Parachlorophenylalanine reversal of tranylcypromine effects in depressed patients.

Hospitalized bipolar and unipolar endogenously depressed patients who showed an antidepressant response to the monoamine oxidase (MAO) inhibitor, tranylcypromine sulfate, relapsed (ie, depression returned) when relatively small doses of parachlorophenylalanine (PCPA) were added for brief periods. Considered together with our findings that PCPA similarly reversed the antidepressant effects of the tricyclic drug, imipramine hydrochloride, implications are (1) serotonergic mechanisms are likely involved in the antidepressant effects of both the tricyclic drugs and MAO inhibitors in man and (2) this indolamine may also play a role in the endogenous clinical state of depression.

Effects of central and peripheral depletion of serotonergic system on carrageenan-induced paw oedema.

The role of serotonergic system was investigated on peripheral inflammation induced by intraplantary injection of carrageenan. Para-chlorophenylalanine (PCPA) was administered intracerebroventriculary (50, 100 microg/rat) or intraperitoneally (150 mg/kg, 3 days) and 2 or 24 h later, respectively, inflammation was induced by injection of carrageenan. Paw oedema was decreased significantly in PCPA-treated (100 microg/rat, i.c.v.) rats compared to control groups. Injection of exogenous serotonin (i.c.v.) by dose of 0.70 nmol/10 microl/rat, but not the dose of 0.35 nmol/10 microl/rat, 15 min after induction of inflammation completely reversed the anti-inflammatory effects of PCPA. Myeloperoxidase activity in inflamed paws was reduced significantly in groups received PCPA (either i.c.v. or i.p.) compared to controls. Exogenous serotonin (0.70 nmol/10 microl/rat) reduced inflammatory response when injected (i.c.v.) 30 min before or 30 min after the induction of inflammation. Injection of serotonin at the time of induction of inflammation had no inflammatory/anti-inflammatory effect. These results suggest that serotonin, as a neurotransmitter in central nervous system, may be involved in modulating peripheral inflammation.

Screening of antiserotoninergic drugs with the genetically dystrophic chicken.

Line 413 early-onset, genetically homozygous dystrophic chickens were given twice-daily intraperitoneal injections of the antiserotoninergic drugs p-chlorophenylalanine hydrochloride, fluoxetine hydrochloride, ergonovine maleate, nortriptyline hydrochloride, methiothepin maleate, and methysergide bimaleate in combination with penicillamine. Except in one case, treatment with drugs significantly prolonged the righting ability of the treated dystrophic chickens, as measured by a periodic standardized flip-test procedure. Abnormally high levels of plasma creatine phosphokinase, lactate dehydrogenase, and SGOT were found in the untreated dystrophic chickens. However, of the drug-treated dystrophic chickens, in some cases the plasma enzyme activities were reduced whereas in others they were enhanced. In agreement with previous findings, the blood serotonin levels of the dystrophic chickens were found at all age groups to be significantly higher than those in the corresponding normal chickens. This phenomenon may in part account for the improvement in righting ability demonstrated in the dystrophic chickens receiving treatment with antiserotoninergic drugs.

Metastatic carcinoid tumors and the carcinoid syndrome. A selective review of chemotherapy and hormonal therapy.

Malignant carcinoid tumors are remarkably varied in their biologic behavior. The disease may be indolent for years with minimal or no symptoms. On the other hand, an acute carcinoid crisis with severe diarrhea, dehydration, and hypotension may develop in the patient. Patients with flushing and/or diarrhea, not responsive to standard symptomatic measures, may benefit from chemotherapy or hormonal therapy. Chemotherapy with single agents or combination chemotherapy may be associated with response rates ranging from 20 to 40 percent. Hepatic de-arterialization by ligation or occlusion is an effective means of inducing rapid tumor shrinkage for patients who have carcinoid tumors and hepatic dominant metastases. The addition of chemotherapy after induction of a partial remission with hepatic de-arterialization may prolong the duration of response, but this remains to be proven in prospective clinical trials. Hormonal therapy with the antiestrogen tamoxifen has been unsuccessful, but treatment of the carcinoid syndrome with a long-acting analogue of somatostatin has been strikingly effective.

Cisplatin-induced early and delayed emesis in the pigeon.

1. Intravenously injected cisplatin at a dose of 4 mg kg(-1) induced early and delayed emesis in all pigeons without occurrence of lethality during a 72 h observation period. The early emetic response occurred with a latency of 81.3+/-8.0 min (n=15) and reached a peak at 2 - 3 h, and decreased gradually within 8 h after injection. Then the delayed emetic response, whose peak was found between 10 to 23 h, lasted up to 48 h. The emetic response markedly declined after 48 h. 2. Reserpine markedly reduced monoamine levels in both brain and intestine and completely abolished the early and delayed emesis. Dexamethasone markedly reduced not only the early but also the delayed emetic responses. p-Chlorophenylalanine decreased the level of serotonin in brain and intestine without affecting noradrenaline and dopamine and partly reduced the early emetic response, but did not affect delayed emesis. 3. Bilateral vagotomy prolonged the latency time to the onset of early emesis, and reduced the emetic responses in both the early and delayed phases. 4. The above results suggest that the cisplatin-induced early emesis in the pigeon is partially mediated via the vagal nerve and reserpine-sensitive monoaminergic systems including the serotonergic system; the delayed emesis is associated with monoaminergic but not the serotonergic systems.

Serotonergic manipulations in experimental neoplastic spinal cord compression.

The effects of differing strategies of serotonergic manipulation on vascular permeability, prostaglandin E2 (PGE2) synthesis, and the clinical course are evaluated in an experimental model of neoplastic spinal cord compression in rats. Serotonergic manipulations include in vivo inhibition of serotonin (5-HT) synthesis by p-chlorophenylalanine (p-CPA) and in vivo blockage of serotonin type 2 (5-HT2) receptors either by the selective antagonist ketanserin or by cyproheptadine. In paralyzed rats, the ratio of 5-hydroxyindole-3-acetic acid (5-HIAA) to 5-HT is significantly elevated in the compressed segments, suggesting that 5-HT utilization is increased. Treatment with p-CPA attenuates spinal 5-HT levels by 62.8% +/- 5.1% (mean +/- standard deviation) and reduces the elevated 5-HIAA:5-HT ratio to the normal value. The increased synthesis of PGE2 observed in the compressed cord is unaffected by p-CPA or ketanserin treatment but is markedly attenuated by cyproheptadine. Ketanserin reduces the 10-fold increase in spinal cord permeability observed in paralyzed rats in a clearly dose-related manner. If given at the first sign of neurological dysfunction, ketanserin delays the onset of paraplegia with the 1-mg/kg dose being clearly superior. Cyproheptadine and p-CPA also reduce the increased permeability and protract the course to paraplegia. A comparison of the effect of dexamethasone, indomethacin, cyproheptadine, p-CPA, and ketanserin reveals that they protract the disease course by 48%, 57%, 60%, 64%, and 78%, respectively. These data suggest that 5-HT2 receptors mediate some of the deleterious vascular consequences observed in the compressed spinal cord by a mechanism not coupled with PGE2 synthesis. A potential benefit of serotonergic manipulations for the acute treatment of neoplastic spinal cord compression is suggested.

The effects of parachlorophenylalanine and naloxone on acupuncture and electroacupuncture modulation of capsaicin-induced neurogenic edema in the rat hind paw. A controlled blind study.

OBJECTIVE: The aim of this work was to study the effect of pre-treatment with parachlorophenylalanine (PCPA) and posttreatment with naloxone on the modulating action on neurogenic inflammation of manual acupuncture and low intensity (5 mAmp), low frequency (5 Hz) electroacupuncture (EA). METHODS: Edema was induced by the subcutaneous administration of 50 micrograms capsaicin in rat paws. Pre-treatment with intraperitoneal PCPA was given for 3 days: 200 mg/Kg on the first day and 100 mg/Kg on the second and third days. Naloxone (1 mg/Kg) was administered at the end of the stimulation. RESULTS: The results show that naloxone and PCPA reduce the anti-edema effect of both manual acupuncture and EA. Combined administration of the two drugs completely eliminated the effect of manual acupuncture, and decreased but did not abolish the effect of electroacupuncture. CONCLUSION: These results indicate that both the opioid and the serotonergic inhibitory control systems are involved in the modulating action of acupunctural stimulation on neurogenic inflammation.

Pathological findings in a case of hypoxic myoclonus treated with 5-hydroxytryptophan and a decarboxylase inhibitor.

A 72-year-old woman suffered a respiratory arrest following intoxication with barbiturates. Her examination 27 months after the anoxic incident revealed involuntary jerks of trunk and limb muscles triggered by willed movements. On a regimen of 1 g L-5-HTP and 100 mg l-alpha-methyldopa hydrazine (carbidopa), action myoclonus disappeared completely. This medication had to be discontinued because of a regressive hysterical reaction. Two months later, she was found unconscious; resuscitation efforts were unsuccessful. Autopsy showed death was caused by choking on food. Coronal slices of the cerebral hemispheres and transverse section of the brainstem and cerebellum revealed no lesion. No evidence of hypoxic damage could be demonstrated in the cerebral cortex, hippocampus, striatum, pallidum, subthalamus, thalamus, or other diencephalic structures. In the caudal half of the midbrain tegmentum, a marked astrocytic reaction of some duration was encountered in the lateral parts of the supratrochlearis nucleus, the lateral subnucleus of the mesencephalic gray, and the immediately adjacent cuneiform and subcuneiform nuclei. In the former nucleus, sites of presumed nerve cell disintegration were found, but the neuronal populations of this nucleus and of the other raphe nuclei were well maintained. The other brainstem structures and the cerebellum were normal. Our neuropathological findings suggest that hypoxic myoclonus (a) does not seem to be explained by demonstrable neuronal loss in motor structures, such as cerebellum, thalamus, or basal ganglia and (b) does not appear to be causally related to a detectable reduction in the serotonin-containing neurons of the brain but rather to a functional derangement of anatomically intact serotonergic pathways originating perhaps from other, as yet unidentified, damaged neuronal structures.

Gastrointestinal and metabolic function in patients with the carcinoid syndrome.

We evaluated gastrointestinal absorption in six consecutive patients with metastatic serotonin-secreting carcinoid tumors. One patient had a consistent defect in fat absorption and two other patients malabsorbed fat during spontaneous or dopamine-induced exacerbation of the carcinoid syndrome. The steatorrhea of the patient with the persistent defect in fat absorption was reduced when tumor serotonin production was reduced by the tryptophan hydroxylase inhibitor parachlorophenylalanine. The six patients had normal hemoglobin levels and the serum concentration of the following urinary constituents was normal in most of the patients: albumin, carotene, 25-hydroxycalciferol, parathyroid hormone, calcitonin, calcium, phosphorous, osteogenous alkaline phosphatase, cholesterol, triglycerides, and serum lipoproteins. The excretion of the following urinary constituents was also normal in most of the patients: creatinine clearance, tubular reabsorption of phosphorous, calcium, D-xylose, cyclic 3'5' monophosphate and hydroxyproline. We conclude that patients with the carcinoid syndrome may have steatorrhea, and that their hyperserotoninemia plays a role in this process.

Effects of autacoid inhibitors and of an antagonist on malaria infection in mice.

The effects of p-chlorophenylalanine, an inhibitor of serotonin synthesis, indomethacin, an inhibitor of prostaglandin synthesis, cyproheptadine, a serotonin, bradykinin and histamine antagonist, were assessed separately and in combination with chloroquine (CQ) in Vom strains of Swiss albino mice (18-22 g) of either sex infected intraperitoneally with 1 x 10(7) Plasmodium yoelii nigeriensis-induced malaria. As prophylactic, these agents reduced from 31.9 +/- 4.5 to 16.1 +/- 8.1% the level of parasitemia relative to control but had no appreciable activity as curative agents when administered subcutaneously once daily for 4 days after 72 h of parasites innoculum in vivo. However, CQ alone and the combination of these agents with CQ in curative and prophylactic treatments significantly reduced (from 50.3 +/- 5.8 to 4.9 +/- 0.75%) the level of parasitemia (P < 0.05), which was taken only once 72 h after the parasites innoculum. The prophylactic result was shown to produce better results than the curative treatment. The data indicate that inhibitors and an antagonist can reduce the parasitemia load (the extent of damage and the severity of infection) as well as enhance the effects of CQ when combined with it for malaria therapy. The study reveals that the production of autacoids in established infection renders autacoid inhibitors and an antagonist ineffective for radical cure in malarial mice; however, selective inhibition of local hormones implicated in the pathological manifestations of malaria infection by autacoid inhibitors and an antagonist may be a possible pathway to reduce the severity of infection and the associated tissue damage and to enhance the efficacy of available anti-malarials.

Influence of ambient temperature and drug treatments on brain oedema induced by impact injury on skull in rats.

The progression and persistence of oedema development following impact-injury on closed skull was studied in anaesthetised as well as in unanaesthetised rats. The degree and rate of oedema development, following trauma, was aggravated in anaesthetised hypothermic animals but was reduced/or delayed by maintenance of body temperature at euthermic level. In general, the unanaesthetised animals showed a greater accumulation of oedema fluid than the corresponding anaesthetised group. The development of oedema corresponded more or less with the accumulation of 5-HT level in plasma and brain. This development of oedema was completely prevented following pretreatment with p-CPA, indomethacin paracetamol and aminophylline in unanaesthetised animals; whereas these drugs were able only to partially reduce the oedema development in euthermic anaesthetised animals. On the other hand the cyproheptadine pretreatment aggravated the oedema development which was more pronounced in unanaesthetised animals. The probable mechanism of the action of these drugs has been discussed.

[Effect of fenformin, L-DOPA and para-chlorophenylalanine on the immunological reactivity and chemical carcinogenesis in BALB/c mice]. / Vliianie fenformina, L-DOFA i parakhlorfenilalanina na immunologicheskuiu reaktivnost' i razvitiie khimicheskogo kantserogeneza u myshei BALB/c.

Treatment with 20-methylcholanthrene resulted in the increase in hypothalamic levels of noradrenaline and serotonin in BALB/c mice. Immunization of carcinogen-treated animals with ovine erythrocytes was followed by changes in the hypothalamic levels of central neurotransmitters, opposite to those in intact immunized controls. After correction of the levels of neurotransmitters in the hypothalamus with phenformin, parachlorophenylalanine or L-dopa carried out prior to immunization, the fraction of antibody-producing cells in the spleen of carcinogen-treated mice returned to normal. A combined administration of immunostimulators and drugs for correction of hypothalamic levels of noradrenaline and serotonin potentiated inhibitory effect of the former on chemical carcinogenesis.

Role of serotonin in zebrafish (Danio rerio) anxiety: relationship with serotonin levels and effect of buspirone, WAY 100635, SB 224289, fluoxetine and para-chlorophenylalanine (pCPA) in two behavioral models.

Serotonin (5-HT) is a neurotransmitter that is involved in many behavioral functions, including the organization of defense, and its putative pathological correlate, anxiety and stress disorders. Recently, behavioral tests for anxiety have been proposed in zebrafish. Exposure to the novel tank test or to the light/dark test increased extracellular fluid 5-HT content in the brain; anxiety-like behavior correlated positively with 5-HT content in the novel tank test, while the correlation was negative in the light/dark test. Acute treatment with a low dose of fluoxetine was anxiolytic in the geotaxis test and anxiogenic in the scototaxis test, while treatment with a higher dose produced a hyperlocomotor effect in both tasks. Buspirone and WAY 100635 were anxiolytic in both tests, while SB 224289 was anxiolytic in the geotaxis and slightly anxiogenic in the scototaxis test. Serotonin depletion with pCPA was anxiogenic in the geotaxis and anxiolytic in scototaxis. These results underline the differential sensitivity of these tasks to assess serotonergic agents; alternatively, serotonin might regulate zebrafish behavior differently in the novel tank test and in the light/dark test.

Antidepressant-like effect of the methanolic extract from Bupleurum falcatum in the tail suspension test.

In traditional Oriental medicine, some herbal combinations that include Bupleurum falcatum (BFM) as a major ingredient are known to effectively treat depressive-like disorders. In the present study, the antidepressant-like effect of methanolic extract of BFM and its neuropharmacological mechanism were investigated in mice. After oral administration of BFM extract, a tail suspension test (TST) and open field test (OFT) were performed to assess the antidepressant activity and psycho-stimulant side-effects, respectively. Pre-treatment with p-chlorophenylalanine (PCPA, a serotonin synthesis inhibitor) and alpha-methyl-p-tyrosine (AMPT, a catecholamine synthesis inhibitor) was used to assess the influence of BFM extract on the antidepressant activity in the TST. At doses of 150 and 300 mg/kg body weight, p.o., the BFM extract significantly reduced the total duration of immobility in the TST, while individual differences in locomotor activities between experimental groups were not observed in the OFT. Moreover, pre-treatment with PCPA (100 mg/kg i.p., for 4 consecutive days) or AMPT (100 mg/kg i.p.) significantly inhibited the antidepressant-like activity of BFM extract (300 mg/kg p.o.), as well as we confirmed the reversal of the antidepressant effect of fluoxetine (30 mg/kg i.p.) by PCPA and bupropion (20 mg/kg i.p.) by AMPT in the TST. Taken together, these findings suggest that the methanolic BFM extract has dose-dependent possibility of antidepressant-like activity valuable to alternative therapy for depression and that the mechanism of action involves the serotonergic and noradrenergic systems although underlying mechanism still remains to be further elucidated.

Involvement of monoaminergic system in the antidepressant-like effect of the flavonoid naringenin in mice.

Dietary flavonoids possess a multiplicity of neuroprotective actions in various central nervous pathophysiological conditions including depression. In this study, the neuropharmacological mechanism of the dietary flavonoid naringenin was investigated in the mouse behavioral models of depression. For this purpose, we investigated the influence of pretreatment with the inhibitors of serotonin or noradrenaline synthesis, p-chlorophenylalanine methyl ester or α-methyl-p-tyrosine, respectively in the anti-immobility effect of naringenin. Compared to the control group, naringenin significantly decreased the immobility time after acute treatment in the mouse tail suspension test (10, 20 and 50 mg/kg), but not in the forced swimming test, without producing locomotor alteration in the open-field test. In addition, pretreatment of mice with p-chlorophenylalanine methyl ester (100 mg/kg) or α-methyl-p-tyrosine (100 mg/kg) prevented the anti-immobility effect of naringenin (20 mg/kg) in the tail suspension test. Taken together, this data demonstrated that naringenin possessed potent antidepressant-like property via the central serotonergic and noradrenergic systems. Thus, our findings suggest the therapeutic potential of this dietary flavonoid in central nervous system disorders especially depression where monoaminergic systems are involved.