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  • 1
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: (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.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1520-4804
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    Journal of neural transmission 96 (1994), S. 163-163 
    ISSN: 1435-1463
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1619-7089
    Keywords: Dopamine transporter ; NNC 12-0722 ; Carbon-11 ; Positron emission tomography ; In vitro autoradiography
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract NNC 12-0722 (1-[2-(bis(4-fluorophenyl)methoxy)ethyl]-4-methyl piperazine) is a new selective inhibitor of the dopamine transporter. [11C]NNC 12-0722 was prepared by N-methylation of the desmethyl compound with [11C]methyl iodide. The total radiochemical yield of [11C]NNC 12-0722 was 40%–50% with an overall synthesis time of 30–35 min. The radiochemical purity was higher than 99% and the specific radioactivity about 1500 Ci/mmol (55 GBq/μmol). Autoradiographic examination of [11C]NNC 12-0722 binding on whole hemisphere cryosections from human brain post mortem demonstrated specific binding in the caudate nucleus and putamen. In a positron emission tomographic examination of [11C]NNC 12-0722 in a cynomolgus monkey there was a rapid uptake of radioactivity in the brain. In the striatum, a region with a high density of dopamine transporters, the radioactivity was two times higher than in the cerebellum. These results indicate that [11C]NNC 12-0722 may be a useful radioligand for labelling of the dopamine transporter in man.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1432-1912
    Keywords: Key words: Halothane – Vanoxerine – GBR 12909 – d-Amphetamine – Dopamine uptake – Microdialysis – Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: 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.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1432-1912
    Keywords: Halothane ; Vanoxerine ; GBR 12909 ; d-Amphetamine ; Dopamine uptake ; Microdialysis ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: 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.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1432-2072
    Keywords: Continuous amphetamine ; Hallucinogens ; Limb flicks ; Shakes ; Grooming ; Model psychosis ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: 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.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1432-2072
    Keywords: Color discrimination ; Signal detection analysis ; LSD ; Amphetamine ; Morphine ; Haloperidol ; Pigeon
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: 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″).
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1432-2072
    Keywords: Amphetamine ; Apomorphine ; Neuroleptics ; Dopamine ; Drinking Behaviour ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: 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.
    Type of Medium: Electronic Resource
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  • 10
    Electronic Resource
    Electronic Resource
    Springer
    Psychopharmacology 54 (1977), S. 203-208 
    ISSN: 1432-2072
    Keywords: DRL' 15 schedule ; Flupenthixol ; Longterm treatment ; Homovanillic acid ; 3-Methoxy-4-hydroxyphenylglycol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: 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.
    Type of Medium: Electronic Resource
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