zimeldine and alaproclate

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

The effects of four antidepressant treatments on platelet tritiated imipramine binding have been studied in 51 hospitalized patients with severe major depressive disorder. There was an increase in maximum binding (Bmax) during the first week of treatment with antidepressants and electroconvulsive therapy, which was further magnified after three weeks' treatment with the serotonin uptake blockers alaproclate and zimeldine hydrochloride, but the Bmax values returned to baseline levels with nortriptyline hydrochloride and electroconvulsive therapy. The equilibrium dissociation affinity constant (Kd) did not change with any of the treatments. On reexamination one or two years after admission to the study, Bmax had not reached control values in clinically recovered, drug-free patients. Low pretreatment Bmax was associated with delusions during illness and with a poor long-term clinical outcome. There was no correlation between binding parameters and monoamine metabolite concentrations in the cerebrospinal fluid, either before or during treatment.

Topics: Adult; Aged; Alanine; Antidepressive Agents; Blood Platelets; Carrier Proteins; Depressive Disorder; Electroconvulsive Therapy; Female; Humans; Imipramine; Male; Middle Aged; Nortriptyline; Outcome and Process Assessment, Health Care; Psychiatric Status Rating Scales; Receptors, Drug; Receptors, Neurotransmitter; Receptors, Serotonin; Zimeldine

Clinical and biochemical effects of two selective 5-HT uptake inhibitors, zimeldine and alaproclate, were studied in 24 hospitalized patients with endogenous depression. According to a randomized parallel group design 14 patients were treated with zimeldine and 10 with alaproclate. The dosage of both zimeldine and alaproclate was 200 mg daily. For the evaluation of the clinical effect, Montgomery & Asberg Depression Rating Scale (MADRS) was used. Seven of 14 patients treated with zimeldine and seven of 10 treated with alaproclate improved. 5-HT uptake inhibition in patients' platelets and concentration of amine metabolites (5-HIAA, HVA, HMPG) in CSF were studied before and during treatment. After 3 weeks of treatment with zimeldine 5-HIAA and HMPG in CSF decreased significantly while HVA in CSF increased significantly. Zimeldine produced a significant 5-HT uptake inhibition in platelets. During treatment with alaproclate no significant change in amine metabolites concentration in CSF was found and there were no mean changes on 5-HT uptake inhibition in platelets.

Topics: Adult; Aged; Alanine; Female; Homovanillic Acid; Humans; Hydroxyindoleacetic Acid; Male; Methoxyhydroxyphenylglycol; Middle Aged; Serotonin; Serotonin Antagonists; Zimeldine

Sleep, waking and EEG power spectra were studied in cats for 15 h following peroral administration of placebo or 10 mg/kg and 20 mg/kg of the 5-HT reuptake inhibitors zimeldine and alaproclate. Behavior was also observed during the initial period following drug administration. Both drugs had effects on motor behavior and initiated hallucinatory like behavior. Zimeldine increased latency to stable sleep and to SWS-2. Alaproclate increased latency to SWS-1. Both drugs increased SWS (NREM sleep) and particularly SWS-2. REM sleep latency was increased and REM sleep was reduced following both drugs. EEG slow wave activity was increased following zimeldine. It is concluded that the 5-HT stimulation caused by the drugs yields complex effects on the sleep-waking axis, both sleep incompatible and sleep promoting effects.

Topics: Alanine; Animals; Behavior, Animal; Cats; Electroencephalography; Female; Hallucinations; Interpersonal Relations; Male; Motor Activity; Serotonin Antagonists; Sleep; Sleep Stages; Sleep, REM; Wakefulness; Zimeldine

Sleep and waking stages and EEG power spectra were investigated in rats following saline injections and injection of 10 and 20 mg/kg zimeldine or 10 and 20 mg/kg alaproclate, both selective 5-HT reuptake inhibitors. Following zimeldine there was a biphasic effect on sleep and waking, waking being increased during the first 2 1/2 h of recording, while slow wave sleep (SWS), in particular highly synchronized SWS-2 with high slow wave activity, was increased during the second 2 1/2 h recording period. Analysis of EEG power spectra indicated that the amount of synchronized slow wave activity was also increased within the sleep that occurred during the waking-dominated initial 2 1/2 h period. These data suggest simultaneous appearance of increased waking and increased synchronization following general serotonergic stimulation. They are interpreted as due to effects on different regions of the serotonergic system or on different serotonergic receptors. Consistent with earlier findings, zimeldine also suppressed rapid eye movement (REM) sleep. Following alaproclate, a clear waking effect was present, but only a weak synchronizing effect was seen. This is consistent with data on regional differences in uptake inhibition for zimeldine and alaproclate. Alaproclate also reduced REM sleep. Zimeldine or alaproclate was also administered to rats that had reduced sleep following pretreatment with a moderate dose of parachlorophenylalanine (PCPA). None of the drugs increased waking any further, but the PCPA-pretreated animals that received zimeldine had increased SWS-2, indicating that the SWS-2 increase following zimeldine alone was not a rebound effect.

Topics: Alanine; Animals; Antidepressive Agents; Arousal; Brain; Cortical Synchronization; Dose-Response Relationship, Drug; Drinking; Eating; Electroencephalography; Evoked Potentials; Fenclonine; Male; Rats; Rats, Inbred Strains; Reaction Time; Receptors, Serotonin; Sleep Stages; Wakefulness; Zimeldine

Substance P receptors were examined in crude synaptosomal fraction preparations of the rat spinal cord using [125I]Bolton Hunter Substance P ([125I]BHSP) which binds with an affinity of 0.043 +/- 0.015 nM. The concentration of binding sites in the dorsal and in the ventral part was 4.55 +/- 0.86 and 2.35 +/- 0.35 fmol mg-1, respectively. GTP inhibited the specific binding of [125I]BHSP in a concentration dependent manner, with 10(-3) mol l-1 GTP yielding 89-90% inhibition and 10(-5) mol l-1 GTP producing 50% inhibition. This value was similar in dorsal and ventral spinal cord. The effects on SP receptors of chronic treatment with the tricyclic antidepressant imipramine (2 x 10 mumol kg-1 day-1 p.o. 14 days) and the specific 5-HT (serotonin) uptake blockers alaproclate (2 x 20 mumol kg-1 day-1 p.o. 14 days) and zimelidine (2 x 10 mumol kg-1 day-1 p.o. 14 days) were examined in the ventral spinal cord, where SP and 5-HT coexist in the terminals of descending neurons from the raphe nucleus. Zimelidine treatment was found to cause a significant reduction in the number of substance P binding sites in the rat ventral spinal cord as compared to saline treated controls. These findings are discussed in light of the previous observation (Brodin et al. 1984) that SP levels are significantly elevated after treatment with antidepressant drugs especially with zimelidine, which alters the firing rates of 5-HT and 5-HT/SP neurons.

Topics: Alanine; Animals; Antidepressive Agents; Guanosine Triphosphate; Imipramine; Rats; Receptors, Neurokinin-1; Receptors, Neurotransmitter; Spinal Cord; Zimeldine

In the present paper the acute actions primarily of the tricyclic antidepressants amitriptyline and desipramine, the atypical antidepressant zimeldine and the potential antidepressant alaproclate were evaluated in six models used for studying antidepressant agents. These included the forced swim test, a modified learned helplessness procedure, the clonidine hypothermia test, the social dominance test (using the interaction with clonidine), a differential-reinforcement-of-low-rates (DRL-72s) schedule and conditioned avoidance response. The results showed desipramine to be effective in all the tests employed. Zimeldine was effective in the learned helplessness, DRL-72s and domination tests, but also caused notable deficits in two-way active avoidance response. Alaproclate was effective in all the tests except the domination paradigm. Amitriptyline was effective in all tests employed. The results are discussed in relation to the possible mechanism of action of these compounds in the test models employed.

Topics: Alanine; Amitriptyline; Animals; Antidepressive Agents; Antidepressive Agents, Tricyclic; Behavior, Animal; Desipramine; Male; Rats; Rats, Inbred Strains; Time Factors; Zimeldine

The tail-flick and increasing temperature hot-plate tests were employed to study the effects of acute or chronic treatment with zimelidine, alaproclate or chlorimipramine on nociception and response to 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) in mice. A single dose of the serotonin (5-HT) uptake inhibitors produced antinociception in the hot-plate test but not in the tail-flick test. After chronic administration, reduced tail-flick latencies were demonstrated 24, 48, 72 and 144 h after withdrawal of zimelidine treatment, 48 h after withdrawal of alaproclate and 48 and 96 h after withdrawal of chlorimipramine treatment. The hot-plate response temperatures were slightly lowered after chronic zimelidine treatment but not after treatment with alaproclate or chlorimipramine. The response to 5-MeODMT was not altered by a single dose of the 5-HT uptake inhibitors, however, after withdrawal of chronic treatment this response was increased in the tail-flick test but not in the hot-plate test. It was concluded that acute and chronic treatment with 5-HT uptake inhibitors modulate nociception differently, and that chronic treatment induces supersensitivity of spinal postsynaptic 5-HT receptors. Different modulation of different 5-HT receptor subpopulations by these compounds may possibly contribute to the test-dependent results.

Topics: Alanine; Animals; Biological Transport, Active; Clomipramine; Male; Methoxydimethyltryptamines; Mice; Nociceptors; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Zimeldine

The effects of subchronic (14 day) treatment with the inhibitors at the uptake of monoamines, zimelidine, alaproclate and imipramine, on regional levels of substance P (SP) and other tachykinins in tissue in the central nervous system of the rat were studied by radioimmunoassay. In the ventral spinal cord, in which substance P is known to exist together with 5-hydroxytryptamine (5-HT), in the terminals of descending neurones, treatment with the selective inhibitors of the uptake of 5-HT zimelidine (2 X 10 mumol/kg p.o.) or alaproclate (2 X 10 mumol/kg or 2 X 20 mumol/kg p.o.), increased the level of substance P-like immunoreactivity (SP-LI). The effect of alaproclate appeared to be dose-dependent. After treatment with imipramine (2 X 10 mumol/kg p.o.) only a tendency to increased levels of substance P-like immunoreactivity spinal cord was seen. Treatment with alaproclate, at the highest dose level, also elevated the concentration of neurokinin A/neurokinin B-like immunoreactivity (NKA/NKB-LI) in the ventral spinal cord. In the frontal cortex, in which separate monoaminergic and tachykinin-containing neurones interact, treatment with imipramine reduced the levels of SP-LI and NKA/NKB-LI, while treatment with alaproclate had the opposite effect. In the periaqueductal grey matter, treatment with zimelidine and alaproclate increased the levels of SP-LI and NKA/NKB-LI, while treatment with imipramine increased only the level of NKA/NKB-LI. In conclusion, subchronic treatment of rats with inhibitors of the uptake of monoamines induced changes in levels of tachykinin in frontal cortex, periaqueductal grey and spinal cord. The selective inhibitors of the uptake zimelidine and alaproclate, had similar effects on levels of tachykinin, while the inhibitor of the uptake of 5-HT and noradrenaline, imipramine induced changes in the frontal cortex, which were qualitatively different from the effects of zimelidine and alaproclate. Furthermore, the levels of different tachykinins were not always changed in parallel by the same treatment.

Topics: Alanine; Animals; Antidepressive Agents; Brain Chemistry; Central Nervous System; Imipramine; Immune Sera; Male; Neurokinin A; Neurokinin B; Neuropeptides; Rats; Rats, Inbred Strains; Spinal Cord; Substance P; Zimeldine

Sleep and waking in cats and rats were studied 6-10 hours following acute administration of zimeldine, alaproclate or saline. The effects on slow wave sleep of the two compounds markedly differed in the cats. Following zimeldine, sleep with a high amount of synchronized slow waves (SWS-2) was increased, and total sleep was unchanged. Following alaproclate, SWS-2 did not increase, and total sleep was reduced. In the rats, zimeldine increased SWS-2 during the first 4 hours after administration, while there was no change in SWS following alaproclate. Both zimeldine and alaproclate increased REM latency and reduced REM sleep in both species with somewhat more pronounced effects in cats than in rats. The results on SWS-2 following zimeldine are consistent with earlier results following serotonin depletion in both species. The differential effects on SWS-2 are discussed in terms of regional differences in uptake inhibition and other differences between the two uptake inhibitors. The results on REM sleep confirm earlier results involving serotonin uptake inhibitors and serotonin precursor loading and indicate that increased synaptic serotonin concentrations suppress REM sleep.

Topics: Alanine; Animals; Brain; Cats; Electroencephalography; Female; Male; Neurotransmitter Uptake Inhibitors; Rats; Serotonin; Sleep Stages; Species Specificity; Zimeldine

Sleep and waking stages in cats were studied 8 h following administration of zimeldine and alaproclate, in combination with saline or 5-hydroxy-1-tryptophan (5-HTP). Both drugs in combination with saline reduced rapid eye movement sleep and ponto-geniculo-occipital wave activity, and the effects were potentiated with 5-HTP. After administration of zimeldine in combination with 5-HTP there was an increase in synchronized waking (W-2), followed by an increase in slow wave sleep (SWS), at first SWS-1 with spindles and then highly synchronized SWS-2. The changes were interpreted as reflecting a serotonergic deactivating effect expressed by an electroencephalographic synchronizing effect. This is consistent with earlier studies following serotonin depletion and serotonin precursor loading. After alaproclate in combination with 5-HTP there were changes in W-2 and SWS-1 suggestive of the same process but much less pronounced. The difference between the two serotonin uptake inhibitors is interpreted as being due to regional differences in their uptake inhibition.

Topics: 5-Hydroxytryptophan; Alanine; Animals; Cats; Drug Synergism; Electroencephalography; Female; Male; Sleep Stages; Sleep, REM; Wakefulness; Zimeldine

This review concerns effects of stereoisomers on 5-HT uptake in brain tissue and/or blood platelets. All studies in which at least a pair of stereoisomers were used are considered. Differences between effects of stereoisomers of antidepressants as well as other drugs on 5-HT uptake are discussed. The findings indicate that 5-HT uptake is a stereoselective process. A topographical model of the 5-HT uptake area is proposed, based mainly on comparisons between spatial features of stereoisomers that inhibit 5-HT uptake.

Topics: Alanine; Amphetamine; Aniline Compounds; Animals; Antidepressive Agents; Blood Platelets; Brain; Fluoxetine; Humans; Male; Methadone; Mianserin; Mirtazapine; Morpholines; Naphthalenes; Nefopam; Nomifensine; Paroxetine; Piperidines; Rabbits; Serotonin; Stereoisomerism; Tranylcypromine; Viloxazine; Zimeldine

The ejaculatory response and the 5-hydroxytryptamine (5-HT) behavioural syndrome induced by 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) (3 mg kg-1 i.p.) were studied following acute and repeated treatment of rats with the selective uptake inhibitors of 5-HT, fluoxetine, zimeldine, alaproclate, and citalopram. The oral doses used were based on the respective ED50 values for uptake inhibition. Acute doses of fluoxetine and zimeldine significantly reduced the ejaculatory response when given 48 h before 5-MeODMT. This blockade was prevented by treatment of the rats with the postsynaptic 5-HT receptor antagonist methergoline. An acute dose of fluoxetine given 7 and 14 days before 5-MeODMT significantly enhanced the ejaculatory response. On day 24, the response returned to the control level. Repeated treatment every second day (5 times over 9 days and 10 times over 19 days) with fluoxetine caused a longer blockade of the ejaculatory response and the sensitization of the response came later than after an acute dose. Parallel with the ejaculatory response three other components of the 5-HT behavioural syndrome also decreased significantly. Acute doses of alaproclate and citalopram significantly blocked the ejaculatory response at 1 h, but they failed to affect the response at any other time point after either acute or repeated treatment. Neither did these drugs attentuate the 5-HT syndrome. It is concluded that acute and repeated treatment of rats with different selective 5-HT uptake inhibitors does not produce a common alteration in 5-HT2-receptor functions.

Topics: Alanine; Animals; Behavior, Animal; Citalopram; Ejaculation; Fluoxetine; Male; Metergoline; Methoxydimethyltryptamines; Propylamines; Rats; Rats, Inbred Strains; Serotonin; Serotonin Antagonists; Time Factors; Zimeldine

The effect of repeated treatment of rats for 21 days with the monoamine reuptake inhibitors imipramine, zimeldine, alaproclate (in each case 10 mumol/kg b.i.d.) and the reversible monoamine oxidase-A inhibitor amiflamine (3 mumol/kg b.i.d.) on brain noradrenergic mechanisms measured at different times of the day and night was investigated. Imipramine treatment produced a down-regulation of the Bmax for 3H-dihydroalprenolol binding to cortical beta-adrenoceptors that was not dependent upon the time of day the animals were killed. Zimeldine, on the other hand, reduced both Bmax and Kd of binding for day-time, but not night-time samples. Alaproclate and amiflamine were without effect on the binding. Twenty-four hour mean values for 1 nM 3H-p-aminoclonidine binding to alpha 2-adrenoceptors were lower for the zimeldine-treated rats than for the saline-treated rats. Pineal melatonin concentrations, which are regulated by beta-adrenoceptors, showed a pronounced diurnal rhythm, with the highest concentrations being found at 02:00. At this time point, a lower pineal melatonin content was found after amiflamine treatment, whereas imipramine, zimeldine and alaproclate were without significant effect. The importance of the use of more than one time point and the use of more than one biochemical test for the determination of the effects of repeated antidepressant treatment on central noradrenergic systems measured ex vivo is discussed.

Topics: Alanine; Animals; Antidepressive Agents; Body Weight; Cerebral Cortex; Circadian Rhythm; Dihydroalprenolol; Hypothalamus; Imipramine; Kinetics; Male; Melatonin; Norepinephrine; Phenethylamines; Pineal Gland; Rats; Rats, Inbred Strains; Receptors, Adrenergic, alpha; Receptors, Adrenergic, beta; Zimeldine

The aim of this study was to determine the effect of 5-hydroxytryptamine (5-HT) uptake blockade on 5-HT turnover by measuring the concentrations of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) in brain with the aid of high performance liquid chromatography and electrochemical detection. The indoleamines were measured in the anterior hypothalamus (AH), posterior hypothalamus (PH) and raphe nuclei 30 min after the i.v. injection of either alaproclate (30 mg/kg) or zimelidine (20 mg/kg). The effect of alaproclate was studied in male rats, pro-oestrous female rats, rats ovariectomized and injected s.c. with 20 micrograms oestradiol benzoate (OB) on dioestrus and at 12.00 h of the next day (presumptive pro-oestrus) with 2 mg progesterone (model 1) and rats ovariectomized 3-4 weeks before an s.c. injection of 20 micrograms OB followed 72 h later by an s.c. injection of 2 mg progesterone (model 2). Alaproclate caused a significant decrease in the 5-HIAA/5-HT ratio in the AH and PH of the brain of male rats, in the PH and raphe nuclei in pro-oestrous rats and model 1, and in the raphe nuclei alone in model 2. Zimelidine had no effect on the 5-HIAA/5-HT ratio in any area in model 2. In male rats the injection of parachlorophenylalanine produced a marked reduction in the brain concentrations of 5-HT and 5-HIAA, but the 5-HIAA/5-HT ratio was unchanged by a subsequent injection of alaproclate. None of the pharmacological agents affected significantly the brain concentrations of noradrenaline, dopamine or dihydroxyphenylacetic acid.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Alanine; Animals; Brain; Castration; Estradiol; Female; Hydroxyindoleacetic Acid; Hypothalamus; Male; Pregnancy; Proestrus; Progesterone; Raphe Nuclei; Rats; Rats, Inbred Strains; Serotonin; Serotonin Antagonists; Zimeldine

The effect of the 5-hydroxytryptamine (5-HT) uptake blockers on the surges of LH and prolactin has been investigated in pro-oestrous rats and various experimental models used frequently to study the effects of steroids on LH and prolactin secretion in female rats. The steroid models were: rats ovariectomized on dioestrus, injected immediately with oestradiol benzoate (OB) and at 12.00 h on the next day (presumptive pro-oestrus) with progesterone (model 1); long-term ovariectomized rats injected with a single injection of OB and 72 h later with either progesterone (model 2) or OB (model 3); long-term ovariectomized rats injected daily with OB (model 4). The uptake blockers alaproclate (3-30 mg/kg) and zimelidine (20 mg/kg) were injected and blood samples withdrawn from previously implanted intra-atrial cannulae. Plasma LH and prolactin concentrations were determined by radioimmunoassay. The present study confirmed that a surge of LH occurs at about 17.00-18.00 h of the presumptive day of pro-oestrus in model 1, at about 5 h after (approximately 17.00 h) the injection of either progesterone or the second injection of OB in models 2 and 3, and diurnally in model 4, and the simultaneous occurrence of a prolactin surge in models 2 and 4. A surge of prolactin at the same time as the LH surge was shown to occur also in models 1 and 3. Alaproclate (30 mg/kg) administered at 15.00 h delayed significantly the peak of the prolactin surge in the pro-oestrous rat and models 1, 3 and 4, and in the latter the magnitude of the prolactin surge was also significantly reduced. By contrast, the peak of the prolactin surge in model 2 was significantly prolonged by alaproclate. Alaproclate had no significant effect on either the timing or the magnitude of the LH surge in the pro-oestrous rat, and models 3 and 4. The peak of the LH surge was delayed by alaproclate in model 1 and abolished in model 2, providing further evidence for the possible importance of interactions between 5-HT and progesterone in neuroendocrine control. Zimelidine had no significant effect on either the LH or prolactin surge in the pro-oestrous rat and in models 1 and 2. These results show that normal 5-HT uptake is necessary for the normal timing and/or magnitude of the spontaneous and steroid-induced prolactin surge but is not essential for the normal timing and magnitude of the spontaneous surge of LH and the LH surge in some but not all steroid models.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Alanine; Animals; Castration; Estradiol; Female; Luteinizing Hormone; Pituitary Gland, Anterior; Pregnancy; Proestrus; Progesterone; Prolactin; Rats; Rats, Inbred Strains; Serotonin; Serotonin Antagonists; Zimeldine

The potential stimulatory and inhibitory effects on female sexual behaviour of five 5HT antagonists and five agents that increase 5HT activity, were noted in ovariectomised rats primed with various steroid regimes such that they were either "receptive" (LQ greater than 50%) or "non-receptive" (LQ less than 50%). The 5HT antagonists cinanserin, mianserin, ketanserin and metergoline all inhibited behaviour in receptive rats. Methysergide and cinanserin stimulated behaviour in non-receptive rats. All the drugs which increased 5HTP activity, i.e., 5HTP, zimelidine, alaproclate, WY 26002 and quipazine stimulated sex behaviour in non-receptive rats. In rats that had been ovariectomised only, part of this effect was probably due to stimulation of adrenal progesterone, but a significant stimulatory effect could still be observed in ovariectomised-adrenalectomised rats. 5HT also had a significant inhibitory effect on receptive rats, and the other agonists showed a similar but non-significant tendency. In view of the fact that 4 out of 5 of the 5HT antagonists inhibited sexual behaviour, we hypothesise that 5HT has a stimulatory role in the control of female sexual behaviour. The possible mechanisms mediating the dual action of 5HTP on female sexual behaviour are discussed.

Topics: 5-Hydroxytryptophan; Adrenalectomy; Alanine; Animals; Castration; Cinanserin; Female; Ketanserin; Metergoline; Methysergide; Mianserin; Piperidines; Progesterone; Quipazine; Rats; Rats, Inbred Strains; Receptors, Serotonin; Serotonin; Sexual Behavior, Animal; Zimeldine

The effects of repeated treatment of rats with the antidepressant or potential antidepressant agents alaproclate, citalopram, clomipramine, desipramine, imipramine, maprotiline, mianserin and zimeldine on the convulsions released by decapitation were examined. The noradrenaline uptake inhibitors desipramine, imipramine and maprotiline increased significantly the latency of onset of the post-decapitation convulsions (PDC's) after repeated administration of 10 mumol/kg orally twice daily, or 66 mumol/kg orally once daily (desipramine), for 15 days. The duration of the PDC's was slightly prolonged by these agents. A single acute dose of desipramine (20 mg/kg) administered at various time intervals before decapitation (1 to 24 hours) had no effect on the PDC's nor did repeated treatment with the other compounds examined, alaproclate, citalopram, clomipramine, mianserin and zimeldine, have any effect upon the PDC latency. The results are interpreted as evidence for noradrenaline receptor subsensitivity following chronic treatment.

Topics: Alanine; Animals; Anticonvulsants; Antidepressive Agents; Desipramine; Imipramine; Male; Maprotiline; Rats; Rats, Inbred Strains; Time Factors; Zimeldine

The dose-dependent effect of acute zimeldine and alaproclate treatment upon the acquisition of two-way and one-way active avoidance in the rat was studied in a single-session and in a repeated-sessions design. Zimeldine (5-20 mg/kg, IP), but not alaproclate, caused disruptions of two-way avoidance acquisition. Acquisition deficits were also caused by citalopram and fluoxetine but not the other antidepressant drugs tested. Zimeldine, but not alaproclate or desipramine, caused a slight but non-significant impairment of one-way active avoidance; neither zimeldine nor alaproclate produced any effects upon fear conditioning and retention testing. The long-term action of p-chloroamphetamine (2 X 10 mg/kg) antagonised the acute zimeldine effect totally, and chronic treatment with zimeldine (15 days, 1 X 50 mumol/kg) and chlorimipramine (15 days, 2 X 10 mumol/kg) also caused some partial blockade of the two-way avoidance deficit. These data seem to suggest some involvement of serotonin (5-HT) in the observed disruptions of two-way active avoidance caused by acute zimeldine treatment.

Topics: Alanine; Animals; Antidepressive Agents; Avoidance Learning; Clomipramine; Fenclonine; Male; Mianserin; Rats; Rats, Inbred Strains; Serotonin Antagonists; Zimeldine

The effects of alaproclate and zimeldine on memory retrieval were examined in male Swiss-Webster mice using a one-trial inhibitory avoidance task. All drugs were administered IP prior to the retention test 24 h after training. Both drugs were found to facilitate memory retrieval significantly in a dose- and time-dependent fashion that could not be explained in terms of non-specific effects of the drug (illness, lack of motility, etc.) at the time of the test. The temporal effects of alaproclate and zimeldine on memory closely followed their course of concentration of the drug within the blood stream. The facilitation of retrieval induced by alaproclate and zimeldine was blocked by the putative serotonergic receptor agonist quipazine but not blocked by the antagonist cyproheptadine. Pretreatment with quipazine alone in a group of animals trained to a shock level which normally results in high levels of suppression was not sufficient to produce memory impairment, suggesting that quipazine was probably antagonizing the facilitative effects of alaproclate and zimeldine directly, rather than overriding the facilitation through an indirect action on retrieval in general. The present results lend further support to the suggestion that serotonin plays a significant role in memory.

Topics: Alanine; Animals; Avoidance Learning; Cyproheptadine; Dose-Response Relationship, Drug; Gas Chromatography-Mass Spectrometry; Male; Memory; Mice; Quipazine; Serotonin; Time Factors; Zimeldine

The dependence of intact noradrenergic and serotonergic nerve terminals for the decrease in the number of beta-adrenoceptors and 5-HT2 binding sites in the cerebral cortex produced by long-term treatment of rats with antidepressant drugs was examined. Noradrenergic nerve terminals were destroyed with the selective noradrenaline neurotoxin DSP4, and serotonergic nerve terminals were destroyed with p-chloroamphetamine (PCA). It was found that lesioning of the noradrenergic nerve terminals abolished the decrease in beta-adrenoceptors produced by desipramine, mianserin and zimeldine and partially antagonized that of the beta-adrenoceptor agonist clenbuterol. PCA pretreatment did not antagonize the long-term effects on the beta-adrenoceptor produced by these compounds. Lesioning of serotonergic nerve terminals affected the down-regulation of 5-HT2 binding sites produced by long-term treatment with mianserin, desipramine and amiflamine. DSP4 pretreatment partially abolished the down-regulation of 5-HT2 binding sites produced by long-term treatment with desipramine, while the effects of mianserin and amiflamine were unaffected by pretreatment with DSP4.

Topics: Alanine; Amines; Animals; Antidepressive Agents; Benzylamines; Binding Sites; Cerebral Cortex; Clenbuterol; Desipramine; Dihydroalprenolol; Male; Mianserin; p-Chloroamphetamine; Rats; Rats, Inbred Strains; Receptors, Adrenergic, beta; Receptors, Serotonin; Serotonin; Spiperone; Zimeldine

Topics: Alanine; Animals; Brain; Hydroxyindoleacetic Acid; Rats; Rats, Inbred Strains; Receptors, Neurotransmitter; Receptors, Serotonin; Serotonin; Synaptic Membranes; Zimeldine

The effects of the specific 5-HT uptake inhibitors alaproclate and zimelidine, the 5-HT releasing compound p-chloroamphetamine (PCA) and the specific NA uptake inhibitor desipramine on pain sensitivity were examined in male rats using the hot-plate and tail-flick methods. The effects of alaproclate and zimelidine on 5-HT uptake mechanisms in the hypothalamus and spinal cord were also studied. Alaproclate, zimelidine, PCA and desipramine produced hypoalgesia in the hot-plate but not in the tail-flick test. Naloxone (1 mg/kg) failed to block the hypoalgesia produced by alaproclate and PCA in the hot-plate test. Zimelidine but not desipramine pretreatment blocked the analgetic action of PCA in the hot-plate test. Alaproclate significantly enhanced morphine analgesia in the hot-plate test but did not affect morphine analgesia in the tail-flick test. In contrast, zimelidine tended to enhance and significantly prolonged morphine analgesia in the tail-flick test but did not affect morphine analgesia in the hot-plate test. Zimelidine inhibited 5-HT uptake with equal potency in the hypothalamus and spinal cord, while alaproclate produced a greater inhibition of 5-HT uptake in the hypothalamus. These findings show test-specific effects after enhancement of central 5-HT neurotransmission. It is suggested that various aspects of pain sensitivity and morphine analgesia may involve different 5-HT pathways in the brain and spinal cord. Moreover, 5-HT pathways in the forebrain may mediate analgesia of a non-opiate type.

Topics: Alanine; Analgesia; Animals; Behavior, Animal; Brompheniramine; Desipramine; Dose-Response Relationship, Drug; Male; Morphine; Naloxone; p-Chloroamphetamine; Pain; Pyridines; Rats; Serotonin; Zimeldine

The accumulation of 14C-5-hydroxytryptamine in human platelets in vitro and plasma levels of a number of hypophyseal hormones and cortisol in healthy male volunteers were determined after acute oral administration of zimelidine and alaproclate, two selective inhibitors of serotonin (5-HT) uptake. Alaproclate (100 mg) significantly inhibited the accumulation of 14C-5-HT by 42% at 90 minutes but showed no significant effect at 4 hours. At 200 mg the decrease in the accumulation was 55% after 90 minutes and 31% after 4 hours. Zimelidine (200 mg) caused a 72% decrease at 90 minutes and 73% at 4 hours. Plasma levels of prolactin, growth hormone, luteinizing hormone, follicle stimulating hormone, and thyroid stimulating hormone remained unchanged after zimelidine and alaproclate, and the levels were comparable to those after placebo. A physiological decline of plasma cortisol levels was noted in the morning during the test period of 4 hours, but there were slight differences in the secretory pattern after the different drugs used.

Topics: Adult; Alanine; Blood Platelets; Brompheniramine; Dose-Response Relationship, Drug; Follicle Stimulating Hormone; Growth Hormone; Humans; Hydrocortisone; In Vitro Techniques; Luteinizing Hormone; Male; Pituitary Hormones, Anterior; Prolactin; Pyridines; Serotonin; Serotonin Antagonists; Thyrotropin; Zimeldine