piperidines and 4-(5-6-dimethyl-2-benzofuranyl)piperidine

The specific effects of a neonatal treatment of rats with the noradrenergic neurotoxin DSP-4 were investigated in the adult rat by measuring monoamine and peptide transmitter levels in eight brain regions. When applied concomitantly with a 5-hydroxytryptamine uptake blocker, neonatal DSP-4 induced a selective depletion of noradrenaline (NA) in cortex, hippocampus and amygdala. An increase of NA was observed in the medulla and substantia nigra/ventral tegmental area and a decrease in dopamine was observed in the thalamus. The vasoactive intestinal polypeptide levels were markedly elevated in the DSP-4 treated rats in almost all CNS regions whereas those of three other neuropeptides remained unchanged. It is concluded that certain adaptational changes can be observed in the peptide systems of the CNS upon disruption of the development of the noradrenergic innervation.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Benzylamines; Brain; Dopamine; Neuropeptides; Neurotoxins; Neurotransmitter Agents; Norepinephrine; Piperidines; Rats; Rats, Inbred Strains; Serotonin Antagonists; Sympathectomy, Chemical

The effect of oxaprotiline (OXA) enantiomers--of which (+)-OXA inhibits noradrenaline (NA) uptake, whereas (-)-OXA does not--on the secretion of adrenocorticotropin hormone (ACTH) and corticosterone was studied in rats. Both enantiomers dose-dependently and with a similar potency increased the plasma level of ACTH and corticosterone, the effect of (-)-OXA on corticosterone being of a longer duration. The stimulation of ACTH secretion and the inability of (+)- and (-)-OXA to increase the plasma corticosterone concentration in animals pretreated with dexamethasone indicate that secretion of the latter hormone results from the action of the enantiomers at a level superior to the adrenal cortex, i.e. the hypothalamus/pituitary. The corticosterone response to (+)- or (-)-OXA was not modified in rats with a selective lesion of NA nerve endings induced by the neurotoxin DSP-4, nor was it affected by the selective alpha 1-antagonist prazosin, the selective alpha 2-antagonist yohimbine, the mixed alpha 1/alpha 2-antagonist phentolamine, the selective dopamine (D2) receptor antagonist sulpiride and the non-selective 5-hydroxytryptamine (5-HT) receptor antagonist metergoline. These results indicate that neither the NA system nor D2 and 5-HT receptors are involved in the hormonal response to the OXA enantiomers. Although the (+)- and (-)-OXA-induced stimulation of corticosterone secretion was not antagonized by diazepam, ipsapirone, naloxone, or propranolol, it cannot be excluded that both these enantiomers act as non-specific stressors.

Topics: Adrenergic alpha-Antagonists; Adrenocorticotropic Hormone; Animals; Antidepressive Agents; Benzylamines; Corticosterone; Dexamethasone; Diazepam; Dose-Response Relationship, Drug; Male; Maprotiline; Metergoline; Naloxone; Piperidines; Pyrimidines; Radioimmunoassay; Rats; Rats, Inbred Strains; Serotonin Antagonists; Stereoisomerism; Sulpiride; Sympathomimetics

CGP 6085 A, a specific 5-hydroxytryptamine (5-HT), serotonin uptake inhibitor, is also a potent hypotensive agent. Its depressor effect in the spontaneously hypertensive (SH) rats correlates well with its ability to inhibit serotonin uptake. Here we report that the effects of CGP 6085 A on arterial blood pressure were greatly reduced in rats pretreated with p-chlorophenylalanine (pCl-Phe), a specific depletor of serotonin. Moreover, in rats pretreated with the serotonin antagonist, methysergide, CGP 6085 A did not produce significant hypotension. We also found that centrally administered naloxone reverses the hypotensive effect of CGP 6085 A. These results provide further evidence for the existence of an important serotonin-opioid interaction in the mechanisms of arterial blood regulation in the rat.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Fenclonine; Male; Methysergide; Naloxone; Piperidines; Rats; Serotonin; Serotonin Antagonists

CGP 6085 A [4-(5,6-dimethyl-2-benzofuranyl)piperidine] HCl, a known serotonin inhibitor, also inhibits rat brainstem monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B) in both in vivo and in vitro experiments. Serotonin (5-HT) deamination by MAO-A is inhibited 35% at a dose of 100 mg/kg i.p. in vivo. Similar experiments show a maximal 20% decrease in phenylethylamine (PEA) deamination by MAO-B at a dosage of 30 mg/kg i.p. Over the range of 0.1 to 10 mg/kg i.p., CGP 6085 A decreases 5-HIAA levels in the brainstem. This in vivo inhibition of MAO activity is confirmed by in vitro experiments. In vitro studies in rat brainstem mitochondrial preparations show a dose-dependent, reversible, inhibition of MAO using tyramine as the substrate for the enzyme reaction. With an in vitro IC50 of 2-3 microM, the potency of CGP 6085 A is comparable to pargyline.

Topics: Animals; Brain Stem; Hydroxyindoleacetic Acid; Male; Mitochondria; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Pargyline; Phenethylamines; Piperidines; Rats; Rats, Inbred WKY; Serotonin; Tyramine

Changes in the density of beta- and alpha 1-adrenoceptors were studied following denervation of the rat cerebral cortex and hippocampus, caused by systemic administration of DSP-4. The noradrenergic denervation increased both beta- and alpha 1-adrenoceptor density by about 30 and 17%, respectively in the cortex, and by about 30% in the hippocampus. In order to estimate the behavioral response of normal and DSP-4-treated rats to alpha 1-agonist, the influence of phenylephrine (25 micrograms ICV) on the exploratory activity of rats in the open field was measured. Phenylephrine failed to change the exploratory activity of normal rats, but significantly increased it in DSP-4 animals. The results indicate that noradrenergic denervation produces an increase in number of both beta- and alpha 1-adrenoceptors and the functional supersensitivity to the alpha 1-adrenergic agonists.

Topics: Animals; Benzylamines; Cerebral Cortex; Denervation; Exploratory Behavior; Hippocampus; Injections, Intraventricular; Male; Norepinephrine; Phenylephrine; Piperidines; Radioligand Assay; Rats; Rats, Inbred Strains; Receptors, Adrenergic, alpha; Receptors, Adrenergic, beta

CGP 6085 A, [4-(5,6-dimethyl-2-benzofuranyl)piperidine HCl], has been found to be a mild to moderately potent hypotensive agent. One hour following CGP 6085 A administration (10 mg/kg, i.p.), a maximal reduction in blood pressure of approximately 20-30 mm Hg is observed in spontaneously hypertensive rats. The maximal reduction in blood pressure was observed at a dose of 3 mg/kg. CGP 6085 A blocks 5-HT uptake in the brainstem when assessed in vivo by use of the serotonin depletor, H 75/12 (3-hydroxy-4-methyl-alpha-ethyl-phenylethylamine). The maximal inhibitory effect on 5-HT uptake occurred at 10 mg/kg CGP 6085 A. The reduction in blood pressure correlates well with the ability of the drug to inhibit 5-HT uptake as assayed by H 75/12, with a correlation coefficient of 0.71 for SH rats. However, since the drug has not been widely characterized, alternate explanations for the cardiovascular pharmacological properties of CGP 6085 A are also proposed.

Topics: Amphetamines; Animals; Blood Pressure; Brain Stem; Heart Rate; Hydroxyindoleacetic Acid; Hypertension; Male; Nitroprusside; Piperidines; Rats; Rats, Inbred SHR; Serotonin

The effects of serotonin (5-hydroxytryptamine; 5-HT) antagonists and 5-HT uptake inhibitors on the behavioral response to amphetamine and haloperidol in monkeys (cercopithecus aethiops) were investigated. Amphetamine increased locomotor activity and reactivity and induced repetitive movements of head, limbs and trunk, but no oral hyperkinesia. Haloperidol induced dystonia and parkinsonism. Pretreatment with the 5-HT antagonists cyproheptadine and mianserin increased amphetamine-induced locomotor activity, reactivity and repetitive movements and decreased haloperidol-induced dystonia and parkinsonism. Conversely the 5-HT uptake inhibitors paroxetine and CGP 6085 A decreased amphetamine-induced repetitive movements and aggravated haloperidol-induced dystonia and parkinsonism. The 5-HT uptake inhibitors produced oral hyperkinesia resembling human tardive dyskinesia, which was intensified by amphetamine and blocked by haloperidol. These findings support the suggestion that 5-HT inhibits dopamine functions and may imply that 5-HT antagonists could have a beneficial effect against acute extrapyramidal side-effects of neuroleptic treatment. 5-HT uptake inhibitors in the monkey may serve as a model for tardive dyskinesia.

Topics: Animals; Chlorocebus aethiops; Cyproheptadine; Dextroamphetamine; Dopamine; Dyskinesia, Drug-Induced; Female; Haloperidol; Male; Mianserin; Motor Activity; Piperidines; Serotonin; Serotonin Antagonists

CGP 6085 A [4-(5,6-dimethyl-2-benzofuranyl) piperidine HCl], a reported serotonin uptake and MAO (16) inhibitor, is a potent hypothermic agent. The hypothermic action of CGP 6085 A is dose dependent with a maximal reduction in rectal core temperature of greater than 1 degree C within one hour after drug administration. Fluoxetine and citalopram elicit a similar response at equal doses. These results suggest that inhibition of serotonin uptake may produce the hypothermic effect. To assess the in vivo action of CGP 6085 A in inhibiting hypothalamic serotonin uptake, CGP 6085 A (10 mg/kg) was injected one hour prior to injection of 3-hydroxy-4-methyl-alpha-ethyl-phenylethylamine (H75/12), a serotonin depletor. The ability of CGP 6085 A to block the uptake of H75/12 by the 5HT uptake system was indicative of its ability to block serotonin uptake. Pretreatment with p-chlorophenylalanine (pCPA), an inhibitor of serotonin synthesis, resulted in the loss of the hypothermic response to CGP 6085 A. Thus, these data are consistent with the idea that CGP 6085 A may produce its hypothermic response by inhibiting serotonin uptake.

Topics: Amphetamines; Animals; Body Temperature; Dose-Response Relationship, Drug; Fenclonine; Hypothalamus; Kinetics; Male; Piperidines; Rats; Rats, Inbred Strains; Serotonin; Serotonin Antagonists

Following long-term in vivo treatment of rats with methiothepin (a serotonin autoreceptor antagonist) or with clorgyline (a monoamine oxidase A inhibitor) plus CGP 6085A (a selective serotonin uptake inhibitor), the release of [3H]serotonin evoked by high-K+ from the cortical synaptosomes was inhibited by exogenous serotonin respectively more or less than following acute treatment with the drugs. The autoreceptor subsensitivity disappeared 10 days after drug withdrawal. The results indicate that, after long-term blockade or stimulation, serotonin autoreceptors become respectively hyper- or hyposensitive towards serotonin.

Topics: Animals; Cerebral Cortex; Clorgyline; Male; Methiothepin; Piperidines; Potassium; Rats; Rats, Inbred Strains; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Synaptosomes; Time Factors

Rats treated with DSP-4 showed a marked enhancement of shock-induced fighting (SIF). Administration of 1-propranolol attenuated or completely counteracted SIF in control animals, but only the highest dose (10 mg/kg) of this beta-adrenergic antagonist was effective in reducing SIF in DSP-4 animals. Other behavioral experiments indicated that the responsiveness of DSP-4 rats to dopaminergic, serotoninergic, and cholinergic agonists was unchanged compared to that of control rats. The results confirm the participation of the noradrenergic system in SIF, and substantiate an involvement of beta-adrenergic receptors in this kind of aggression.

Topics: 5-Hydroxytryptophan; Aggression; Amines; Animals; Benzylamines; Drug Interactions; Electroshock; Humans; Male; Neurotoxins; Norepinephrine; Oxotremorine; Piperidines; Propranolol; Rats; Rats, Inbred Strains; Stereotyped Behavior

The sensitivity of rostral and cingulate cortical neurons to microiontophoretically administered serotonin (5-HT) was compared in groups of rats treated either acutely or chronically for different periods with various drugs. The drugs used were: desipramine (10 mg/kg), clomipramine (10 mg/kg), CGP 6085 (10 mg/kg), clorgyline (0.3 mg/kg), and deprenyl (1 mg/kg). Serotonin and, in some instances, gamma-aminobutyric acid (GABA) were applied microiontophoretically over periods of 60 sec with various ejection currents to spontaneously active neurons in the rostral and cingulate cortex. Of all the compounds tested, only clorgyline produced a marked desensitization to 5-HT in both cortical areas. After prolonged treatment with all the other drugs, no change in the sensitivity to serotonin was observed. The desensitization to 5-HT induced by clorgyline developed after 4 to 10 days of treatment. The responsiveness of these cells to GABA was unchanged after chronic exposure to clorgyline. The present results are consistent with those biochemical studies showing that chronic treatment with 5-HT-uptake-blocking compounds has no effect on 5-HT-binding characteristics, as well as with the observation that prolonged treatment with the monoamine-oxidase A-type blocker clorgyline reduces the number of 5-HT-binding sites.

Topics: Animals; Benzofurans; Cerebral Cortex; Clomipramine; Clorgyline; Desipramine; Electric Conductivity; gamma-Aminobutyric Acid; Male; Monoamine Oxidase Inhibitors; Neurons; Piperidines; Rats; Selegiline; Serotonin; Serotonin Antagonists

Potentiation of the effect of haloperidol on dopamine metabolism by the 5-HT uptake inhibitor CGP 6085 A, and antagonism of this effect by the 5-HT antagonist mianserin were observed in the mesolimbic area and the frontal cortex of the rat brain. A similar effect was reported earlier in the corpus striatum. This suggests that serotoninergic modulation of dopamine neurons is a generally-occurring phenomenon in the brain.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Benzofurans; Cerebral Cortex; Corpus Striatum; Dopamine; Fenclonine; Haloperidol; Homovanillic Acid; Limbic System; Mianserin; Neurons; Organ Specificity; Piperidines; Rats; Serotonin

Topics: Aggression; Animals; Benzofurans; Brain; Electric Stimulation; Humans; Male; Mesencephalon; Mice; Piperidines; Quipazine; Raphe Nuclei; Rats; Receptors, Serotonin; Serotonin

Topics: Animals; Benzofurans; Blood Platelets; Brain; Dopamine; Humans; Hydroxyindoleacetic Acid; In Vitro Techniques; Liver; Monoamine Oxidase; Myocardium; Norepinephrine; Piperidines; Rats; Serotonin; Serotonin Antagonists; Synaptosomes; Time Factors

The potentiation of the effect of haloperidol on rat striatal homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) by a serotonin (5-HT) uptake inhibitor, CGP 6085 A, has been further investigated. The evidence that this effect of CGP 6085 A is related to its 5-HT uptake inhibitory properties is discussed. The potentiation was antagonized by scopolamine and baclofen, and disappeared more rapidly than the uptake inhibitory effects of CGP 6085 A, presumably because the effects of uptake inhibition were counteracted by a reduction in 5-HT synthesis. CGP 6085 A also potentiated the effects of fluphenazine and pimozide, but not those of a number of other neuroleptics. It also failed to restore the effect of haloperidol in animals treated chronically with the neuroleptic. These results appear to indicate that CGP 6085 A can only stimulate DA neurons if their activity is already above the resting level. The antagonism of this effect by scopolamine suggests that the site of action of the 5-HT uptake inhibitor is before a cholinergic neuron.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Baclofen; Benzofurans; Corpus Striatum; Dopamine; Female; Haloperidol; Homovanillic Acid; Piperidines; Rats; Scopolamine; Serotonin Antagonists; Time Factors

The effects of two new compounds, 1-(1-methylamino-2-hydroxy-3-propyl)-dibenzo[b,e]bicyclo[2,2,2]octadiene-HCl (C 49802-B-Ba) and 4-(5,6-dimethyl-2-benzofuranyl) piperidine HCl (CGP 6085 A), on noradrenaline (NA) and serotonin (5-HT) uptake were investigated in different test systems, CGP 6085 A is a very potent and selective inhibitor of 5-HT uptake in rat brain (ED50 1-4 mg/kg p.o., depending on test system). Doses up to 1000 mg/kg p.o. did not inhibit NA uptake. C 49802-B-Ba is a potent and selective inhibitor of NA uptake in rat brain (ED50 5-10 mg/kg p.o. depending on test system) and heart (ED50 1.5 mg/kg p.o.). At 300 mg/kg p.o., this compound caused no inhibition of 5-HT uptake.

Topics: Animals; Benzofurans; Brain; Bridged Bicyclo Compounds; Bridged-Ring Compounds; Depression, Chemical; Female; In Vitro Techniques; Myocardium; Norepinephrine; Piperidines; Rats; Serotonin