/chemical synthesis , Serotonin Antagonists , Thiazoles/chemical synthesis , Animals , Antipsychotic Agents/pharmacology , Apomorphine/pharmacology , Behavior, Animal/drug effects , Binding, Competitive , Catalepsy/chemically induced , Corpus Striatum/metabolism , Cyclization , Frontal Lobe/metabolism , Hippocampus/metabolism , Indoles/metabolism , Indoles/pharmacology , Isoindoles , Male , Mice , Molecular Structure , Motor Activity/drug effects , Phthalazines/metabolism , Phthalazines/pharmacology , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptors, Dopamine D2/metabolism , Receptors, Serotonin/metabolism , Structure-Activity Relationship , Thiazoles/metabolism , Thiazoles/pharmacology
9.
J Pharmacol Exp Ther ; 267(2): 852-7, 1993 Nov.
Article in English | MEDLINE | ID: mdl-8246159

ABSTRACT

Four different opioid receptor binding assays and three different isolated tissue studies were used to screen for delta receptor-selective nonpeptidic compounds. (+/-)-4-((alpha-R*)-alpha-((2S*,5R*)-4-Allyl-2,5- dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide (BW373U86) was a potent delta receptor-selective ligand in receptor binding assays. The Ki values were 1.8 +/- 0.4, 15 +/- 3, 85 +/- 4 and 34 +/- 3 nM for delta, mu, epsilon and kappa receptor binding sites, respectively. BW373U86 inhibited electrically evoked muscle contraction of mouse vas deferens with an ED50 value of 0.2 +/- 0.06 nM. This inhibitory effect of BW373U86 was antagonized by the delta receptor-selective antagonist naltrindole in a competitive manner: the Schild plot indicated a slope of 1 and a pA2 value of 9.43 (Ke = 3.7 x 10(-10) M), which is consistent with the high affinity of naltrindole in delta receptors. BW373U86 did not interact significantly with other receptors. BW373U86 inhibited the acoustic startle reflex after subcutaneous administration from 0.2- to 2-mg/kg doses in rats, and this inhibition was blocked by naltrindole. BW373U86 also induced a dose-dependent increase of locomotor activity in rats at similar doses. This effect was inhibited by naltrindole. These data suggest that BW373U86 is a potent and selective nonpeptidic delta agonist, and it elicits distinct in vivo pharmacological activities.


Subject(s)
Benzamides/pharmacology , Piperazines/pharmacology , Receptors, Opioid, delta/physiology , Amino Acid Sequence , Animals , Drug Hypersensitivity/etiology , Injections, Subcutaneous , Locomotion/drug effects , Male , Molecular Sequence Data , Motor Activity/drug effects , Nociceptors/drug effects , Rats , Rats, Sprague-Dawley , Rats, Wistar , Receptors, Opioid, delta/drug effects , Receptors, Opioid, delta/metabolism , Reflex, Acoustic/drug effects
10.
J Pharmacol Exp Ther ; 263(2): 486-93, 1992 Nov.
Article in English | MEDLINE | ID: mdl-1432685

ABSTRACT

Presentation of a nonstartling stimulus (prepulse) 100 msec before a startle-eliciting auditory stimulus (pulse) reduces startle reflex amplitude in mammals. Prepulse inhibition of acoustic startle reflex is smaller in schizophrenics than in nonschizophrenics, a phenomenon that has been hypothesized to reflect sensorimotor gating deficits underlying schizophrenic psychosis. Five 5-hydroxytryptamine1a (5-HT1a, serotonin) receptor agonists: 8-hydroxy-2-(di-n-propylamino) tetraline (8-OHDPAT), 5-methoxydimethyltryptamine, buspirone, gepirone and ipsapirone, were tested for effects on prepulse inhibition and startle reflex amplitude in rats. All five agents reduced prepulse inhibition at doses that had no effect on startle reflex amplitude or motor activity. Reduction of prepulse inhibition by 8-OHDPAT was antagonized by (-)propranolol, a 5-HT1a receptor antagonist, and partially by haloperidol, a dopamine D2 receptor antagonist, but not by ketanserin or methysergide, 5-HT2 receptor antagonists. 8-OHDPAT did not reduce prepulse inhibition in subjects pretreated with reserpine or tetrabenazine to deplete neuronal amines, but interpretation of this result is complicated because reserpine and tetrabenazine given alone reduced prepulse inhibition. The results indicate that 5-HT1a receptor agonists block prepulse inhibition of acoustic startle reflex, possibly via dopaminergic mechanisms.


Subject(s)
Reflex, Startle/drug effects , Serotonin Receptor Agonists/pharmacology , 8-Hydroxy-2-(di-n-propylamino)tetralin/antagonists & inhibitors , 8-Hydroxy-2-(di-n-propylamino)tetralin/pharmacology , Acoustic Stimulation , Animals , Buspirone/pharmacology , Dose-Response Relationship, Drug , Drug Interactions , Haloperidol/pharmacology , Male , Methoxydimethyltryptamines/pharmacology , Pyrimidines/pharmacology , Rats , Rats, Wistar , Receptors, Serotonin/drug effects , Schizophrenia/prevention & control , Serotonin Receptor Agonists/antagonists & inhibitors
12.
Psychopharmacology (Berl) ; 102(3): 419-21, 1990.
Article in English | MEDLINE | ID: mdl-2251339

ABSTRACT

Apomorphine disruption of prepulse inhibition (PPI) has been proposed as an animal model of sensorimotor gating deficits exhibited by schizophrenics. The effects of apomorphine on PPI of the acoustic startle reflex in male rats of Wistar and CD (Sprague-Dawley derived) strains were compared under identical test conditions. In Wistar rats, subcutaneous administration of 0.25-1.0 mg/kg apomorphine blocked PPI without affecting startle amplitude. In CD rats, apomorphine (0.3-3.0 mg/kg, SC) had no effect on PPI, but increased startle amplitude. Therefore, choice of rat strain is an important factor in the design of experiments studying apomorphine effects on PPI.


Subject(s)
Apomorphine/pharmacology , Reflex, Startle/drug effects , Acoustic Stimulation , Animals , Male , Rats , Rats, Inbred Strains , Species Specificity
13.
Neurotoxicol Teratol ; 11(2): 121-8, 1989.
Article in English | MEDLINE | ID: mdl-2733651

ABSTRACT

Administration of high doses of monosodium glutamate (MSG) to rats during the first postnatal week results in severe losses of retinal ganglion cells and interneurons in the retina. This study was conducted to determine what effect severe retinal damage would have upon the ontogeny of rat flash evoked potentials (FEPs) and the adult pattern reversal evoked potential (PREP). MSG (4 mg/g) or isotonic saline was administered to rat pups daily from postnatal day (PND) 2 until PND 9. FEPs were recorded following 2 stimulation frequencies from unanesthetized, unrestrained MSG treated and control rats on PND 15, PND 22, and PND 60 or older. PREPs were recorded from unanesthetized, restrained rats older than PND 60 from each treatment group. On PND 15, 9 of 12 control animals exhibited responses to light flashes, while only 4 of 13 MSG treated animals did so. All animals from both treatment groups exhibited FEPs on PND 22 and beyond. All FEP peak latencies were significantly increased in MSG treated animals with the magnitude of the effect being greater during development. Peak N1 amplitude was reduced in MSG treated animals by 50% or more at each age. Frequency x treatment interactions were observed on peak P2 and peak N3 latency, and a frequency x age x treatment interaction was observed on peak N3 amplitude. MSG treatment severely impaired the ability to generate PREPS. Only small responses to the pattern reversal stimulus could be detected and the normal PREP peaks could not be identified with confidence. Perinatal MSG treatment results in profound alterations in FEP ontogeny and the generation of PREPs.


Subject(s)
Evoked Potentials, Visual/drug effects , Glutamates/toxicity , Maternal-Fetal Exchange , Optic Nerve/pathology , Retina/pathology , Sodium Glutamate/toxicity , Aging , Animals , Evoked Potentials/drug effects , Female , Male , Optic Nerve/drug effects , Optic Nerve/growth & development , Photic Stimulation , Pregnancy , Rats , Retina/drug effects , Retina/growth & development
14.
Pharmacol Biochem Behav ; 30(2): 421-6, 1988 Jun.
Article in English | MEDLINE | ID: mdl-3174774

ABSTRACT

Discovering the neurotransmitters involved in the generation of flash evoked potentials (FEPs) would enhance the use of FEPs in screening for and assessment of neurological damage. Recent evidence suggests that the excitatory amino acids, glutamate and aspartate, may be transmitters in the visual system. Ketamine selectively antagonizes the actions of excitatory amino acids on n-methyl-d-aspartate receptors and may be administered systemically. Two experiments were designed to test the effects of ketamine on rat FEPs. First, the effects of ketamine (37, 75, 150 mg/kg) on FEPs recorded in light and dark backgrounds were investigated at a single (10 min) posttreatment interval. Ketamine administration resulted in dose-dependent alterations in FEP peak amplitudes and latencies. Peak P1 amplitude increased by a factor of 4, in a dose-dependent manner. Peak N1 virtually disappeared at 150 mg/kg. Peak P2 amplitude increased by 50%, but only in the light background, and only at 150 mg/kg. Second, ketamine (150 mg/kg) effects on FEPs were investigated 5 min and 30 min following administration. The decrease in peak N1 amplitude was maximal 5 min after administration and the amplitude was recovering at 30 min. The effects on peak P1 and peak N3 amplitudes were maximal 5 min after ketamine administration, but were not recovering 30 min postinjection. The various peak latencies were also affected differently. The possible role of glutamate or aspartate in the generation of rat FEPs is discussed.


Subject(s)
Evoked Potentials, Visual/drug effects , Ketamine/pharmacology , Animals , Body Temperature/drug effects , Dose-Response Relationship, Drug , Male , Photic Stimulation , Rats , Rats, Inbred Strains
15.
Int J Dev Neurosci ; 5(5-6): 447-54, 1987.
Article in English | MEDLINE | ID: mdl-3503515

ABSTRACT

The effects of age and stimulation frequency (0.2/sec, 1.0/sec, 2.0/sec, or 4.0/sec) on flash-evoked potentials (FEPs) were investigated in awake, unsedated, unrestrained rats. Animals were tested daily from postnatal day (PND) 8 to PND 20, and every 3 or 4 days thereafter until PND 41. On PND 9, a single negative wave (N1a) was observed following 0.2/sec flash presentation. Animals tested on PND 10 exhibited a positive wave (P2) following the return of peak N1a to baseline. On PND 13 another negative wave (N1) appeared on the leading shoulder of peak N1a. Peak N1 became the dominant negative wave on PND 14. Peak N1a merged into N1 and had disappeared by PND 19. Peak N3 was first observed as a negative shift following peak P2 on PND 15. Peaks N2 and P3 were not observed in the group average waveforms until PND 34. Peak latencies decreased through the fifth postnatal week. Peak amplitudes increased with age until after eye opening (PND 15), but were variable thereafter. No FEPs were observed following higher than 0.2/sec flash presentation until PND 13. Increasing stimulation frequency decreased N1 and P2 peak amplitudes, but had no effect on peak latencies.


Subject(s)
Aging/physiology , Cerebral Cortex/physiology , Evoked Potentials, Visual , Visual Cortex/physiology , Animals , Cerebral Cortex/growth & development , Female , Male , Photic Stimulation , Rats , Reaction Time/physiology , Visual Cortex/growth & development
16.
Physiol Behav ; 41(4): 327-30, 1987.
Article in English | MEDLINE | ID: mdl-3432386

ABSTRACT

Urethane is an anesthetic which is commonly used in neurophysiological studies because it is presumed to have minimal effects upon neuronal activity. This study investigated the influence of urethane anesthesia upon flash evoked potentials (FEPs) recorded from hooded rats. Subanesthetic dosages (25 g/kg and 0.5 g/kg) and an anesthetic dosage (1.0 g/kg) were administered, and subsequently recorded FEPs were compared to vehicle-injected controls. Urethane produced profound qualitative and quantitative effects upon the FEP. At 0.5 g/kg, the P1 (normal latency = 20 msec) and N1 (normal latency = 30 msec) peaks became unrecognizable. Peak N1 disappeared and peak P1 merged with P2 (normal latency = 45 msec). Peak P2 increased in amplitude by about 100%. The results indicate that in the visual system, urethane has a significant influence upon neuronal activity. Caution should be used in interpreting data obtained from urethane-anesthetized rats.


Subject(s)
Anesthesia , Evoked Potentials, Visual/drug effects , Urethane , Animals , Dose-Response Relationship, Drug , Male , Rats , Rats, Inbred Strains , Urethane/administration & dosage
17.
J Neurosci ; 6(9): 2535-42, 1986 Sep.
Article in English | MEDLINE | ID: mdl-3746421

ABSTRACT

Rat frontal cortex neurons exhibit alterations in firing in response to a 2 sec tone cue followed by rewarding medial forebrain bundle (MFB) stimulation. Nucleus basalis neurons supply up to 75% of the cortical cholinergic innervation. The nucleus basalis and ACh have been implicated as playing a role in cognitive function. Three experiments were designed to test the hypothesis that the nucleus basalis cholinergic system is involved in the generation of conditioned neuronal responses in the rat frontal cortex. Local microinjection of the cholinergic antagonist, atropine, into the frontal cortex suppressed the conditioned responses of 22 of 25 cortical single units. Unilateral kainic acid lesioning of the nucleus basalis resulted in a significant decrease in the proportion of units exhibiting conditioned responses in the cortex ipsilateral to the lesion (25%) compared to the proportion of responding units from the cortex of untreated animals (70%). When the firing rates of units encountered in the region of the nucleus basalis were monitored during presentation of the cue-MFB paradigm, 28 of 38 unit recordings exhibited significant increases or decreases in firing rate. Therefore, the results of the experiments indicate that the nucleus basalis cholinergic neurons are involved in the generation of conditioned neuronal responses in the rat frontal cortex.


Subject(s)
Basal Ganglia/physiology , Conditioning, Psychological/physiology , Frontal Lobe/physiology , Neurons/physiology , Substantia Innominata/physiology , Action Potentials/drug effects , Animals , Atropine/pharmacology , Choline O-Acetyltransferase/metabolism , Conditioning, Psychological/drug effects , Frontal Lobe/cytology , Frontal Lobe/enzymology , Injections , Kainic Acid/pharmacology , Male , Rats , Rats, Inbred Strains
18.
Electroencephalogr Clin Neurophysiol ; 63(5): 464-75, 1986 May.
Article in English | MEDLINE | ID: mdl-2420562

ABSTRACT

These experiments were conducted to gather information regarding the role of cholinergic innervation to the cortex in the generation of event-related slow potentials. The effects of unilateral drug treatments or lesions on ipsilateral and contralateral frontal cortex slow potential (SP) responses were examined in rats. The SP responses were recorded with silver-silver chloride electrodes and were generated by a 2 sec light cue which preceded rewarding medial forebrain bundle stimulation. The following approaches were used: microinjection of GABA, procaine or saline into the nucleus basalis magnocellularis; microinjection of atropine or saline subdurally in the SP recording area; electrolytic lesion of the nucleus basalis area; and kainic acid lesion of the nucleus basalis area. The following bilateral measurements were obtained lesion studies: choline acetyltransferase (ChAT) in cortex and hippocampus; serotonin in cortex, hippocampus, striatum and nucleus accumbens; norepinephrine in cortex and hippocampus; dopamine in striatum and nucleus accumbens; and metabolites of serotonin, norepinephrine and dopamine in these areas. The cortical SP responses were reduced on the side ipsilateral to the injections of GABA and procaine into the nucleus basalis, and on the side of the subdural atropine injection. With either type of lesion, the SP responses on the lesioned side were significantly reduced as compared to the non-lesioned side. Reductions in cortical ChAT and other measures were observed ipsilateral to the electrolytic lesion, but only cortical ChAT activity was reduced in the kainic acid-lesioned animals. Thus, pharmacological depression of nucleus basalis neurons, blockade of cholinergic muscarinic receptors in the cortex, and nucleus basalis lesions that reduce cortical choline acetyltransferase activity depress event-related slow potentials in the rat frontal cortex. These results provide evidence that cortical slow potential responses in the rat are dependent upon cholinergic innervation from the nucleus basalis.


Subject(s)
Acetylcholine/physiology , Electrophysiology , Frontal Lobe/physiology , Vestibular Nuclei/physiology , Action Potentials/drug effects , Animals , Atropine/pharmacology , Electroencephalography , Frontal Lobe/drug effects , Male , Rats , Rats, Inbred Strains , gamma-Aminobutyric Acid/pharmacology
19.
Int J Neurosci ; 25(3-4): 263-71, 1985 Jan.
Article in English | MEDLINE | ID: mdl-3872287

ABSTRACT

Responses of frontal cortex single units to a tone preceding medial forebrain bundle (MFB) stimulation were recorded in urethane anesthetized rats. The animals were implanted with monopolar electrodes for MFB stimulation and, following recovery, stimulation parameters which supported self-stimulation were determined for each rat. Prior to the unit recording experiment, the animals were trained to associate a 2-sec tone with MFB stimulation. Trials were presented at variable intervals. Under urethane anesthesia, single units were isolated and the responses of units to paired and unpaired tones were determined. The results indicate that conditioning-related responses of frontal cortex single units can be recorded in urethane anesthetized rats.


Subject(s)
Conditioning, Classical/drug effects , Frontal Lobe/drug effects , Medial Forebrain Bundle/drug effects , Neural Pathways/drug effects , Urethane/pharmacology , Anesthesia, General , Animals , Evoked Potentials, Auditory/drug effects , Extinction, Psychological/drug effects , Male , Rats , Rats, Inbred Strains
20.
Exp Neurol ; 85(2): 283-96, 1984 Aug.
Article in English | MEDLINE | ID: mdl-6086379

ABSTRACT

Male rats were chronically implanted for recording of single units in the frontal cortex during a cue-event paradigm. The rats were sedated and restrained during the experiments. Units were selected which had large-amplitude, clearly isolated action potentials. The animals were first trained to associated a 2-s tone cue with rewarding medial forebrain bundle stimulation. After training, units responded to the cue by an increase or decrease in discharge rate. Cumulative histograms of the unit response to the cue were obtained and then either procaine hydrochloride or GABA was microinjected into the nucleus basalis magnocellularis (nBM). Immediately after drug administration another histogram was obtained to ascertain the drug effect. Procaine microinjections to the nBM suppressed the frontal cortex unit responses in 9 of 10 units that had previously responded with an increase in firing rate and 10 of 12 units that had decreased their firing rate before drug administration. GABA microinjections antagonized the response in 15 of 19 excited units and 2 of 2 inhibited units. Recovery was obtained in 23 units. Other units did not remain isolated long enough to obtain complete recovery. The nBM supplies the frontal cortex with as much as 70% of its cholinergic innervation. Lesions of the region do not significantly alter the amounts of neurotransmitters other than acetylcholine in the frontal cortex. These results indicate that neurons in the nucleus basalis magnocellularis are involved in the cue-elicited changes in the rate of discharge of units in the rat frontal cortex.


Subject(s)
Brain Stem/physiology , Cues/physiology , Frontal Lobe/physiology , Procaine/administration & dosage , gamma-Aminobutyric Acid/administration & dosage , Action Potentials , Animals , Male , Microinjections , Rats , Rats, Inbred Strains , Synaptic Transmission/drug effects
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