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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 302 (1978), S. 313-321 
    ISSN: 1432-1912
    Keywords: Receptors ; Serotonin ; 5-HT-Sensitive adenylate cyclase ; 5-HT High affinity binding ; 5-HT Turnover
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Since metergoline (1-methyl-8-beta-carbobenzyloxy-aminomethyl-10-alpha-ergoline) is a potent 5-HT antagonist in peripheral organs, its possible blocking effects on 5-HT receptors in the rat brain were investigated. In vitro, metergoline inhibited both the specific high affinity binding of 3H-5-HT onto synaptosomal membranes (IC 50=18 nM) and the stimulating effect of 10 μM 5-HT on the adenylate cyclase activity in colliculi homogenates from newborn rats (IC 50=12 μM). In vivo, the administration of metergoline (10 mg/kg i.p., 60 min before death) resulted in a significant decrease in the 3H-5-HT binding capacity of synaptosomal membranes from the forebrain of adult rats. Taken together, these data clearly indicated that metergoline is a potent blocker of some serotoninergic receptors in the rat brain. Surprisingly, the changes in 5-HT turnover occurring in the brainstem and in the forebrain 1 h after metergoline (2–10 mg/kg) treatment were similar to those normally induced by a central 5-HT agonist: both the rate of 5-HT utilisation and that of 5-HT synthesis were significantly decreased. These changes were in contrast to the acceleration of 5-HT turnover induced by the administration of another potent central 5-HT antagonist, methiothepin. These results are discussed in relation to the possible existence of several types of serotoninergic receptors in the rat brain. It is possible that the positive feedback regulation of 5-HT turnover is triggered by the blockade of serotoninergic receptors sensitive to methiothepin, but not to metergoline.
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 309 (1979), S. 241-245 
    ISSN: 1432-1912
    Keywords: DA receptor ; DA-sensitive adenylate cyclase ; ACh neurons ; Striatum ; DA drugs
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The dopamine (DA)-receptor mediated changes in striatal acetylcholine (ACh) levels have been studied to determine if this effect involves a D1-(adenylate cyclase dependent) or D2-(not linked to an adenylate cyclase) type of DA-receptor. Various DA-agonists (apomorphine, N-diphenethylamine derivatives) increased striatal ACh levels in both intact and 6-OHDA lesioned rats whereas only apomorphine stimulated the adenylate cyclase activity of striatal homogenates. The N-diphenethylamine compounds (RU 24213, RU 24926 and RU 26933) were without effect either on basal or DA-stimulated activities of this enzyme. In contrast, D-LSD (which acts as a partial agonist of the striatal DA-sensitive adenylate cyclase) did not modify the striatal ACh content. More interestingly, an intrastriatal injection of cholera toxin greatly stimulated striatal adenylate cyclase without altering ACh concentrations. Both haloperidol and methergoline antagonized the DA stimulation of adenylate cyclase, but only haloperidol decreased striatal ACh levels. These results indicate that the DA receptor involved in regulating the activity of striatal cholinergic neurons is of the D2-type.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-1912
    Keywords: Harmaline ; Striatal acetylcholine ; DA, 5-HT, GABA transmission ; DA and 5-HT sensitive adenylate cyclases
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Harmaline (10 mg/kg i.p. 45 min) increased acetylcholine (ACh) levels in the rat striatum but did not affect the ACh content of the parietal cortex, the hippocampus or certain limbic nuclei. This change in striatal ACh levels may reflect a decreased utilization of the transmitter. The selective effect of harmaline on striatal cholinergic neurones is probably mediated by interneuronal processes. Various hypotheses were examined: 1. The harmaline-induced increase in striatal ACh levels was not abolished after destruction of the nigrostriatal dopaminergic neurones. Harmaline (10−5 M or 10−4 M) and its metabolites (harmalol, harmine) also failed to modify the activity of the striatal dopamine-sensitive adenylate cyclase. This excludes any involvement of dopaminergic mechanisms in the action of harmaline on striatal cholinergic neurones. 2. The harmaline-induced increase in striatal ACh levels could not be prevented by diazepam (5 mg/kg i.p. 65 min). In contrast the increase in ACh content elicited by picrotoxin (25 mg/kg i.p. 60 min) was abolished by diazepam. Furthermore, the harmaline-and picrotoxin-induced rises in striatal ACh levels were additive. These results suggest that GABA mechanisms are not involved in the effect of harmaline on striatal cholinergic neurones. 3. Parachlorophenylalanine pretreatment (48 and 24 h, 300 mg/kg i.p.) which reduced striatal serotonin (5-HT) levels by 95%, failed to affect ACh levels in the striatum. The inhibitor of 5-HT synthesis did not prevent the harmaline-induced rise in ACh levels. Harmaline (10−5 M or 10−4 M), harmine and harmalol, did not stimulate the 5-HT sensitive adenylate cyclase in the colliculi of newborn rats. It is thus unlikely that harmaline reduces the activity of striatal cholinergic neurones by its effects on 5-HT transmission. Moreover, other monoamine oxidase inhibitors (pargyline and tranylcypromine) were also ineffective on cholinergic neurones.
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 294 (1976), S. 99-108 
    ISSN: 1432-1912
    Keywords: Quipazine ; Serotonin uptake ; MAO activity ; 5-HT sensitive adenylate cyclase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Since quipazine is a potent 5-HT agonist in peripheral organs, its possible stimulatory effects on serotoninergic receptors in the rat brain were investigated. Quipazine administration (10 mg/kg, i.p.) induced a significant decrease in the synthesis and turnover rates of serotonin in the brain stem as well as in the forebrain. It is not likely that these changes were mediated by a negative feed-back mechanism triggered by adirect action of quipazine on central 5-HT postsynaptic receptors. Indeed, in contrast to LSD and 5-methoxy-N,N-dimethyltryptamine, this compound failed to activate the 5-HT sensitive adenylate cyclase in colliculi homogenates of newborn rats. However, quipazine exerted direct effects on serotoninergic terminals. It inhibited competitively the reuptake process in synaptosomes (Ki =1.38×10−7 M) and stimulated the K+ evoked release of newly synthesized3H-5-HT in slices of the brain stem. Injected in vivo in a dose which affected 5-HT uptake and release, quipazine did not modify MAO activity. However, this activity was noncompetitively inhibited by high concentration of the drug in vitro (Ki=3.0×10−5 M). These actions are very likelyindirectly responsible for the stimulation of central 5-HT receptors.
    Type of Medium: Electronic Resource
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