4-Chlor-3-phenylalanin

This study examined the effects of serotonergic depletion and beta-adrenergic antagonism on performance in both visible platform and hidden platform versions of the water maze task. Male Long-Evans rats received systemic injections of p-chlorophenylalanine (500 mg/kg x 2) to deplete serotonin, or propranolol (20 or 40 mg/kg) to antagonize beta-adrenergic receptors. Some rats received treatments in combination. To separate strategies learning from spatial learning, half of the rats underwent Morris' water maze strategies pretraining before drug administration and spatial training. Individual depletion of serotonin or antagonism of beta-adrenergic receptors caused few or no impairments in either naive or pretrained rats in either version of the task. In contrast, combined depletion of serotonin and antagonism of beta-adrenergic receptors impaired naive rats in the visible platform task and impaired both naive and strategies-pretrained rats in the hidden platform task, and also caused sensorimotor impairments. ...

The goal of this study was to assess the interactive effects of chronic anabolic androgenic steroid (AAS) exposure and brain serotonin (5-hydroxytryptamine, 5-HT) depletion on behavior of pubertal male rats. Serotonin was depleted beginning on postnatal day 26 with parachlorophenylalanine (PCPA 100 mg/kg, every other day); controls received saline. At puberty (P40), half the PCPA-treated rats and half the saline-treated rats began treatment with testosterone (T, 5 mg/kg, 5 days/week). Behavioral measures included locomotion, irritability, copulation, partner preference, and aggression. Animals were tested for aggression in their home cage, both with and without physical provocation (mild tail pinch). Brain levels of 5-HT and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were determined using HPLC. PCPA significantly and substantially depleted 5-HT and 5-HIAA in all brain regions examined. Chronic T treatment significantly decreased 5-HT and 5-HIAA in certain brain areas, but to a much lesser extent than PCPA. Chronic exposure to PCPA alone significantly decreased locomotor activity and increased irritability but had no effect on sexual behavior, partner preference, or aggression. T alone had no effect on locomotion, irritability, or sexual behavior but increased partner preference and aggression. The most striking effect of combining T+PCPA was a significant increase in attack frequency as well as a significant decrease in the latency to attack, particularly following physical provocation. Based on these data, it can be speculated that pubertal AAS users with low central 5-HT may be especially prone to exhibit aggressive behavior.

...The dose-dependency and time-course of 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy")-nduced perturbations of cerebral glucose metabolism in freely moving rats /was investigated/ ... A single dose of MDMA (2-10-20 mg/kg iv) evoked a transient increase of interstitial glucose concentrations in striatum (139-223%) with rapid onset and of less than 2 hr duration, a concomitant but more prolonged lactate increase (>187%) at the highest MDMA dose and no significant depletions of striatal serotonin. Blood glucose and lactate levels were also transiently elevated (163 and 135%) at the highest MDMA doses. The blood glucose rises were significantly related to brain glucose and brain lactate changes. The metabolic perturbations in striatum and the hyperthermic response (+1.1 degrees C) following systemic MDMA treatment were entirely blocked in p-chlorophenylalanine pre-treated rats, indicating that these effects are mediated by endogenous serotonin.

This study examined the effect of both separate and combined depletion of brain somatostatin and serotonin on acquisition of the water maze (WM) task. Naive male Long-Evans rats received injections of p-chlorophenylalanine (PCPA; 500 mg/kg x 2) to deplete serotonin or cysteamine (90 or 200 mg/kg) to deplete somatostatin, or both treatments prior to spatial and reversal training in the water maze. Some rats first received Morris' nonspatial pretraining to train them in the behavioral strategies that are required for successful spatial place learning in this task, prior to drug treatment and spatial training. A detailed behavioral analysis indicated that somatostatin or serotonin depletion alone caused little or no impairment in naive animals. Depletion of both somatostatin and serotonin in naive rats impaired performance, with differences in the impairments that depended on the dose of cysteamine. Nonspatially pretrained rats were not impaired. Thus, neither somatostatin nor serotonin alone is crucial for the water maze task, but impairments occur if both somatostatin and serotonin are depleted in naive rats. The results indicate that some of the performance impairment was due to strategies impairment rather than a spatial place learning impairment. Depletion of both somatostatin and serotonin in naive rats produces results comparable to the spatial navigation deficits seen in some Alzheimer patients and suggests that combinations of antagonist treatments may better model this disorder than single antagonist treatments do.

For more Interactions (Complete) data for Fenclonine (11 total), please visit the HSDB record page.

/SIGNS AND SYMPTOMS/ Some of the mystery surrounding serotonin has been unraveled recently after the development of a means of selectively depriving the organism of this amine. Key aspects of recent advances include biochemical characterization of the first enzymatic step in tissue serotonin biosynthesis, that of tryptophan 5-hydroxylation; discovery of an inhibitor (para-chlorophenylalanine (PCPA)) of the reaction; and observations on the effects of serotonin deprival as produced by PCPA in man and animals. Control of diarrhea in the carcinoid syndrome by PCPA treatment indicates that the major target organ of circulating serotonin is the intestinal tract. Induction of psychiatric effects with high doses of PCPA, along with other evidence, is compatible with a serotonin-deficiency hypothesis of affective illness. Serotonin plays a role in sleep mechanisms, with PCPA suppressing and 5-hydroxytryptophan (serotonin precursor) restoring rapid eye movement sleep in man. Finally, animal data raise exciting possibilities of the involvement of brain serotonin in control of sexual behavior.

/CASE REPORTS/ Para-chlorophenylalanine is a potent depleter of tissue serotonin (5-hydroxytryptamine). Since 5-hydroxytryptamine may contribute to the pathogenesis of several aspects of the carcinoid syndrome, for 1 year ... a patient with this syndrome /was treated/ with para-chlorophenylalanine. A 59-year-old man developed chronic diarrhea, hepatomegaly, right-sided valvular heart lesion, and cutaneous flush. Exploratory abdominal examination showed ileal carcinoid tumor metastatic to liver and nodes. Urine 5-hydroxyindoleacetic acid and serum 5-hydroxytryptamine levels were abnormally high. Para-chlorophenylalanine treatment promptly reduced both levels to normal and halted the diarrhea. Chronic treatment with para-chlorophenylalanine controlled the production of 5-hydroxytryptamine and diarrhea but did not prevent tumor growth, flushing, or progression of cardiac lesions. /Former/

/CASE REPORTS/ Eighteen patients with severe symptoms of the carcinoid syndrome were assessed for hepatic embolisation. Four were too ill, and one had mild symptoms; thus 13 received a periembolisation regimen of cyproheptadine, fenclonine, aprotinin, methylprednisolone, tobramycin, flucloxacillin, and metronidazole. Embolization was not performed in one patient with an occluded portal vein and was unsatisfactory in two others, in one because she was moribund and in the other because the hepatic artery had been ligated. Dramatic improvement in symptoms occurred in the nine patients in whom embolisation was successfully carried out, with abolition of flushing, severe abdominal pain, and wheeze and reduction in diarrhea from 10.5 (SD 7.6) to 1.6 (0.9) stools/day. Urinary excretion of 5-hydroxyindole acetic acid fell from 1048 (716) to 289 (184) umol/24 hr (200 (137) to 55 (35) mg/24 hr). Complications included one death from septicaemia, a hepatic abscess requiring surgical drainage, abdominal pain in three patients, pleural effusion in two, and transient encephalopathy in one. Relief of symptoms lasted for one to 24 months, and second embolisation in two patients produced further remissions of four to six months. Five patients died, one to 40 months after embolisation, in four cases because of metastases or heart failure. ... /Former/

/LABORATORY ANIMALS: Acute Exposure/ The effects of a single injection of parachlorophenylalanine (PCPA, 300 mg/kg ip) on sleep, motor activity and consummatory behavior were investigated in unrestrained rats which were continuously recorded with telemetric techniques on two control days and six drug days. Slow wave sleep (SWS) was defined as the non-REM sleep (NREMS) fraction with a low predominant EEG frequency. In the 24 hr following PCPA administration, motor activity and food intake were reduced and sleep was increased. SWS was massively enhanced, while REM sleep (REMS) was depressed. The initial phase of sedation was followed by a phase of partial insomnia lasting 1-2 days. SWS and REMS were particularly depressed. A rebound phenomenon was observed at the end of recovery period when some of the SWS and REMS values exceeded the control level. The administration of tryptophan (Trp, 150 mg/kg ip) 28 hr after PCPA pretreatment, causing a significant rise in the brain serotonin (5-HT) concentration, produced a temporary increase in SWS and REMS, and a reduction of motor activity. The experiments show that the depression of SWS and REMS, and the hyperactivity 1-2 days after PCPA administration, are a consequence of the reduced 5-HT level, whereas the involvement of serotonergic mechanisms in the initial sedative phase and in the recovery phase is less clear. The persistence of the daily distribution of sleep and activity, and of the specific pattern of SWS and REMS, indicates that the circadian sleep organization is little affected by 5-HT depletion.

/LABORATORY ANIMALS: Acute Exposure/ Male and female kittens and adult cats were given p-chlorophenylalanine orally /in single doses of 200, 400, 600 mg/kg and at 600 or 800 mg/kg over two days/. After treatment, some of the male cats showed mounting behaviour and the kittens and non-estrous females showed an increase in treading and rubbing which was similar to one aspect of pro-estrus behavior. The treated animals also appeared to suffer from skin irritation and showed increased restlessness which accompanied sleep deprivation. Injection of 5-hydroxytryptophan stopped abnormal sexual activity and restored normal sleep for about 5 hours. It is concluded that 5-hydroxytryptamine-containing neurones inhibit sexual behaviour in cats and that this role can be seen in male and, to some extent, also in female animals.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Weanling rats given a diet containing 300 mg/100 gm para-chlorophenylalanine develop characteristic anterior and posterior lens changes. Approximately 35% continue to complete cataract development and/or a peculiar retractile lens line. Including phenylalanine 1% or 5% to the same diet protects rats against mature cataracts. However, minor lens changes and the refractile line still appear. The absence of any ocular toxicity in monkeys treated with this agent at 300 mg/kg/ day for one year suggests a specific effect only in rats. Mature rats are more resistant to this cataractogenic effect. These lesions do not regress within one year after drug withdrawal.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

Competitive inhibitor of the serotonin (5-HT) synthesis enzyme tryptophan hydroxylase

... The combined administration of phenylalanine (phe) and p-chlorophenylalanine (PCPA) /are models for/... research into the pathogenesis and treatment of PKU. ...

MEDICATION /Former/