zimeldine and nisoxetine

Topics: Albuterol; Animals; Antidepressive Agents; Brompheniramine; Bupropion; Clinical Trials as Topic; Depressive Disorder; Dibenzocycloheptenes; Drug Evaluation, Preclinical; Fluoxetine; History, 20th Century; Humans; Monoamine Oxidase Inhibitors; Propiophenones; Psychopharmacology; Receptors, Adrenergic; Receptors, Serotonin; Trazodone; Zimeldine

Topics: Albuterol; Animals; Antidepressive Agents; Brompheniramine; Bupropion; Clinical Trials as Topic; Depressive Disorder; Dibenzocycloheptenes; Drug Evaluation, Preclinical; Fluoxetine; History, 20th Century; Humans; Monoamine Oxidase Inhibitors; Propiophenones; Psychopharmacology; Receptors, Adrenergic; Receptors, Serotonin; Trazodone; Zimeldine

The discriminative-stimulus effects of cocaine have been reported to be mediated by indirect agonist actions initiated by the blockade of dopamine uptake, and the potencies of drugs that have discriminative-stimulus effects like cocaine are directly related to their dopamine transporter binding affinities. The binding to the dopamine transporter by cocaine and many of its analogs has been reported to fit better using a two-site model than a one-site model.. The present study examined the relationship among binding affinities of dopamine uptake inhibitors at these two sites and their potencies to produce discriminative-stimulus effects.. The inhibition constants (K(i) values) were derived for unlabeled dopamine uptake inhibitors for displacement of [(3)H]WIN 35,428 from rat caudate putamen membranes. These K(i) values were related to the ED(50) values obtained in rats trained to discriminate 10 mg/kg cocaine from saline injections under a fixed-ratio 20 schedule of food reinforcement.. Among the dopamine uptake inhibitors studied, the binding data for eight compounds (WIN 35,428, nomifensine, WIN 35,981, WIN 35,065-2, methylphenidate, cocaine, cocaethylene, and bupropion) were better fit by a two-site model than a one-site model. The data for the remaining eleven compounds (RTI-31, RTI-55, RTI-121, RTI-32, LU19-005, BTCP, GBR12909, GBR12935, mazindol, LU17-133, and EXP561) were better fit by a one-site model. Of the drugs that were fit best by a two-site model, there was a higher correlation among the K(i) values for the high-affinity site and the ED(50) values (R(2)=0.655; P=0.015) than there was for the low-affinity site (R(2)=0.543; P=0. 037). Of the remaining drugs, there was a high correlation among the K(i) values and the ED(50) values for the discriminative-stimulus effects (R(2)=0.523; P=0.012).. These data suggest that the discriminative-stimulus effects of cocaine are more closely related to actions mediated by high-affinity binding to the dopamine transporter than they are to actions mediated by the low-affinity site. The further assessment of the respective contributions of high- and low-affinity binding to the behavioral effects of cocaine will be greatly enhanced with the development of pharmacological tools that have a high degree of selectivity for one of these components.

Topics: Animals; Binding, Competitive; Carrier Proteins; Caudate Nucleus; Cocaine; Dopamine Plasma Membrane Transport Proteins; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Fluoxetine; Male; Membrane Glycoproteins; Membrane Transport Proteins; Membranes; Nerve Tissue Proteins; Psychomotor Performance; Putamen; Rats; Rats, Sprague-Dawley; Selective Serotonin Reuptake Inhibitors; Tritium; Zimeldine

The effects of GBR-12909 (selective DA uptake inhibitor), zimelidine (selective 5-HT uptake inhibitor) and nisoxetine (selective NE uptake inhibitor) on the uptake of 30 nM [3H]DA into cultured rat astrocytes were examined. [3H]DA uptake was inhibited by approximately 50% by GBR-12909 or zimelidine in a concentration-dependent manner (100 nM to approximately 10 microM). Furthermore, the inhibition curves of GBR-12909 were biphasic, and uptake was completely inhibited by a high concentration of GBR-12909 (100 microM). [3H]DA uptake was also inhibited by approximately 50% by nisoxetine in a concentration-dependent manner (0.1 to approximately 100 nM), and nisoxetine was more potent than GBR-12909 or zimelidine. The inhibitory potencies were in the order nisoxetine > GBR-12909 > zimelidine. The uptake of [3H]DA under Na+-free conditions was approximately 50% of that under normal conditions. Thus, DA was taken up by both Na+-dependent and Na+-independent mechanisms. Nisoxetine (100 nM), zimelidine (100 microM) and GBR-12909 (10 microM) inhibited [3H]DA uptake into astrocytes only in the presence of Na+. On the other hand, this uptake was completely inhibited by a high concentration of GBR-12909 (100 microM) in the absence of Na+. The present data suggest that the Na+-dependent uptake of [3H]DA in cultured rat astrocytes may occur in the NE uptake system. Furthermore, astrocytes express the extraneuronal monoamine transporter (uptake2), which is an Na+-independent system, and this transporter is involved in the inactivation of centrally released DA.

Topics: Animals; Astrocytes; Biological Transport, Active; Carrier Proteins; Cells, Cultured; Dopamine; Dopamine Uptake Inhibitors; Fluoxetine; Kinetics; Norepinephrine; Norepinephrine Plasma Membrane Transport Proteins; Piperazines; Rats; Selective Serotonin Reuptake Inhibitors; Sodium; Symporters; Zimeldine

The effects of antidepressant drugs on the synthesis of noradrenaline and serotonin (5-HT) were assessed using the accumulation of 3,4-dihydroxyphenylalanine (dopa) and 5-hydroxytryptophan (5-HTP) after decarboxylase inhibition as a measure of the rate of tyrosine and tryptophan hydroxylation in the rat brain in vivo. Three inhibitory synthesis-modulating receptors were investigated simultaneously: the alpha2C-autoreceptor modulating dopa/noradrenaline synthesis, and the alpha2A-heteroreceptor and 5-HT1A-autoreceptor modulating 5-HTP/5-HT synthesis. Acute treatment (2 h, i.p.) with desipramine (1-10 mg/kg), protriptyline (0.3-10 mg/kg) and nisoxetine (3-10 mg/kg), selective NA reuptake blockers, dose-dependently decreased dopa synthesis in cortex (15%-40%) and hippocampus (20%-53%). Fluoxetine (1-10 mg/kg) and zimelidine (1-10 mg/kg), selective 5-HT reuptake blockers, did not alter dopa synthesis. Fluoxetine and zimelidine dose-dependently decreased 5-HTP synthesis in cortex (14%-43%) and hippocampus (27%-54%). Desipramine and protryptyline did not alter 5-HTP synthesis in cortex but in hippocampus it was decreased (36%). Repeated desipramine (10 mg/kg for 1-21 days) or fluoxetine (3 mg/kg for 3-21 days) treatment resulted in a time-dependent loss in their ability to decrease dopa or 5-HTP synthesis. Desipramine (1-21 days) did not alter 5-HTP synthesis in cortex, but in hippocampus it was decreased (21%-37%, days 1-14) followed by recovery to control values (day 21). Fluoxetine (3-21 days) did not alter brain dopa synthesis. To further assess the desensitization of alpha2C-autoreceptors, alpha2A-heteroreceptors and 5-HT1A autoreceptors regulating the synthesis of dopa/NA or 5-HTP/5-HT after chronic desipramine and fluoxetine, the effects of clonidine (agonist at alpha2-auto/heteroreceptors) and 8-OH-DPAT (agonist at 5-HT1A-autoreceptors) were tested. In saline-treated rats, clonidine (1 mg/kg, 1 h) decreased dopa and 5-HTP synthesis in cortex (58% and 54%) and hippocampus (54% and 42%). In desipramine-treated rats (10 mg/kg, 21 days), but not in fluoxetine-treated ones (3 mg/kg, 14 days), the effect of clonidine was attenuated in cortex (12% and 18%) and only for dopa synthesis in hippocampus (31%). In saline-treated rats, 8-OH-DPAT (1 mg/kg, 1 h) decreased 5-HTP synthesis in cortex (63%) and hippocampus (75%). In fluoxetine-treated rats, but not in desipramine-treated ones, this inhibitory effect was markedly attenuated in cortex (26%) and hippocampus (

Topics: 5-Hydroxytryptophan; Adrenergic Uptake Inhibitors; Animals; Antidepressive Agents, Tricyclic; Autoreceptors; Brain; Carboxy-Lyases; Cerebral Cortex; Desipramine; Dihydroxyphenylalanine; Dose-Response Relationship, Drug; Drug Interactions; Fluoxetine; Hippocampus; Male; Norepinephrine; Protriptyline; Rats; Rats, Sprague-Dawley; Serotonin; Time Factors; Tryptophan; Tyrosine; Zimeldine

Tramadol is a centrally acting analgesic with low affinity to opioid receptors. A further mode of action is inhibition of noradrenaline uptake as measured in standard assays. Since tramadol shows antinociception at the spinal site, it was to be tested whether uptake blockade could be verified in spinal tissue. Therefore, synaptosomes and slices had to be prepared from the dorsal half of the spinal cord and the uptake of [3H]noradrenaline into synaptosomes to be characterized. The uptake was linear for at least 3 min. The apparent Km was 0.16 microM and Vmax was 7.9 pmol/min/mg protein. Tramadol inhibited the uptake competitively as analysed with Dixon plots with a Ki of 0.6 microM. Uptake inhibition was effected in order of potency by (+)-oxaprotiline > nisoxetine > (-)-tramadol > (-)-oxaprotiline = tramadol > (+)-tramadol. Slices were preincubated with [3H]noradrenaline then superfused and stimulated electrically. Nisoxetine, tramadol and its (-)-enantiomer enhanced mainly the stimulation-evoked overflow indicating uptake inhibition without releasing effects. Experiments with inclusion of the noradrenaline uptake inhibitor desipramine provided evidence that tramadol interfered with the noradrenaline transporter. The results show that spinal synaptosomes and slices are valid preparations to study local noradrenaline uptake and release. Tramadol enhances extraneuronal noradrenaline levels in the spinal cord by competitive interference with the noradrenaline uptake mechanism.

Topics: Animals; Fluoxetine; In Vitro Techniques; Kinetics; Male; Norepinephrine; Rats; Rats, Sprague-Dawley; Spinal Cord; Stereoisomerism; Synaptosomes; Tramadol; Zimeldine