zimeldine and indalpine

Although relatively few drugs that specifically influence serotonin neurons have been used in humans, a wide variety of drugs has been used to modify serotonergic function in experimental animals. Several classes of agents increase serotonergic function. These include serotonin precursors (L-5-hydroxytryptophan and L-tryptophan) and monoamine oxidase inhibitors, which elevate serotonin stores; uptake inhibitors and releasers, which increase the concentration of serotonin in the synaptic cleft; and direct serotonin agonists, which mimic the action of serotonin on synaptic receptors. In addition, several kinds of drugs decrease serotonergic function, including serotonin depletors and agents that destroy serotonin neurons, as well as direct serotonin-receptor antagonists. The array of drugs now available improves the opportunities for clarifying the physiological roles of serotonin and gives promise of several therapeutic applications, including treatment of myoclonus.

Topics: Alanine; Brain; Citalopram; Clomipramine; Fenfluramine; Fluoxetine; Fluvoxamine; Humans; Monoamine Oxidase Inhibitors; Neurons; Oximes; p-Chloroamphetamine; Paroxetine; Piperidines; Propylamines; Receptors, Serotonin; Reserpine; Serotonin; Serotonin Antagonists; Synapses; Tetrabenazine; Zimeldine

Depression has been associated with a disturbance in serotonin function as reflected in platelet uptake of the transmitter as well as in CSF levels of its major metabolite, 5-hydroxyindoleacetic acid (5-HIAA). CSF 5-HIAA levels are subnormal in approximately 30% of melancholia patients. Early studies suggested that patients with a disturbed serotonin metabolism were less responsive to treatment with uptake inhibitors with a preferential action on noradrenaline neurons. Such findings encouraged the search for compounds with a selective effect on serotonin neurons. Although some classical antidepressants are potent inhibitors of serotonin uptake, they are not selective, since their metabolites, which appear to have antidepressant effects, inhibit noradrenaline uptake. The consistent findings of an increased risk for suicide in patients with low CSF 5-HIAA underlines the importance of exploring drugs that act on serotonin transmission. The biochemical effects of some serotonin uptake inhibitors and their clinical and research potential in depression are reviewed.

Topics: 5-Hydroxytryptophan; Alanine; Citalopram; Depressive Disorder; Fluoxetine; Fluvoxamine; Humans; Imipramine; Oximes; Paroxetine; Piperidines; Propylamines; Serotonin; Serotonin Antagonists; Trazodone; Zimeldine

Effects of an inhibitor of the uptake of noradrenaline (maprotiline, 75 and 150 mg) and two inhibitors of the uptake of 5-hydroxytryptamine (zimelidine, 100 and 200 mg; indalpine, 25 and 50 mg) on sleep were studied in healthy man. Maprotiline reduced the duration of rapid eye movement (REM) sleep and increased the duration of stage 2 sleep, and there was evidence of sedation the next day. Zimelidine and indalpine reduced the duration of REM sleep, but also reduced the total sleep time and increased wakefulness and stage 1 (drowsy) sleep. It is suggested that in acute studies, the effects of inhibition of uptake on sleep are likely to arise from presynaptic inhibition of release of transmitter, although other mechanisms cannot be excluded. Suppression of REM sleep is believed to be due to the balance between cholinergic and monoaminergic influences being disturbed rather than a specific effect arising from the modulation of a particular transmitter.

Topics: Adolescent; Adult; Double-Blind Method; Electroencephalography; Humans; Male; Maprotiline; Neurotransmitter Uptake Inhibitors; Norepinephrine; Piperidines; Psychomotor Performance; Serotonin; Sleep; Sleep, REM; Zimeldine

Effects of experience with Pavlovian autoshaping procedures on lever-press autoshaping conditioned response (CR) performance and 3H-8-OH-DPAT-labeled binding of 5-HT(1a) receptors as well as 125I-LSD-labeled binding of 5-HT(2a) receptors were evaluated in four groups of male Long-Evans hooded rats. Two groups of rats (Group Paired High CR and Group Paired Low CR) received Pavlovian autoshaping procedures wherein the presentation of a lever (conditioned stimulus, CS) was followed by the response-independent presentation of food (unconditioned stimulus, US). Rats in Group Paired High CR (n=12) showed more rapid CR acquisition and higher asymptotic levels of lever-press autoshaping CR performance relative to rats in Group Low CR (n=12). Group Omission (n=9) received autoshaping with an omission contingency, such that performing the lever-press autoshaping CR resulted in the cancellation the food US, while Group Random (n=9) received presentations of lever CS and food US randomly with respect to one another. Though Groups Omission and Random did not differ in lever-press autoshaping CR performance, Group Omission showed significantly lower levels of 3H-8-OH-DPAT-labeled 5-HT(1a) binding in post-synaptic areas (frontal cortex, septum, caudate putamen), as well as significantly higher plasma corticosterone levels than Group Random. In addition, Group Random showed higher levels of 3H-8-OH-DPAT-labeled 5-HT(1a) binding in pre-synaptic somatodendritic autoreceptors on dorsal raphe nucleus relative to each of the other three groups. Autoradiographic analysis of 125I-LSD-labeled 5-HT(2a) receptor binding revealed no significant differences between Groups Paired High CR and Paired Low CR or between Groups Omission and Random in any brain regions.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Anti-Anxiety Agents; Autoradiography; Brain Chemistry; Buspirone; Central Nervous System Depressants; Conditioning, Classical; Corticosterone; Ethanol; Iodine Radioisotopes; Lysergic Acid Diethylamide; Male; Piperidines; Rats; Rats, Long-Evans; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Selective Serotonin Reuptake Inhibitors; Serotonin Receptor Agonists; Zimeldine

This study investigated whether benzodiazepines reduce the capacity of animals to wait for food reward. Rats trained in a T-maze were allowed to choose between two magnitudes of reward: immediate, but small (two pellets) vs delayed, but large (eight pellets). The rats learned within ten sessions to select (80-100%) the arm leading to the largest reward. Separate groups of rats were then confined for 15, 30 or 60 s in the arm associated with the largest reward before gaining access to the spacially contiguous goal-box. The choice of the other arm was not followed by a period of waiting. Under these conditions, the frequency with which the small-reward arm was chosen increased linearly as a function of the duration of the waiting period. Diazepam (2-4 mg/kg IP) dose-dependently increased the number of times the small-reward arm was chosen during the sessions for which the waiting period was fixed at 15 or 30 s. Nitrazepam (2 mg/kg IP), chlordiazepoxide (16 mg/kg IP) and clobazam (16 mg/kg IP) had similar effects. The action of diazepam was counteracted by simultaneous administration of flumazepil (Ro 15-1788, 8 mg/kg PO). In the absence of confinement, these benzodiazepines, diazepam (4 mg/kg) excepted, did not modify selection of the large-reward arm. Conversely, the serotonin uptake blockers indalpine (2-4 mg/kg IP) and zimelidine (8-16 mg/kg IP) dose-dependently increased preference for the arm leading to the delayed (25 s) but large reward. These results suggest that benzodiazepines, perhaps by increasing impulsivity, render the animals less prone than controls to tolerate delayed access to reward.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Anti-Anxiety Agents; Benzodiazepinones; Choice Behavior; Diazepam; Flumazenil; Male; Piperidines; Rats; Rats, Inbred Strains; Reward; Serotonin Antagonists; Synaptic Transmission; Zimeldine