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  • 1
    ISSN: 1471-4159
    Quelle: Blackwell Publishing Journal Backfiles 1879-2005
    Thema: Medizin
    Notizen: (R)-N-[4,4-Bis(3-methyl-2-thienyl)but-3-en-l-yl]nipecotic acid (NO 328) has previously been shown to be a potent anticonvulsant in both mice and rats. Here, we report that NO 328 is a potent inhibitor of γ-[3H]aminobutyric acid ([3H]GABA) uptake in a rat forebrain synaptosomal preparation (IC50= 67 nM) and in primary cultures of neurons and astrocytes. Inhibition of [3H]GABA uptake by NO 328 is apparently of a mixed type when NO 328 is preincubated before [3H]GABA uptake; the inhibition is apparently competitive without preincubation. NO 328 itself is not a substrate for the GABA uptake carrier, but NO 328 is a selective inhibitor of [3H]GABA uptake. Binding to benzodiazepine receptors, histamine H1 receptors, and 5-hydroxytryptaminelA receptors was inhibited by NO 328 at 5—30 μM, whereas several other receptors and uptake sites were unaffected. [3H]NO 328 showed saturable and reversible binding to rat brain membranes in the presence of NaCI. The specific binding of [3H]NO 328 was inhibited by known inhibitors of [3H]GABA uptake; GABA and the cyclic amino acid GABA uptake inhibitors were, however, less potent than expected. This indicates that the binding site is not identical to, but rather overlapping with, the GABA recognition site of the uptake carrier. The affinity constant for binding of [3H]NO 328 is 18 nM, and the Bmax is 669 pmol/g of original rat forebrain tissue. The regional distribution of NaCl-dependent [3H]NO 328 binding followed that of synaptosomal [3H]GABA uptake. It is concluded that NO 328 is a potent and selective inhibitor of neuronal and glial GABA uptake and that [3H]NO 328 is a useful radioligand for labeling the GABA uptake carrier in brain membranes. In the mouse brain in vivo, [3H]NO 328 likewise showed saturable and reversible binding that could be displaced by analogues of NO 328. Further studies are needed to demonstrate whether the uptake carrier is indeed labeled by [3H]NO 328 in vivo.
    Materialart: Digitale Medien
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  • 2
    ISSN: 1520-4804
    Quelle: ACS Legacy Archives
    Thema: Chemie und Pharmazie
    Materialart: Digitale Medien
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  • 3
    Digitale Medien
    Digitale Medien
    Springer
    Psychopharmacology 85 (1985), S. 80-86 
    ISSN: 1432-2072
    Schlagwort(e): Conditioned suppression ; Drug stimuli ; Stimulus control ; Overshadowing ; Classical conditioning ; Operant behavior ; Drugs ; Rat
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Rats were trained to press a lever under a variable-interval (VI) schedule of water reinforcement. After stable responding had developed, a 4.5-KHz tone (CS) was conditioned classically to a 2.5-mA electric shock (US) in groups of animals which had been given various psychoactive drugs or saline. Twenty-four hours later, a stimulus generalization test was conducted in the absence of drug; during this session, tones that varied in frequency around 4.5 KHz were presented while the animals were responding under the VI schedule. In animals conditioned under saline, all tones (non-differentially) suppressed responding which, however, recovered gradually over time. This suppressive effect was eliminated by lysergic acid diethylamide (LSD; 0.2 and 0.32 mg/kg), cocaine (20 mg/kg), diazepam (2.5 mg/kg), lisuride (0.08 mg/kg), mescaline (20 mg/kg) and 5-methoxy-N,N-dimethyltryptamine (4 mg/kg), and was attenuated by amphetamine (4 mg/kg), pentobarbital (15 mg/kg) and morphine (4 mg/kg). Atropine (10 mg/kg), scopolamine (1 mg/kg), clonazepam (0.5 mg/kg), and chlorpromazine (4 mg/kg) did not alter the suppressive effect of the tone. The serotonin antagonist BC-105 (6 mg/kg) reversed the effect of 0.2 mg/kg of LSD. These results suggest (1) that drug-induced stimuli may “overshadow” other (e.g., external) stimuli during classical conditioning and, (2) that drugs might affect behavior by altering processes (stimulus control or others) that do not simultaneously involve response or motor control.
    Materialart: Digitale Medien
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  • 4
    Digitale Medien
    Digitale Medien
    Springer
    Psychopharmacology 59 (1978), S. 85-89 
    ISSN: 1432-2072
    Schlagwort(e): flupenthixol ; Long-term treatment ; Cell loss ; Corpus striatum ; Neuroleptics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract The number of nerve cells in two different areas of the corpus striatum (i.e., ventrolateral and dorsomedial) was estimated in rat brain after long-term (36 weeks) treatment with the neuroleptic flupenthixol. Nine rats were given weekly injections of 4 mg/kg flupenthixol dissolved in Viscoleo® i.m., and seven rats received Viscoleo® alone. Fourteen to 18 weeks after the last drug injection, the animals were decapitated and half of each brain was fixated with formalin for cellcount analysis and the remaining half used for a biochemical analysis (Nielsen, 1977). Separate cell counts in the ventrolateral and dorsomedial corpus striatum yielded a significant cell loss of approximately 10%, but only in the ventrolateral striatum of treated animals. These results suggest at least one concrete anatomical basis for the behavioral and biochemical deficits found in the same animals, as reported earlier. The results further suggest that persistent irreversible anatomical changes can follow long-term neuroleptic treatment. The inconsistencies of results regarding cell loss in the corpus striatum may be due to neglect of dorsal-ventral structural differences in corpus striatum.
    Materialart: Digitale Medien
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  • 5
    Digitale Medien
    Digitale Medien
    Springer
    Psychopharmacology 80 (1983), S. 24-28 
    ISSN: 1432-2072
    Schlagwort(e): Color discrimination ; Signal detection analysis ; LSD ; Amphetamine ; Morphine ; Haloperidol ; Pigeon
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Six pigeons were trained in a chamber with three response keys. Following an observing response on the center key, either colored or noncolored (white) lights were projected on that key. A second center key observing response provided an opportunity to respond on one of the side keys, appropriate to the stimuli presented, to obtain food; responding on the incorrect side produced a 30-s time-out. A delay period of varying duration with no stimuli followed stimulus presentation; the length of the delay was determined ‘on-line’, such that performance would be maintained at about 80% correct. Lysergic acid diethylamide (LSD, 0.04–0.2 mg/kg) had no significant effect on the accuracy of the discrimination (overall percent conrrect responses), even at doses that produced cessation of responding in some animals. Amphetamine (1–4 mg/kg) and morphine (0.5–4 mg/kg) decreased accuracy by decreasing sensitivity (A') and had little effect on reaction time. Haloperidol (0.5–2 mg/kg) had no significant effect on any measure of performance. None of the drugs altered response bias (B″).
    Materialart: Digitale Medien
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  • 6
    Digitale Medien
    Digitale Medien
    Springer
    Psychopharmacology 68 (1980), S. 197-200 
    ISSN: 1432-2072
    Schlagwort(e): Continuous amphetamine ; Hallucinogens ; Limb flicks ; Shakes ; Grooming ; Model psychosis ; Rat
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Rats injected with LSD or mescaline show the behavioral syndrome which has been previously reported following injections of hallucinogens in higher mammals: limb flicks and whole body shakes. Although these behaviors are not elicited by acute injections of amphetamine, they are present in rats which have been pretreated for 108 h with a slow-release amphetamine pellet, given a 12h rest period, and then injected with d-amphetamine. Such pellet-pretreated animals also groom their body surface excessively. We propose that this novel syndrome which follows continuous amphetamine administration can serve as an animal model of the type of amphetamine psychosis that is produced by a similar drug regimen in humans.
    Materialart: Digitale Medien
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  • 7
    Digitale Medien
    Digitale Medien
    Springer
    Psychopharmacology 54 (1977), S. 203-208 
    ISSN: 1432-2072
    Schlagwort(e): DRL' 15 schedule ; Flupenthixol ; Longterm treatment ; Homovanillic acid ; 3-Methoxy-4-hydroxyphenylglycol
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract The effects of long-term treatment (36 weeks) with a neuroleptic drug (flupenthixol) were investigated behaviourally and biochemically in rats. Sixteen rats were trained on a DRL (differential reinforcement of low rate) 15-s schedule until stable responding was obtained. During the following 36 weeks 9 rats were injected weekly with flupenthixol dissolved in Viscoleo® [4 mg/kg (i.m.)] and seven rats received Viscoleo® alone. During this perod the animals were not run on the DRL schedule. Retesting on DRL 7 weeks after the last drug injection yielded highly significant differences between the flupenthixol-treated animals and the controls. Thorough neurological examinations of the animals just preceding the retesting period also revealed some deficits in the flupenthixol-treated animals. At sacrifice, 14–18 weeks after the last drug injection, levels of homovanillic acid (HVA) were measured in the corpus striatum and total 3-methoxy-4-hydroxyphenylglycol (MOPEG) in the rest of the forebrain. The results indicate a nonsignificant increase of 25% in the dopamine metabolite HVA, while the noradrenergic metabolite MOPEG was significantly decreased by 14% in experimental animals. The possibility of persistent functional and biochemical effects produced by prolonged treatment with a neuroleptic drug is highlighted in the results presented here.
    Materialart: Digitale Medien
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  • 8
    ISSN: 1432-2072
    Schlagwort(e): Amphetamine ; Apomorphine ; Neuroleptics ; Dopamine ; Drinking Behaviour ; Rat
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Hypodipsia produced by injection of d-amphetamine (2.0 mg/kg) or apomorphine (0.8 mg/kg) in rats, was partially antagonized by two DA-specific neuroleptic drugs, Pimozide and Spiramide, respectively. Pimozide revealed a maximal amphetamine-antagonistic effect at dose levels between 0.1–0.4 mg/kg. Hypodipsia could also be produced by Pimozide alone in doses greater than 1.0 mg/kg. Pretreatment of the apomorphine-induced hypodipsia with 0.05 mg/kg Spiramide also reliably counteracted drinking deficits. The interaction of water deprivation combined with the presence or absence of food in the test situation was also examined, but no effect was found. The possibility that perseverative rearing on the hind legs under d-amphetamine might interfere with drinking was tested with high vs. low drinking-tubes in the Pimozide-amphetamine experiments. There was evidence for a slight initial effect of drinking position, but the general form of the dose-response curve was not greatly altered. It was concluded that dopamine effects cannot easily be excluded from a role in the control of drinking, and that the primary role often accorded norepinephrine in relation to amphetamine effects should be re-examined with respect to the specific behavioural functions which are altered.
    Materialart: Digitale Medien
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  • 9
    ISSN: 1432-1912
    Schlagwort(e): Key words: Halothane – Vanoxerine – GBR 12909 – d-Amphetamine – Dopamine uptake – Microdialysis – Rat
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract. The anesthetic, isoflurane, has been shown to potentiate the ability of the dopamine (DA)-uptake inhibitor, nomifensine, to increase the brain interstitial dopamine level ([DA]e). Since the effect of the more commenly used anesthetic, halothane, on this system is unknown, we determined [DA]e by microdialysis in the striatum of rats, conscious or anesthetized with halothane, in the presence of the more selective DA uptake inhibitor, vanoxerine (GBR 12909), or the DA releaser, d-amphetamine. Basal [DA]e was not changed by halothane. However, in halothane-anesthetized rats, the vanoxerine (3 mg/kg i.v.)-induced DA response increased severalfold compared to the response in conscious rats. The initial peak response to d-amphetamine (1 mg/kg i.v.) did not change, but the late response (1–3 h after injection) was augmented in anesthetized rats. Halothane is believed to increase firing of DA neurons in the substantia nigra and, hence, to release striatal DA. We hypothesize that [DA]e is maintained at a normal level during the increased firing by equally increased activity of the DA transporter. However, when the DA transporter is blocked by vanoxerine, the increased DA release is unimpaired and [DA]e rises.
    Materialart: Digitale Medien
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  • 10
    ISSN: 1432-1912
    Schlagwort(e): Halothane ; Vanoxerine ; GBR 12909 ; d-Amphetamine ; Dopamine uptake ; Microdialysis ; Rat
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract The anesthetic, isoflurane, has been shown to potentiate the ability of the dopamine (DA)-uptake inhibitor, nomifensine, to increase the brain interstitial dopamine level ([DA]e). Since the effect of the more commenly used anesthetic, halothane, on this system is unknown, we determined [DA]e by microdialysis in the striatum of rats, conscious or anesthetized with halothane, in the presence of the more selective DA uptake inhibitor, vanoxerine (GBR 12909), or the DA releaser, d-amphetamine. Basal [DA]e was not changed by halothane. However, in halothane-anesthetized rats, the vanoxerine (3 mg/kg i.v.)-induced DA response increased severalfold compared to the response in conscious rats. The initial peak response to d-amphetamine (1 mg/kg i.v.) did not change, but the late response (1–3 h after injection) was augmented in anesthetized rats. Halothane is believed to increase firing of DA neurons in the substantia nigra and, hence, to release striatal DA. We hypothesize that [DA]e, is maintained at a normal level during the increased firing by equally increased activity of the DA transporter. However, when the DA transporter is blocked by vanoxerine, the increased DA release is unimpaired and [DA]e rises.
    Materialart: Digitale Medien
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