The effects of 5-HTP on para-chlorophenylalanine (p-CPA) attenuation of “conflict” behavior
TL;DR: The 5-HTP reversal of p-CPA effects on “conflict” suggests the possible interpretation that the p- CPA effects are due to serotonin (5-HT) depletion.
About: This article is published in European Journal of Pharmacology.The article was published on 1970-03-01. It has received 159 citations till now.
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TL;DR: A large number of predicted genes encoding surface and secreted proteins, transporters, and transcriptional regulators are found, consistent with the ability of both species to adapt to diverse environments.
Abstract: Listeria monocytogenes is a food-borne pathogen with a high mortality rate that has also emerged as a paradigm for intracellular parasitism. We present and compare the genome sequences of L. monocytogenes (2,944,528 base pairs) and a nonpathogenic species, L. innocua (3,011,209 base pairs). We found a large number of predicted genes encoding surface and secreted proteins, transporters, and transcriptional regulators, consistent with the ability of both species to adapt to diverse environments. The presence of 270 L. monocytogenes and 149 L. innocua strain-specific genes (clustered in 100 and 63 islets, respectively) suggests that virulence in Listeria results from multiple gene acquisition and deletion events.
1,430 citations
TL;DR: Observations lead to the conclusion that different 5-HT mechanisms, mediated by different receptor subtypes, are involved in the genesis of anxiety.
448 citations
TL;DR: In this paper, the role of serotonin function in the development of panic anxiety was assessed in healthy subjects and agoraphobic and panic disorder patients with m-chlorophenylpiperazine (MCPP).
Abstract: To assess the role of serotonin function in the development of panic anxiety, the behavioral and biochemical responses to the serotonin receptor agonist, m-chlorophenylpiperazine (MCPP) was examined in healthy subjects and agoraphobic and panic disorder patients. MCPP had anxiogenic effects in both the healthy subjects and patients. Panic attacks meeting DSM-III criteria occurred following MCPP in 12 of 23 patients and 6 of 19 healthy subjects (NS) and other ratings of anxiety also did not distinguish the two groups. MCPP resulted in significant but similar increases in cortisol, prolactin, and growth hormone in the healthy subjects and patients. The results of this investigation suggest that serotonin neuronal dysfunction may not be of etiologic significance in most panic disorder patients. However, the observed anxiogenic properties of MCPP suggest that additional studies of the role of serotonin systems in the pathophysiology of human anxiety disorders are indicated.
435 citations
TL;DR: The anxiety-reducing activity, and the decrease in serotonin turnover induced by benzodiazepines, were maintained over repeated doses, whereas depressant activity,and the decrease induced in norepinephrine turnover, both rapidly underwent tolerance.
Abstract: The anxiety-reducing effects of minor tranquilizers in the rat conflict test were mimicked by serotonin antagonists and by p-chlorophenylalanine, an inhibitor of serotonin synthesis; the depressant effects of the minor tranquilizers were mimicked by norepinephrine antagonists Intraventricular injections of serotonin led to a suppression of behavior, and also antagonized the anxiety-reducing action of benzodiazeprines Intraventricular injections of norepinephrine led to a release of punished behavior from suppression, and also antagonized the depressant action of benzodiazepines The anxiety-reducing activity, and the decrease in serotonin turnover induced by benzodiazepines, were maintained over repeated doses, whereas depressant activity, and the decrease induced in norepinephrine turnover, both rapidly underwent tolerance Tranquilizers may exert their anxiety-reducing effects by a reduction of serotonin activity in a behaviorally suppressive punishment system, and they may exert their depressant effects by a reduction of norepinephrine activity in a behaviorally facilitatory reward system
322 citations
TL;DR: The use of 5-HT3 receptor antagonists reveals an important role for 5-hydroxytryptamine in the control of disturbed behavior in the absence of effect on normal behavior.
251 citations
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Book•
01 Jan 19573,148 citations
Journal Article•
TL;DR: The results suggest that p -chlorophenylalanine may effect 5HT depletion by inhibiting the biosynthesis of this monoamine, possibly by blocking tryptophan hydroxylation.
Abstract: p -Chlorophenylalanine has been found to be a potent and selective depletor of brain serotonin (5HT) in mice, rats and dogs. Brain 5-hydroxy-3-indolylacetic acid (5HIAA) content was also depleted by the drug, but catecholamine concentrations were only slightly decreased. Peripheral stores of 5HT were also lowered. In rats, p -chlorophenylalanine reduced the normal increase in brain 5-hydroxyl-3-indolyl compounds following L-tryptophan loading (without apparently affecting tryptophan uptake into brain), completely prevented the increase in brain 5HT accompanying inhibition of monoamine oxidase by pargyline and blocked the increase in brain 5HIAA usually observed after reserpine treatment. p -Chlorophenylalanine slightly diminished the usual increase in brain 5HT in rats following 5-hydroxytryptophan (5HTP) administration, but decreased the rate of disappearance of excess 5HT and antagonized the increase in brain 5HIAA. p -Chlorophenylalanine did not inhibit monoamine oxidase or 5HTP-decarboxylase in vitro and exerted no effect on monoamine oxidase or 5HTP decarboxylase activity of rat tissues in vivo. In contrast, p -chlorophenylalanine inhibited liver tryptophan hydroxylase in vitro and strongly suppressed the tryptophan- and phenylalanine-hydroxylating capabilities of livers of rats treated with it. These results suggest that p -chlorophenylalanine may effect 5HT depletion by inhibiting the biosynthesis of this monoamine, possibly by blocking tryptophan hydroxylation. A blockade of uptake of amino acid precursor might also contribute to the effect of decreasing 5HT biosynthesis. The slow depletion (2-3 days) of brain 5HT induced by p -chlorophenylalanine suggests that an active metabolite might be formed. p -Chlorophenylpyruvic acid exerted essentially the same pharmacologic effects as the amino acid, but it cannot be ascertained at present whether it is the active metabolite because of the interconversion of α-amino acids and α-keto acids in vivo. p -Chlorophenethylamine may be excluded as the metabolite responsible for the action of p -chlorophenylalanine because of the brief duration of the amine in brain and the short lasting, nonselective decrease of both 5HT and norepinephrine produced by the amine. A study of structural variation in the phenylalanine series indicated a specific requirement of a single chlorine substituent in the para position for potent in vivo activity. Rats treated with p -chlorophenylalanine displayed few apparent signs, and certainly not sedation. p -Chlorophenylalanine did not block characteristic signs elicited by reserpine or tetrabenazine in rats. Accordingly, the central actions of reserpine and reserpine-like drugs may possibly be dissociated from both 5HT concentrations and the formation of new 5HT in brain.
1,754 citations
TL;DR: The technique permits a separation on a behavioral basis of meprobamate, pentobarbital and phenobarbitals from promazine and d-amphetamine from promazines and d -amphetamine.
Abstract: Conflict behavior was induced in rats by simultaneously rewarding with liquid food and punishing with pain shock every lever response made in the presence of a tone. Meprobamate, phenobarbital and pentobarbital increased the number of shocks a rat would accept in order to obtain the food reward; in contrast, promazine and d-amphetamine decreased the number of shocks taken. The technique thus permits a separation on a behavioral basis of meprobamate, pentobarbital and phenobarbital from promazine and d-amphetamine.
751 citations
TL;DR: The data suggest that the alteration in pain sensitivity was a result of serotonin depletion in the central nervous system, and the compound resulted in decreased “emotional reactivity” (as measured by a conditioned emotional stimulus) and some decreased spontaneous motor activity.
Abstract: p-Chlorophenylalanine, a potent depletor of brain serotonin, produces faster acquisition of a conditioned (active) avoidance response if a low intensity of current is used. This faster acquisition appears to be primarily, and perhaps solely, a result of the drug's action in increasing animals' sensitivity to pain (electric shock). The data suggest that the alteration in pain sensitivity was a result of serotonin depletion in the central nervous system. The compound also resulted in decreased “emotional reactivity” (as measured by a conditioned emotional stimulus) and some decreased spontaneous motor activity. It is possible that the reduced emotional reactivity produced by p-ClPhe could have also contributed to a faster acquisition of the avoidance response. The drug did not affect learning ability as measured by acquisition of a position habit in a simple T-maze (water reinforcement). The decreased “emotional reactivity” and decreased spontaneous motor activity should not be confused with a picture of sedation or tranquilization. p-ClPhe treated animals generally appear quite normal in terms of gross behavior, and might even be somewhat more “irritable” when handled (Koe and Weissman, 1966b) possibly because of an increased sensitivity to touch as well as pain.
420 citations
Journal Article•
TL;DR: The findings support the conclusion that tryptophan hydroxylation is the rate-limiting enzymic step in serotonin biosynthesis and cause an irreversible inactivation of the enzyme in vivo.
Abstract: Administration of the specific serotonin depletor p-chlorophenylalanine to rats results in marked inhibition of tryptophan hydroxylase of the brain. The enzyme inhibition can be correlated with and is assumed to be responsible for brain serotonin depletion. Although p-chlorophenylalanine is a competitive inhibitor of tryptophan hydroxylase in vitro, it causes an irreversible inactivation of the enzyme in vivo. The findings also support the conclusion that tryptophan hydroxylation is the rate-limiting enzymic step in serotonin biosynthesis.
418 citations