![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
1 Department of Pharmacology, Medical Research Laboratories, Charles Pfizer and Company, Inc., Groton, Connecticut
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 
-amino acids and -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.
This article has been cited by other articles:
|
|
 |
|
  Q. Liu, Q. Yang, W. Sun, P. Vogel, W. Heydorn, X.-Q. Yu, Z. Hu, W. Yu, B. Jonas, R. Pineda, et al. Discovery and Characterization of Novel Tryptophan Hydroxylase Inhibitors That Selectively Inhibit Serotonin Synthesis in the Gastrointestinal Tract J. Pharmacol. Exp. Ther., April 1, 2008; 325(1): 47 - 55. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. R. Hodges, G. J. Tattersall, M. B. Harris, S. D. McEvoy, D. N. Richerson, E. S. Deneris, R. L. Johnson, Z.-F. Chen, and G. B. Richerson Defects in Breathing and Thermoregulation in Mice with Near-Complete Absence of Central Serotonin Neurons J. Neurosci., March 5, 2008; 28(10): 2495 - 2505. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Izikki, N. Hanoun, E. Marcos, L. Savale, A. M. Barlier-Mur, F. Saurini, S. Eddahibi, M. Hamon, and S. Adnot Tryptophan hydroxylase 1 knockout and tryptophan hydroxylase 2 polymorphism: effects on hypoxic pulmonary hypertension in mice Am J Physiol Lung Cell Mol Physiol, October 1, 2007; 293(4): L1045 - L1052. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Leon-Ponte,, G. P. Ahern, and P. J. O'Connell Serotonin provides an accessory signal to enhance T-cell activation by signaling through the 5-HT7 receptor Blood, April 15, 2007; 109(8): 3139 - 3146. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Alexandre, D. Popa, V. Fabre, S. Bouali, P. Venault, K.-P. Lesch, M. Hamon, and J. Adrien Early life blockade of 5-hydroxytryptamine 1A receptors normalizes sleep and depression-like behavior in adult knock-out mice lacking the serotonin transporter. J. Neurosci., May 17, 2006; 26(20): 5554 - 5564. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Eddahibi, C. Guignabert, A.-M. Barlier-Mur, L. Dewachter, E. Fadel, P. Dartevelle, M. Humbert, G. Simonneau, N. Hanoun, F. Saurini, et al. Cross Talk Between Endothelial and Smooth Muscle Cells in Pulmonary Hypertension: Critical Role for Serotonin-Induced Smooth Muscle Hyperplasia Circulation, April 18, 2006; 113(15): 1857 - 1864. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A.-E. Allain, P. Meyrand, and P. Branchereau Ontogenic Changes of the Spinal GABAergic Cell Population Are Controlled by the Serotonin (5-HT) System: Implication of 5-HT1 Receptor Family J. Neurosci., September 21, 2005; 25(38): 8714 - 8724. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Cervo, A. Canetta, E. Calcagno, S. Burbassi, G. Sacchetti, S. Caccia, C. Fracasso, D. Albani, G. Forloni, and R. W. Invernizzi Genotype-Dependent Activity of Tryptophan Hydroxylase-2 Determines the Response to Citalopram in a Mouse Model of Depression J. Neurosci., September 7, 2005; 25(36): 8165 - 8172. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Hiraoka, N. Kimura, Y. Furukawa, K.-i. Ogawara, T. Kimura, and K. Higaki Up-Regulation of P-Glycoprotein Expression in Small Intestine under Chronic Serotonin-Depleted Conditions in Rats J. Pharmacol. Exp. Ther., January 1, 2005; 312(1): 248 - 255. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M.-A. Comet, C. Sevoz-Couche, N. Hanoun, M. Hamon, and R. Laguzzi 5-HT-mediated inhibition of cardiovagal baroreceptor reflex response during defense reaction in the rat Am J Physiol Heart Circ Physiol, October 1, 2004; 287(4): H1641 - H1649. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Borg, B. Andree, H. Soderstrom, and L. Farde The Serotonin System and Spiritual Experiences Am J Psychiatry, November 1, 2003; 160(11): 1965 - 1969. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Fukumoto, M. Tatewaki, T. Yamada, M. Fujimiya, C. Mantyh, M. Voss, S. Eubanks, M. Harris, T. N. Pappas, and T. Takahashi Short-chain fatty acids stimulate colonic transit via intraluminal 5-HT release in rats Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2003; 284(5): R1269 - R1276. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-F. Pflieger, F. Clarac, and L. Vinay Postural Modifications and Neuronal Excitability Changes Induced by a Short-Term Serotonin Depletion during Neonatal Development in the Rat J. Neurosci., June 15, 2002; 22(12): 5108 - 5117. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Branchereau, J. Chapron, and P. Meyrand Descending 5-Hydroxytryptamine Raphe Inputs Repress the Expression of Serotonergic Neurons and Slow the Maturation of Inhibitory Systems in Mouse Embryonic Spinal Cord J. Neurosci., April 1, 2002; 22(7): 2598 - 2606. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Persico, E. Mengual, R. Moessner, S. F. Hall, R. S. Revay, I. Sora, J. Arellano, J. DeFelipe, J. M. Gimenez-Amaya, M. Conciatori, et al. Barrel Pattern Formation Requires Serotonin Uptake by Thalamocortical Afferents, and Not Vesicular Monoamine Release J. Neurosci., September 1, 2001; 21(17): 6862 - 6873. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A.M. Persico, C. Altamura, E. Calia, S. Puglisi-Allegra, R. Ventura, F. Lucchese, and F. Keller Serotonin Depletion and Barrel Cortex Development: Impact of Growth Impairment vs. Serotonin Effects on Thalamocortical Endings Cereb Cortex, February 1, 2000; 10(2): 181 - 191. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. L. Upton, N. Salichon, C. Lebrand, A. Ravary, R. Blakely, I. Seif, and P. Gaspar Excess of Serotonin (5-HT) Alters the Segregation of Ispilateral and Contralateral Retinal Projections in Monoamine Oxidase A Knock-Out Mice: Possible Role of 5-HT Uptake in Retinal Ganglion Cells During Development J. Neurosci., August 15, 1999; 19(16): 7007 - 7024. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. E Austic, C.-L. Su, B. J Strupp, and D. A Levitsky Effects of dietary mixtures of amino acids on fetal growth and maternal and fetal amino acid pools in experimental maternal phenylketonuria Am. J. Clinical Nutrition, April 1, 1999; 69(4): 687 - 696. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Tada, K. Kasamo, N. Ueda, T. Suzuki, T. Kojima, and K. Ishikawa Anxiolytic 5-Hydroxytryptamine1A Agonists Suppress Firing Activity of Dorsal Hippocampus CA1 Pyramidal Neurons through a Postsynaptic Mechanism: Single-Unit Study in Unanesthetized, Unrestrained Rats J. Pharmacol. Exp. Ther., February 1, 1999; 288(2): 843 - 848. [Abstract] [Full Text]
|
|
|
|
|
|
P. De Deurwaerdere, L. Stinus, and U. Spampinato Opposite Change of In Vivo Dopamine Release in the Rat Nucleus Accumbens and Striatum That Follows Electrical Stimulation of Dorsal Raphe Nucleus: Role of 5-HT3 Receptors J. Neurosci., August 15, 1998; 18(16): 6528 - 6538. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Imeri, S. Bianchi, and M. Mancia Muramyl dipeptide and IL-1 effects on sleep and brain temperature after inhibition of serotonin synthesis Am J Physiol Regulatory Integrative Comp Physiol, November 1, 1997; 273(5): R1663 - R1668. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. E. Ciarlone Alteration of Lidocaine- or Procaine-induced Convulsions by Manipulation of Brain Amines Journal of Dental Research, February 1, 1981; 60(2): 182 - 186. [PDF]
|
|
|
|
 |
|
 M. S. Hudecki, C. M. Pollina, A. K. Bhargava, and R. S. Hudecki Screening of Antiserotoninergic Drugs With the Genetically Dystrophic Chicken Arch Neurol, September 1, 1980; 37(9): 545 - 550. [Abstract] [PDF]
|
|
|
|
 |
|
 J. Reinhard Jr, J. Liebmann, A. Schlosberg, and M. Moskowitz Serotonin neurons project to small blood vessels in the brain Science, October 5, 1979; 206(4414): 85 - 87. [Abstract] [PDF]
|
|
|
|
|
|
V. Nahmod, S Finkielman, E. Benarroch, and C. Pirola Angiotensin regulates release and synthesis of serotonin in brain Science, December 8, 1978; 202(4372): 1091 - 1093. [Abstract] [PDF]
|
|
|
|
|
|
C. Ambrus, J. Ambrus, C Horvath, H Pedersen, S Sharma, C Kant, E Mirand, R Guthrie, and T Paul Phenylalanine depletion for the management of phenylketonuria: use of enzyme reactors with immobilized enzymes Science, September 1, 1978; 201(4358): 837 - 839. [Abstract] [PDF]
|
|
|
|
 |
|
 B. Shopsin, E. Friedman, and S. Gershon Parachlorophenylalanine Reversal of Tranylcypromine Effects in Depressed Patients Arch Gen Psychiatry, July 1, 1976; 33(7): 811 - 819. [Abstract] [PDF]
|
|
|
|
|
|
O Greengard, M. Yoss, and J. Del Valle Alpha-methylphenylalanine, a new inducer of chronic hyperphenylalaninemia in sucling rats Science, June 4, 1976; 192(4243): 1007 - 1008. [Abstract] [PDF]
|
|
|
|
|
|
S. Breisch, F. Zemlan, and B. Hoebel Hyperphagia and obesity following serotonin depletion by intraventricular p-chlorophenylalanine Science, April 23, 1976; 192(4237): 382 - 385. [Abstract] [PDF]
|
|
|
|
|
|
D. Emery and B. Sachs Ejaculatory pattern in female rats without androgen treatment Science, October 31, 1975; 190(4213): 484 - 486. [Abstract] [PDF]
|
|
|
|
|
|
J. Harvey, S. McMaster, and L. Yunger P-Chloramphetamine: Selective neurotoxic action in brain Science, March 7, 1975; 187(4179): 841 - 843. [Abstract] [PDF]
|
|
|
|
|
|
J. Mendels and A. Frazer Brain Biogenic Amine Depletion and Mood Arch Gen Psychiatry, April 1, 1974; 30(4): 447 - 451. [Abstract] [PDF]
|
|
|
|
|
|
R. M. Quock and A. Horita Apomorphine: Modification of Its Hyperthermic Effect in Rabbits by p-Chlorophenylalanine Science, February 8, 1974; 183(4124): 539 - 540. [Abstract] [PDF]
|
|
|
|
|
|
H. S. Akiskal and W. T. McKinney Jr. Depressive Disorders: Toward a Unified Hypothesis: Clinical, experimental, genetic, biochemical, and neurophysiological data are integrated Science, October 5, 1973; 182(4107): 20 - 29. [Abstract] [PDF]
|
|
|
|
|
|
F. P. Zemlan, I. L. Ward, W. R. Crowley, and D. L. Margules Activation of Lordotic Responding in Female Rats by Suppression of Serotonergic Activity Science, March 9, 1973; 179(4077): 1010 - 1011. [Abstract] [PDF]
|
|
|
|
|
|
T. N. Chase Serotonergic Mechanisms in Parkinson's Disease Arch Neurol, October 1, 1972; 27(4): 354 - 356. [Abstract] [PDF]
|
|
|
|
|
|
W. E. Bunney Jr., F. K. Goodwin, D. L. Murphy, K. M. House, and E. K. Gordon The "Switch Process" in Manic-Depressive Illness: II. Relationship to Catecholamines, REM Sleep, and Drugs Arch Gen Psychiatry, September 1, 1972; 27(3): 304 - 309. [Abstract] [PDF]
|
|
|
|
|
|
T. N. Chase, A. M. Watanabe, H. K. H. Brodie, and E. F. Donnelly Huntington's Chorea: Effect of Serotonin Depletion Arch Neurol, March 1, 1972; 26(3): 282 - 284. [Abstract] [PDF]
|
|
|
|
|
|
D. E. Redmond Jr., I. W. Maas, A. Kling, C. W. Graham, and H. Dekirmenjian Social Behavior of Monkeys Selectively Depleted of Monoamines Science, October 22, 1971; 174(4007): 428 - 431. [Abstract] [PDF]
|
|
|
|
|
|
K. M. Meyers, W. M. Dickson, J. E. Lund, and G. A. Padgett Muscular Hypertonicity: Episodes in Scottish Terrier Dogs Arch Neurol, July 1, 1971; 25(1): 61 - 68. [Abstract] [PDF]
|
|
|
|
|
|
G. K. Aghajanian and I. M. Asher Histochemical Fluorescence of Raphe Neurons: Selective Enhancement by Tryptophan Science, June 11, 1971; 172(3988): 1159 - 1161. [Abstract] [PDF]
|
|
|
|
|
|
G. K. Aghajanian, A. W. Graham, and M. H. Sheard Serotonin-Containing Neurons in Brain: Depression of Firing by Monoamine Oxidase Inhibitors Science, September 11, 1970; 169(3950): 1100 - 1102. [Abstract] [PDF]
|
|
|
|
|
|
R. E. Whalen and W. G. Luttge P-Chlorophenylalanine Methyl Ester: An Aphrodisiac? Science, September 4, 1970; 169(3949): 1000 - 1001. [Abstract] [PDF]
|
|
|
|
|
|
J. Ferguson, S. Henriksen, H. Cohen, G. Mitchell, J. Barchas, and W. Dement "Hypersexuality" and Behavioral Changes in Cats Caused by Administration of p-Chlorophenylalanine Science, April 24, 1970; 168(3930): 499 - 501. [Abstract] [PDF]
|
|
|
|
|
|
A. Tagliamonte, P. Tagliamonte, G. L. Gessa, and B. B. Brodie Compulsive Sexual Activity Induced by p-Chlorophenylalanine in Normal and Pinealectomized Male Rats Science, December 12, 1969; 166(3911): 1433 - 1435. [Abstract] [PDF]
|
|
|
|
|
|
M. Jouvet Biogenic Amines and the States of Sleep Science, January 3, 1969; 163(3862): 32 - 41. [PDF]
|
|
|
|
|
|
E. L. Way, H. H. Loh, and F.-h. Shen Morphine Tolerance, Physical Dependence, and Synthesis of Brain 5-Hydroxytryptamine Science, December 13, 1968; 162(3859): 1290 - 1292. [Abstract] [PDF]
|
|
|
|
|
|
R. D. Myers and W. L. Veale Alcohol Preference in the Rat: Reduction Following Depletion of Brain Serotonin Science, June 28, 1968; 160(3835): 1469 - 1471. [Abstract] [PDF]
|
|
|
|
|
|
E. D. Weitzman, M. M. Rapport, P. McGregor, and J. Jacoby Sleep Patterns of the Monkey and Brain Serotonin Concentration: Effect of p-Chlorophenylalanine Science, June 21, 1968; 160(3834): 1361 - 1363. [Abstract] [PDF]
|
|
|
|
 |
|
 S. Chiavegatto, V. L. Dawson, L. A. Mamounas, V. E. Koliatsos, T. M. Dawson, and R. J. Nelson Brain serotonin dysfunction accounts for aggression in male mice lacking neuronal nitric oxide synthase PNAS, January 30, 2001; 98(3): 1277 - 1281. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
