Normalization of brain serotonin by L-tryptophan in levodopa-treated rats.

To test possible biochemical mechanisms by which L-tryptophan may reverse mental side effects of levodopa therapy in parkinsonism we administered levodopa, 250 mg per kilogram intraperitoneally, alone and with L-tryptophan, 500 mg per kilogram intraperitoneally, to rats pretreated with the peripheral dopa decarboxylase inhibitor, carbidopa (25 mg per kilogram). Rats were decapitated 0.5, 1, and 2 hours following amino acid injection and brain levels of amino acids, amines, and acid metabolites were determined. As expected, levodopa alone reduced tryptophan and serotonin and increased dopa and dopamine at the 1 and 2 hour intervals. Concurrent administration of L-tryptophan did not significantly alter the increased dopa and dopamine but did restore serotonin levels to within normal range at all time points. If similar events occur in parkinsonian patients, normalization of brain serotonin and not competitive reduction of brain dopa and dopamine may be the basis for the improvement in mental status.     

Interaction between bromocriptine and levodopa. Biochemical basis for an improved treatment for parkinsonism

The present investigation examined the biochemical interaction of bromocriptine and levodopa with respect to monoamine and gamma-aminobutyric acid metabolism in the brain. Rats were treated with levodopa, 250 mg per kilogram of body weight intraperitoneally, with or without carbidopa, 25 mg per kilogram, 1 or 2 hours before sacrifice. Some were also given bromocriptine, 5.0 mg per kilogram, 4 hours before sacrifice. Rats were killed 1 and 2 hours after levodopa and brain levels of gamma-aminobutyric acid and monoamines, and their metabolites were measured. Dopamine levels and metabolism were not markedly altered when bromocriptine was added to levodopa treatment. The level of serotonin, which was reduced 25 to 40 percent by levodopa alone, was close to normal with the combination treatment. Serotonin metabolism was also enhanced by the addition of bromocriptine as shown by increased levels of 5-hydroxyindoleacetic acid. The results suggest that bromocriptine not only may improve the motor disorder of parkinsonism but also may reduce some side effects of levodopa therapy, such as depression, which could be due to serotonin depletion.     

In vivo biogenic amine efflux in medial prefiontal cortex with imipramine,fluoxetine, and fluvoxamine

In vivo brain microdialysis was used to determine the effects of the standard tricyclic antidepressant imipramine and the two selective serotonin reuptake inhibitors (SSRIs) antidepressants, fluoxetine and fluvoxamine, on extracellular levels of norepinephrine (NE), dopamine (DA), and serotonin (5-HT) in rat medial prefrontal cortex. When given intraperitoneally (IP), imipramine increased NE in the microdialysis perfusate, and elevated DA and 5-HT to a lesser extent. Similar dose-dependent increases in DA and 5-HT were detected after IP fluoxetine, although NE was less affected. In contrast, IP fluvoxamine produced no change in basal NE nor DA, although a large increase in 5-HT occurred at an intermediate dose. When administered directly into cortex, all three antidepressants increased 5-HT by the same amount in a dose-dependent fashion. Intracortical imipramine and fluoxetine increased NE, and fluoxetine and fluvoxamine both increased DA, with fluoxetine doing so at a lower concentration. These data suggest that the SSRIs are not entirely selective for serotonin in vivo. © 1994 Wiley-Liss, Inc.     

Acute treatments with GMP produce antidepressant-like effects in mice

This study examined the effect of GMP in two models of depression in mice. The immobility times in the forced swimming test (FST) and in the tail suspension test (TST) were significantly reduced by GMP (dose range: 5-50 mg/kg and 5-100 mg/kg, i.p., respectively), without accompanying changes in ambulation in an open-field. I.c.v. injection of GMP (320-480 nmol/site) also reduced the immobility in the FST without affecting ambulation. The immobility of mice treated with MK-801 (0.01 mg/kg) + GMP (50 mg/kg) was not significantly different from the result obtained with MK-801 or GMP alone, but GMP (or MK-801) + imipramine (15 mg/kg) treatment induced a stronger effect in FST than administration of either drug alone. Pretreatment with p-chlorophenylalanine (100 mg/kg, 4 days) completely blocked the anti-immobility effect of GMP, MK-801 or fluoxetine (32 mg/kg), but only partially that of imipramine in the FST. The results suggest that the antidepressant-like effects produced by the administration of GMP, like MK-801, may be due to an indirect serotonin activation resulting from blockade of NMDA receptors.     

Involvement of NMDA receptors and L-arginine-nitric oxide pathway in the antidepressant-like effects of zinc in mice

This study investigated the involvement of NMDA receptors and the L-arginine-nitric oxide (NO) pathway in the antidepressant-like effects of zinc in the forced swimming test (FST). The immobility times in the FST and in the tail suspension test (TST) were reduced by zinc chloride (ZnCl(2), 30 and 10-30 mg/kg intraperitoneal (i.p.), respectively). The doses active in the FST and TST reduced locomotor activity in an open-field. The antidepressant-like effect of ZnCl(2) in the FST was prevented by pre-treatment of animals with guanosine 5'-monophosphate (GMP), ascorbic acid, L-arginine, or S-nitroso-N-acetyl-penicillamine (SNAP), but not with D-arginine, administered at doses that per se produced no anti-immobility effect. The immobility time of mice treated with ZnCl(2)+MK-801 was not different from the result obtained with ZnCl(2) or MK-801 alone, but ZnCl(2)+imipramine had a greater effect in the FST than administration of either drug alone. Pre-treatment of animals with a sub-threshold dose of ZnCl(2) prevented the anti-immobility effect of MK-801, ketamine, GMP, L-arginine or N(G)-nitro-L-arginine (L-NNA), but did not alter the effect of imipramine or fluoxetine. Taken together, the results demonstrate that zinc produced an antidepressant-like effect that seems to be mediated through its interaction with NMDA receptors and the L-arginine-NO pathway.     

Skeletal muscle necrosis following membrane-active drugs plus serotonin.

Administration of imipramine plus serotonin (5-HT) to rats has been proposed as an animal model of Duchenne muscular dystrophy. We studied the skeletal muscle necrosis produced in male rats given 5-HT after pretreatment with imipramine, other tricyclic antidepressants, or antihistamines, which like the tricyclic antidepressants, can block neuronal reuptake of 5-HT. Following one of these agents plus 5-HT, 20 mg/kg subcutaneously (s.c.), necrosis was more severe in the soleus muscle than the quadriceps. There was no significant difference in the incidence of necrosis in the soleus and quadriceps muscles following one of these agents plus 5-HT, 100 mg/kg, intraperitoneally (i.p.). After one of these agents plus 5-HT i.p., but not 5-HT s.c., extensive necrosis was significantly more frequent and severe in the quadriceps muscle than after 5-HT s.c. Chlorpheniramine (CP) plus 5-HT, 2.5 mg/kg intravenously, produced less muscle necrosis than CP plus 5-HT s.c. or i.p. The necrosis produced by CP plus 5-HT s.c. was comparable ipsilateral and contralateral to the injection site. The necrosis following CP plus 5-HT i.p. was maximal at 24 hr and remained fairly constant until 5 days. Regeneration was prominent by 7 days. The muscle necrosis produced by CP plus 5-HT is blocked by some 5-HT blockers, e.g., methiotepin and methysergide. It is also partially blocked by denervation. The capacity of tricyclic antidepressants and antihistamines to block neuronal 5-HT reuptake tended to be negatively correlated with the capacity to potentiate the muscle necrosis they produced with 5-HT, which suggests that blockade of 5-HT uptake is not the mechanism of the pathology produced by the combined treatment. The tricyclic antidepressants and the antihistamines are "membrane stabilizers-labilizers". Other drugs which are "membrane stabilizers-labilizers" such as trihexyphenidyl and procaine also promoted skeletal muscle necrosis when given prior to 5-HT. It is proposed that the effects of imipramine plus 5-HT on skeletal muscle are not due to the blockade of neuronal uptake of 5-HT and subsequent vascular-induced ischemia, but reflect direct toxic effects of these agents on skeletal muscle.     

Clinical evidence of an interaction between imipramine and acetylsalicylic acid on protein binding in depressed patients

The binding of imipramine to plasma proteins was studied in 20 adult patients with endogenous depression, with the purpose of assessing the effect produced by its simultaneous administration with an analgesic. Patients were administered 150 mg/day imipramine for 5 days and the binding to plasma proteins was determined. This was repeated 2 days later, after simultaneous administration of imipramine with 1,000 mg/day acetylsalicylic acid (ASA). Adverse effects for each patient were registered during both phases and were classified as mild, moderate, or severe. Results showed 84.4 +/- 7.07% of imipramine bound to plasma proteins and 72.18 +/- 6.5% when imipramine was administered with ASA (p < 0.05). When imipramine was administered alone, 1.95 mild adverse events per patient were registered. When imipramine was administered with ASA, the mild adverse events increased to 3.1 (p < 0.01) and the severe adverse events increased from 0.6 to 1.5 (p < 0.01). The levels of free imipramine increased when ASA was administered, indicating a displacement on the binding to plasma proteins. When adverse events were compared for each treatment, the accumulation of the free fraction of imipramine caused an increase in adverse events as well as in their clinical severity.     

Neurotoxic effects of (±)fenfluramine and phentermine,alone and in combination,on monoamine neurons in the mouse brain

Until recently, (±)fenfluramine (FEN) was widely prescribed as an appetite suppressant. In animals, FEN is a potent and selective brain serotonin neurotoxin. The present studies assessed the effects of phentermine (PHEN), an appetite suppressant frequently used clinically in combination with FEN, on FEN-induced serotonin neurotoxicity. Groups (n = 6/group) of mice were treated with FEN (10 mg/kg), PHEN (20 mg/kg or 40 mg/kg), FEN (10 mg/kg) plus PHEN (20 mg/kg or 40 mg/kg), or vehicle twice daily for four days. Food intake and body weight were measured during and after drug treatment. Brains were evaluated for regional brain serotonin and dopamine axonal markers two weeks after drug treatment. PHEN enhanced the anorectic and weight-reducing effects of FEN. PHEN also significantly enhanced FEN's long-term toxic effects on 5-HT axons. This effect was evident in some (hypothalamus, striatum) but not all (hippocampus, cortex) brain regions examined. PHEN alone produced no long-term effects on 5-HT axonal markers. However, whether given alone or in combination with FEN, PHEN produced significant, dose-related decreases in striatal DA axonal markers. These results, coupled with those from previous studies, suggest that PHEN has the potential to exacerbate FEN-induced serotonin neurotoxicity, if utilized in certain doses. Further, the present results indicate that PHEN possesses dopamine (DA) neurotoxic potential. The relevance of these data to humans previously treated with FEN/PHEN is discussed. Synapse 30:239–246, 1998. © 1998 Wiley-Liss, Inc.     

p,p'-DDT-induced neurotoxic syndrome: experimental myoclonus.

p,p'-DDT (100 to 600 mg per kilogram orally) produced spontaneous and stimulus-sensitive myoclonus in mice and rats. Drugs that enhance brain serotonergic activity reduced p,p'-DDT-induced myoclonus, and serotonin antagonists invariably aggravated this syndrome. p,p'-DDT-treated rats had increased concentrations of 5-hydroxyindoleacetic acid (5-HIAA) in seven regional areas, but serotonin was increased only in the midbrain and cerebellum. We postulate that p,p'-DDT-induced myoclonus may be causally related to blockage of serotonin receptors or inhibition of serotonin release into the synapse, resulting in functional deficiency of this neurotransmiter at the receptor site.     

Epileptic phenomena induced in the cat by the antidepressants maprotiline, imipramine, clomipramine, and amitriptyline.

The epileptogenic properties of four tricyclic antidepressant drugs: maprotiline, imipramine, clomipramine, amitriptyline, were investigated in locally anesthetized cats immobilized with gallamine and supplied with neocortical, hippocampal, and reticular recording electrodes. The drugs were infused intravenously at a constant rate (0.5 or, in some cases, 0.25 mg/kg per min) up to a final dose of 45 mg/kg. Already in small doses (1 to 5 mg/kg) all four antidepressants produced local signs of epileptiform pathology. Generalized sustained discharges occurred, on the average, at between 20 and 25 mg/kg with all four drugs. Imipramine and amitriptyline, after the first or first few generalized discharges, led to a pattern of repeated short generalized seizures alternating with silent periods. Maprotiline invariably produced this later alternating pattern only after a 10- to 30-min period of a seminormal high amplitude pattern. Clomipramine assumed a position between maprotiline on the one hand and imipramine and amitriptyline on the other. Starting at doses of 2-4 mg/kg, imipramine, clomipramine and amitriptyline, all three being norepinephrine and serotonin uptake inhibitors, induced a high amplitude "sleep" pattern. Maprotiline, a norepinephrine uptake inhibitor, which is thought devoid of serotonin-uptake inhibiting properties, led to high amplitude slow waves only with doses of at least 12.5 to 15 mg/kg.     

Ketamine plus imipramine treatment induces antidepressant-like behavior and increases CREB and BDNF protein levels and PKA and PKC phosphorylation in rat brain

A growing body of evidence has pointed to the N-methyl-d-aspartate (NMDA) receptor antagonists as a potential therapeutic target for the treatment of major depression. The present study investigated the possibility of synergistic interactions between antidepressant imipramine with the uncompetitive NMDA receptor antagonist ketamine. Wistar rats were acutely treated with ketamine (5 and 10 mg/kg) and imipramine (10 and 20 mg/kg) and then subjected to forced swimming tests. The cAMP response element bindig (CREB) and brain-derived neurotrophic factor (BDNF) protein levels and protein kinase C (PKC) and protein kinase A (PKA) phosphorylation were assessed in the prefrontal cortex, hippocampus and amygdala by imunoblot. Imipramine at the dose of 10 mg/kg and ketamine at the dose of 5 mg/kg did not have effect on the immobility time; however, the effect of imipramine (10 and 20 mg/kg) was enhanced by both doses of ketamine. Ketamine and imipramine alone or in combination at all doses tested did not modify locomotor activity. Combined treatment with ketamine and imipramine produced stronger increases of CREB and BDNF protein levels in the prefrontal cortex, hippocampus and amygdala, and PKA phosphorylation in the hippocampus and amygdala and PKC phosphorylation in prefrontal cortex. The results described indicate that co-administration of antidepressant imipramine with ketamine may induce a more pronounced antidepressant activity than treatment with each antidepressant alone. This finding may be of particular importance in the case of drug-resistant patients and could suggest a method of obtaining significant antidepressant actions whilst limiting side effects.     

The reductions in sweetened milk intake induced by interleukin-1 and endotoxin are not prevented by chronic antidepressant treatment.

Administration of interleukin-1 (IL-1) and endotoxin (lipopolysaccharide, LPS) to rodents can decrease food intake, a behavioral response resembling the diminution of appetite observed in human depression. IL-1 and LPS are known to affect cerebral neurotransmission involving norepinephrine and serotonin, both of which have been implicated in feeding behavior and in the pharmacotherapy of depression in man. The ability of chronic antidepressant treatment to attenuate LPS-induced depressed feeding in rats has been cited as evidence that cytokines may be involved in human depression. Thus, we studied the effects of chronic treatment with the tricyclic antidepressant, imipramine, and the novel antidepressant, venlafaxine, on the sweetened milk intake challenged with intraperitoneally injected IL-1 beta and LPS. Chronic (from 2 to 8 weeks) treatment of the mice with imipramine (10 mg/kg once or twice daily) or venlafaxine (10 and 20 mg/kg/day) did not significantly alter the decreases in milk intake in response to mIL-1 beta or LPS. In some experiments, chronic imipramine slightly decreased body weight and slightly increased milk intake, but not food pellet intake. Venlafaxine had none of these effects. Analysis of variance did not indicate any significant interactions between the antidepressant and IL-1 or LPS treatments. These results indicate that chronic treatment with antidepressants does not significantly alter the responses to IL-1 or LPS in the mouse sweetened milk model of sickness behavior.     

Effect of Aminophylline and Enprofylline on the Protective Efficacy of Common Antiepileptic Drugs Against Electroconvulsions in Mice

The anticonvulsant potency of phenobarbital (PB) (120 min before the test), phenytoin (PHT) (120 min), carbamazepine (CBZ) (60 min), valproate (VPA) (30 min), and acetazolamide (60 min) alone or in combination with either aminophylline (50 mg/kg, 30 min) or enprofylline (46.2 mg/kg, 30 min) was measured against maximal electroshock-induced convulsions in mice. All drugs were administered intraperitoneally (i.p.), and the protective efficacy of each drug was expressed as ED50 in milligrams per kilogram. Aminophylline decreased anticonvulsant activity of PB, PHT, CBZ, and VPA, increasing the respective ED50 values from 16 to 28 mg/kg, 7.4 to 14 mg/kg, 18 to 26 mg/kg, and 260 to 335 mg/kg. On the contrary, enprofylline in the equimolar dose did not exert such effect. Furthermore, neither aminophylline nor enprofylline affected anticonvulsant action of acetazolamide. The present data favor enprofylline as a preferable drug for treatment of obstructive lung diseases in epilepsy patients. However, accurate pharmacokinetic data in mice and men for both xanthines are necessary if one attempts to compare their cerebral and pulmonary actions.     

Specific serotonin reuptake inhibitor-induced decreases in lymphocyte activity require endogenous serotonin release

OBJECTIVES: We have previously reported that acute administration of the specific serotonin reuptake inhibitor (SSRI), fluoxetine, resulted in a decrease in mitogen-induced blood lymphocyte proliferation. The present studies further examine the specificity of this response to serotonin reuptake systems and the potential role of endogenous serotonin in mediating these effects. METHODS: Male Sprague-Dawley rats were treated intraperitoneally with the SSRIs, fluoxetine (6-10 mg/kg) or sertraline (20 mg/kg), dopamine and norepinephrine reuptake inhibitors, GBR 12909 and desipramine, respectively (6 mg/kg) or the serotonin precursor, 5-hydoxytryptophan (5-HTP, 50 mg/kg) 2 h prior to sacrifice. The serotonin-depleting agents, p-chlorophenylalanine (PCPA, 2 x 200 mg/kg) or the serotonin-lesioning agent, p-chloroamphetamine (PCA, 2 x 10 mg/kg) were administered intraperitoneally 5-7 days prior to fluoxetine (10 mg/kg) administration. RESULTS: Unlike the SSRIs, which significantly suppressed lymphocyte proliferation responses, selective norepinephrine or dopamine reuptake inhibition had no effect on lymphocyte proliferation. Elevation of extracellular serotonin levels with the serotonin precursor, 5-HTP, resulted in a similar decrease in lymphocyte proliferation as that seen with SSRI administration. Conversely, decreases in endogenous serotonin following PCA or PCPA treatment prevented the fluoxetine-induced decreases in lymphocyte proliferation. CONCLUSIONS: These results suggest that decreases in mitogen-induced lymphocyte proliferation following acute fluoxetine administration were due to elevations in extracellular serotonin following reuptake inhibition.     

Effect of various classes of antidepressants in behavioral paradigms of despair

The forced swim test (FST) and tail suspension test (TST) are widely used as animal models for screening potential antidepressants. Immobility or despair behavior produced in both FST and TST are taken as paradigm of depression and antidepressant drugs reduce the immobility period. Recent studies have suggested dissimilar hemodynamic, behavioral, physiological and pharmacological variations in these two models. Also, studies have proposed the significance of strain in these models of despair in an attempt to replicate results from one laboratory to another. The present study was undertaken to compare the antidepressant action of four major classes of antidepressants namely tricyclics (imipramine), selective serotonin reuptake inhibitor (fluoxetine), dual reuptake inhibitor of serotonin and norepinephrine (venlafaxine) and atypical antidepressants (mianserin and trazodone) using male laca mice in order to validate the two test procedures. Total immobility period was recorded during the period of 6 min in both the tests and the results were expressed as percentage decrease in immobility period with respect to vehicle control. Chlorpromazine (4 mg/kg, i.p.) or pentobarbitone (20 mg/kg, i.p.) were used as negative control. Imipramine (2, 5, 10 and 20 mg/kg), fluoxetine (5, 10, 20 and 40 mg/kg), or venlafaxine (2, 4, 8 and 16 mg/kg) dose dependently decreased the immobility period in mice. ED(50) values of imipramine, fluoxetine, and venlafaxine in FST and TST were found to be 9.2 and 10 mg/kg i.p, 18 and 20 mg/kg, i.p., and 8.5 and 12 mg/kg, i.p respectively. The relative potency of standard drugs in both FST and TST is imipramine=venlafaxine>fluoxetine. Mianserin (16 and 32 mg/kg., i.p.) or trazodone (1 and 2 mg/kg., i.p.) were ineffective to reduce the immobility period in both the tests showing the atypical nature of these antidepressants. Chlorpromazine or pentobarbitone was ineffective in reversing the immobility period thus validating the models for testing antidepressants. The present study further validated that both the test procedures are equi-sensitive to antidepressant drugs of different class in the strain of animals used.     

Effect of subchronic antidepressants administration on serotonin-stimulated phosphoinositide hydrolysis in para-chlorophenylalanine-treated rat hippocampal slices.

1. This study examines the effect of subchronic parachlorophenylalanine (PCPA) treatment upon serotonin (5-HT)-stimulated inositol monophosphate (IP-1) accumulation in rat hippocampal slices and also the effect of antidepressants upon this 5-HT response in the hippocampus from rats treated with or without concurrent administration of PCPA. 2. For high dose PCPA treatment, animals were injected intraperitoneally with 300 mg/kg daily for the first 5 days and then 100 mg/kg for 5 days, while for low dose PCPA treatment animals were injected for 10 days at a dose of 100 mg/kg. Imipramine or iprindole (15 mg/kg i.p.) was given once daily for 10 consecutive days. 3. 10-Day treatment with high dose of PCPA resulted in a significant increase in 5-HT-stimulated IP-1 accumulation, whereas low dose of PCPA had no significant effect upon the 5-HT response as compared to vehicle. 5-HT-stimulated IP-1 accumulation in rat hippocampus was not affected by subchronic treatment with imipramine or iprindole. The enhancement of the 5-HT response induced by high dose of PCPA was not attenuated by repeated antidepressants treatment.     

Double-blind study of the efficacy and safety of milnacipran and imipramine in elderly patients with major dipressive episode

The novel antidepressant agent milnacipran is a dual and equipotent serotonin and noradrenaline reuptake inhibitor. The aim of this double-blind study was to compare the efficacy and safety of milnacipran (50 mg twice daily) with that of imipramine (50 mg twice daily) in elderly patients with major depressive episode. A total of 219 patients were randomly assigned to 8 weeks of double-blind treatment with either milnacipran or imipramine; 72 patients withdrew from the study. At the end of treatment no significant differences were found between milnacipran and imipramine in antidepressant efficacy. A significantly greater number of side-effects, particularly anticholinergic effects, was observed in the imipramine group. Milnacipran may be preferable to imipramine in elderly depressed patients, as it provides the same antidepressant activity as imipramine with a lower incidence of side-effects, and does not impair cognitive ability.     

Effects of imipramine on behavior and brain norepinephrine metabolism in tetrabenazine treated rats: comparative study of a single administration with repeated administrations of imipramine

The effects of a single and repeated administrations of imipramine on the tetrabenazine-induced sedation in rats were studied. The 3-methoxy-4-hydroxyphenylethyleneglycol-sulfate (MHPG-SO4) level in the brain was measured. A single administration of imipramine of 20 mg/kg had no significant effect on the rats' locomotor activity and the brain MHPG-SO4. The administration of 30 mg/kg of tetrabenazine produced marked sedation and significantly increased the brain MHPG-SO4. The imipramine pretreatment reversed the tetrabenazine-induced sedation. The brain MHPG-SO4 in the rats treated with a single administration of imipramine along with tetrabenazine decreased significantly, compared with that in the rats treated with tetrabenazine only. The administration of alpha-methyl-para-tyrosine (alpha-MT) of 250 mg/kg suppressed the reversal of the tetrabenazine-induced sedation. The administration of Ro4-4602 of 50 mg/kg and L-3,4-dihydroxyphenylalanine (L-DOPA) of 100 mg/kg had no significant effect on the reversal. The repeated daily administrations of imipramine of 20 mg/kg reversed the tetrabenazine-induced sedation and produced the locomotor hyperactivity. When the rats were treated with the repeated administrations of imipramine for five days and had tetrabenazine administered on the last day, the brain MHPG-SO4 increased significantly as compared with that in the rats treated with a single administration of imipramine and tetrabenazine. There was no difference in the amount of locomotor activity between the rats administered imipramine of 20 mg/kg and tetrabenazine and those administered imipramine of 40 mg/kg and tetrabenazine. Several considerations were given to the above-mentioned results.     

Effects of zimeldine and its metabolites, clomipramine, imipramine and maprotiline in experimental allergic neuritis in Lewis rats.

The influence of the selective serotonin (5-HT) reuptake inhibiting antidepressant zimeldine and its metabolite norzimeldine was tested on experimental allergic neuritis (EAN) in Lewis rats, which is an animal model of the Guillain-Barré syndrome (GBS) in man. Zimeldine and norzimeldine both suppressed clinical signs of actively induced EAN when given at a dose of 20 mg/kg/day intraperitoneally via osmotic pumps. The effects of zimeldine, its metabolites norzimeldine and CPP 200 as well as of the antidepressants clomipramine, imipramine and maprotiline on in vitro immune response were tested. Thereby we used an immunospot assay for interferon-gamma (IFN-gamma) produced by lymph node mononuclear cells (MNC), which reflects number of memory T lymphocytes activated by antigen or lectin, in this experiment bovine peripheral nerve myelin (BPM) and phytohemagglutinin (PHA), respectively. In the IFN-gamma secretion assay zimeldine, CPP 200, clomipramine and maprotiline all in a concentration-dependent mode reduced the number of IFN-gamma secreting cells while norzimeldine and imipramine did not affect the IFN-gamma secretion. In assays for proliferation in response to antigen or lectin, the concentration 10(-4) M was judged toxic for all substances tested, and at concentrations below that all but zimeldine showed a dose-dependent slight reduction of MNC proliferation. The action of several drugs on induced T cell secretion of IFN-gamma suggests that the mechanisms for the suppressive effect of zimeldine and norzimeldine on EAN symptoms can be due to an action on myelin T cell autoreactivity. All the monoamine reuptake inhibiting antidepressants tested in this study showed immunomodulatory effects by either a reduction of the number of IFN-gamma-secreting cells or the MNC proliferation. These observations call for further studies of immunological mechanisms in the pathogenesis of mental disorders as well as on the potential role of drugs acting on the monoamine systems in the treatment of recognized autoimmune diseases.     

Neuropharmacology of the anxiolytic drug opipramol, a sigma site ligand

Although opipramol is structurally related to imipramine, it does not represent a tricyclic antidepressant drug as it does not inhibit the neuronal uptake of norepinephrine and/or serotonin. Unlike imipramine it is a rather potent sigma ligand with modest subclass selectivity which is similar in vitro as well as ex vivo. Opipramol is active in several behavioural paradigms indicative of anxiolytic properties at doses (1-10 mg/kg), which are also needed to occupy sigma binding sites. Somewhat higher doses (10-20 mg/kg) are needed for "antidepressant like" effects. The data allow the conclusion that interaction with sigma sites is involved in the anxiolytic and antidepressant effects of opipramol albeit a contribution of its weaker D (2)-antagonistic and 5-HT2-antagonistic properties cannot be totally be excluded.