Download Tryptophan-Free Diets: A Physiological Tool to Study

Tryptophan-Free Diets: A Physiological Tool to
Study Brain Serotonin Function
F. Fadda
Tryptophan-free diets produce a specific reduction of brain serotonin synthesis and release. This
method for lowering neural serotonin function has been extensively used in both laboratory animals and humans to study the role of serotonin in a variety of behaviors, such as aggressiveness, sleep, sexual behavior, anxiety, mood, memory, and so forth.
ince the early 1970s, one of the more exciting developments in nutrition research has been the demonstration that
brain function may be influenced by the availability of various
nutrients in the diet (for review see Ref. 3). Midway through the
1970s, Gessa et al. (5) first demonstrated that the acute administration of a mixture of essential amino acids lacking tryptophan (TRP) produced a specific and long-lasting reduction of
brain TRP and serotonin (5-HT) levels in rats. This result
opened up an active field of research. On the one hand,
attempts have been made to understand the mechanisms
through which tryptophan-free amino acid mixtures reduce
brain 5-HT levels, and on the other hand, TRP-free diets have
offered a specific and nontoxic tool for studying the role of
5-HT in the regulation of different physiological parameters
and behavioral indexes in laboratory animals and humans.
The role of TRP in the physiological regulation of 5-HT
biosynthesis in the brain
The initial step in the biosynthesis of 5-HT is the conversion
of TRP to 5-hydroxytryptophan, a reaction catalyzed by the
enzyme tryptophan hydroxylase. The activity of this enzyme is
considered the rate-limiting step in the synthesis of 5-HT.
Indeed, the Michaelis-Menten constant for tryptophan hydroxylase is several times higher than that of TRP concentration in
the brain, thus suggesting that under normal physiological conditions the activity of this enzyme is not saturated in vivo with
its substrate. The degree of enzyme saturation, and therefore the
rate of tryptophan hydroxylation, is linked to the brain TRP concentration (Fig. 1A). Thus the concentration of TRP in the brain
is the major factor in controlling the synthesis of 5-HT (6). Inasmuch as the concentration of brain TRP is controlled by the
peripheral availability of this amino acid, the rate of synthesis of
5-HT depends on the plasma concentration of TRP. In particular, the concentration of TRP in the brain and, therefore, the rate
of 5-HT synthesis may depend on 1) the concentration of free
serum TRP in the plasma (TRP is the only amino acid present in
the plasma bound to serum proteins) and 2) the concentration
of the large neutral amino acids (LNAAs) sharing the same transport mechanism from blood to brain with TRP (Fig. 1A) (6).
F. Fadda is in the Department of Biochemistry and Human Physiology, Section of Human Physiology, University of Cagliari, Via Porcell 4, 09124
Cagliari, Italy.
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Biochemical effects of TRP-free diets
The TRP-free amino acid mixture described by Gessa et al.
(5) contained all of the essential amino acids except TRP, plus
glycine as integrator of nitric groups. The composition of the
mixture was (in %) 45.9 L-glycine, 15.3 L-lysine, 3.0 L-histidine, 6.1 L-methionine, 6.9 L-phenylalanine, 3.0 L-leucine, 6.1
L-isoleucine, 5.3 L-threonine, 7.6 L-valine, and 0.8 arginine.
The administration of this TRP-free amino acid mixture in rats
produced a sharp drop in the concentration of serum TRP,
associated with a decrease in brain TRP, 5-HT, and 5-hydroxyindolacetic acid (5-HIAA) levels in rat brain. The same effect
was observed either in response to a balanced diet in which
TRP was removed or in response to foods deficient in this
essential amino acid (1). Interestingly, Young et al. (13) found
that after the administration of a TRP-free mixture of amino
acids, the concentration of TRP and 5-HIAA decreased in the
cerebrospinal fluid of primates but the concentration of tyrosine and the catecholamine metabolites homovanillic acid
and 3-methoxy-4-hydroxyphenylethylene glycol did not, suggesting that the catecholaminergic system is not influenced
by the mixture.
In our laboratory, the TRP-free amino acid mixture was first
used in human subjects to evaluate possible mental changes
(2). The mixture contained all essential amino acids, the composition of which (in %) was: 33 L-glycine, 8.8 L-lysine, 12 Lmethionine, 12 L-phenylalanine, 12 L-leucine, 7.7 L-isoleucine,
5.5 L-threonine, and 8.8 L-valine. We observed that 18.2 g of
the above mixture caused a substantial decline in plasma TRP
(60% of initial value 4 h after the ingestion), which was
related to a high level of anxiety (see below). Inasmuch as the
TRP-free amino acid mixtures in humans produced a fall in
serum TRP similar to that obtained in laboratory animals, this
indicated that such a technique offered a nonpharmacological means for effectively decreasing brain TRP content and
presumably brain 5-HT. Young et al. (14) also used a TRP-free
amino acid mixture in humans, but the composition was different from the one used by our group. They used all of the
amino acids (except aspartic and glutamic acid) in the same
proportions occurring in human milk. Five hours after the
ingestion of this TRP-free amino acid mixture, a 76%
decrease of plasma TRP was found.
Recently, Nishizawa et al. (9) reported an in vivo measurement of 5-HT synthesis in the human brain with the use of
positron emission tomography. They measured the rate of
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S
5-HT synthesis in baseline conditions and after the ingestion
of the TRP-free amino acid mixture. Dietary depletion of TRP
lowered the rate of brain 5-HT synthesis in male and female
subjects. The TRP-free diet also produced a decline in cerebrospinal fluid TRP and 5-HIAA in healthy human subjects.
These results clearly indicate that TRP depletion in humans
induces a decline in 5-HT synthesis and turnover as well as
a probable decrease in the neuronal release of this amine.
The role of TRP in the regulation of central 5-HT
transmission
It has been suggested that the rate at which 5-HT is released
varies with that of 5-HT synthesis. This assumption is based on
studies reporting modifications in some behavioral indexes
related to 5-HT function when plasma and brain TRP concentrations are altered in vivo. Recently, Stancampiano et al. (12),
using in vivo brain microdialysis, examined the effect of the
reduction of brain TRP content on the release of endogenous
5-HT. They demonstrated for the first time that the reduction
of TRP levels induced by the acute administration of a TRPfree amino acid mixture decreases d-fenfluramine-induced
(Fig. 2) and spontaneous (Fig. 3) release of 5-HT in the hippocampus of freely moving rats. Moreover, when a TRP-free
diet is administered for 5 days, there is a progressive and
marked decrease in the release of 5-HT. In rats treated with a
TRP-free diet, at the fifth day of dieting 5-HT was not
detectable in the hippocampus (Fig. 4) (unpublished observations). The reduction of extracellular content of 5-HT in control rats was due to a glial reaction around the dialysis tube.
In conclusion, a decrease in brain TRP concentration reduces
5-HT synthesis and subsequently its release.
The mechanism through which the administration of a
TRP-free amino acid diet causes the reduction of plasmatic
TRP, and consequently brain TRP and 5-HT synthesis, has
been suggested by Gessa et al. (6). These researchers hypothesized that protein synthesis is the major mechanism causing
a TRP decrease in the blood. The amino acids administered
with the diet induce protein synthesis at tissue levels. During
the protein synthesis, the tissues should utilize the extracellular endogenous TRP, thus lowering its concentration (Fig. 1B).
To verify this hypothesis, researchers have studied the effect
of the ingestion of the TRP-free diet in rats previously treated
with a protein synthesis inhibitor, cycloheximide. The blockade of protein synthesis after administration of increasing
FIGURE 2. Effect of T– and B amino acid mixture on d-fenfluramine-evoked
5-HT release in hippocampus. Values represent means ± SE of 5 rats. The average
of values taken at 120 min after ingestion of B and T– mixtures were 48.6 ± 5.7
and 33.2 ± 4.3 fmol/40 µl sample respectively. d-Fenfluramine (10 mg/kg) was
administered 120 min after the oral administration with the amino acid mixture. +P < 0.05 with respect to 120 min values. *P < 0.05 between B and T– in
the corresponding period. Adapted from Stancampiano et al. (12).
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FIGURE 1. Serotonin synthesis and release. A: normal condition. Two enzymes synthesize serotonin (5-HT): tryptophan hydroxylase makes 5-hydroxytryptophan
(5-HTP), and aromatic L-amino acid decarboxylase forms 5-HT. Tryptophan hydroxylase is considered the rate-limiting step in the synthesis of 5-HT. Tryptophan
(TRP) competes with other large neutral amino acids (LNAAs) for uptake in the brain. After release, 5-HT interacts with various serotonergic receptors; it is recaptured and stored in the synaptic vesicles and/or catabolized by the enzyme monoamine oxidase (MAO) to 5-hydroxyindolacetic acid (5-HAA). B: after TRP-free
diet. Following a challenge dose of a TRP-free amino acid mixture (T–) the endogenous serum TRP is rapidly removed from circulation and primarily utilized for
incorporation into tissue protein. The fall in blood TRP reduces the synthesis and release in the serotonergic neurons.
doses of cycloheximide blocks the decrease of plasmatic TRP
induced by the TRP-free diet (6).
Another mechanism that contributes to the reduction of
brain TRP after the acute ingestion of a TRP-free diet is that
TRP competes for the same carrier system that transports all
of the LNAAs across the blood-brain barrier. However, it has
been found that, following administration of the six neutral
amino acids, the effect on brain TRP is very slight, thus suggesting that the competition at the blood-brain barrier is a relatively minor factor in decreasing brain 5-HT (5, 6).
Behavioral effects of TRP depletion
The TRP-free amino acid diet offers a nonpharmacological
means for effectively decreasing brain 5-HT function. With
respect to other antagonists, the advantage of this method lies
in its high specificity and nontoxicity. Therefore, this selective
method for lowering central serotonergic activity has been
extensively used both in laboratory animals and humans to
study the role of 5-HT in a variety of physiological and
behavioral functions, such as macronutrient selection, pain
sensitivity, aggressiveness, sleep, sexual behavior, mood,
anxiety, and memory and learning. A short review of documented behavioral and physiological effects is given below.
Macronutrients selection. It has been observed that animals are able to spontaneously choose a balanced amount of
macronutrients. This observation suggested the existence of a
possible brain control mechanism for food selection. It is well
known that diet influences the concentration of TRP in the
brain and therefore the concentration of 5-HT. The ingestion
of proteins diminishes rat brain TRP and 5-HT, because all of
the LNAAs compete with TRP for transportation across the
blood-brain barrier. Conversely, carbohydrate consumption
increases TRP and 5-HT in the brain because the ingestion of
carbohydrates induces an increase in blood insulin, which in
turn increases the uptake of the branched chain amino acids
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FIGURE 4. Effect of 5 days consumption of TRP-free (T–) or balanced (B) diets
on 5-HT release in the hippocampus expressed as a percentage of basal
release measured before (day 0) and during dieting. *P < 0.05; **P < 0.01
between T– and B on corresponding day. Statistical analysis were performed
by Newman Keuls test.
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FIGURE 3. Effect of TRP-free amino acid mixture (T–) and a balanced one (B) on
5-HT release in the hippocampus expressed as a percentage of basal release.
Average of values of T– and B groups taken at time = 0 was 112 ± 11 fmol/40 µl
sample. *P < 0.05 between T– and B in the corresponding period. Adapted from
Stancampiano et al. (12).
(leucine, isoleucine, and valine) into muscle, thus decreasing
their plasmatic concentration and competition at the bloodbrain barrier. Since proteins and glucides have opposite
effects on brain 5-HT, these fluctuations in 5-HT can control
the relative intake of proteins and glucides. In confirmation
of this hypothesis, the acute administration of a TRP-free
amino acid mixture increased carbohydrate selection,
whereas a glucide meal supplemented with TRP markedly
increases protein selection in laboratory animals.
The effect of a TRP-free amino acid mixture on food selection has also been studied in humans (15). In this study,
human subjects ingested a TRP-free amino acid mixture or a
nutritionally balanced one. Five hours after ingestion of the
mixtures, subjects were allowed to choose different foods
from a buffet. The TRP-free mixture was associated with a
decrease in protein selection, but not in carbohydrates, fat, or
total calories. The decline in protein selection observed in
humans is consistent with the decrease in protein selection
observed in laboratory animals, thus suggesting that brain
5-HT may be involved in the control of the choice of
macronutrients in humans as well.
Pain sensitivity. In laboratory animals, the TRP depletion
method confirms data obtained by using serotonergic antagonists: a reduction of pain perception threshold. The acute
administration of a TRP-free amino acid mixture as well as
the chronic administration of food deficient in TRP causes an
increase in pain sensitivity in laboratory animals. Together,
these findings confirm the hypothesis that 5-HT is implicated
in sensitivity to painful stimuli (3).
Aggressiveness. Mouse-killing behavior is considered an
index of aggressiveness in rats. Mouse-killing behavior was
induced in nonkiller rats and was facilitated in killer rats
kept on a TRP-free diet for 4–6 days (see Ref. 12). This
increased killing behavior was associated with a reduction in
brain 5-HT and 5-HIAA. Different research groups, using
several models of aggression (i.e., shock-induced fighting,
mood. It has been suggested that these psychological effects
may have a negative effect on the performance of an accuracy
task (see Ref. 11). Further studies with a larger number of subjects are needed to confirm the data obtained in humans.
Acute TRP depletion in some psychiatric disturbances
The last decade has seen the investigation of the effect of
short-term TRP depletion in some psychopathological disturbances, in which experimental evidence suggests that they are
related to 5-HT dysfunction. For example, in drug-remitted
depressed patients, depressive relapses have been observed
following ingestion of a TRP-free amino acid mixture, with a
gradual return to a normal mood when patients returned to a
normal diet. In women with premenstrual syndrome, TRP
depletion causes an augmented irritability, anxiety, and overreactivity. In bulimic patients, the TRP-free amino acid mixture
enhanced dysphoria as well as anxiety. It has been suggested
that these effects may be due to decreased 5-HT release in the
brain. On the other hand, in other psychiatric disturbances in
which the 5-HT system appears to be important, no effect has
been observed after acute TRP depletion. For example, patients
with obsessive-compulsive disorders did not significantly
change their mean rating of obsession and compulsion subsequent to acute ingestion of TRP-free amino acid mixture. In
patients with panic disorder, TRP depletion was not anxiogenic
or panicogenic. In these cases, other neurotransmitter systems
as well as 5-HT are probably implicated.
In conclusion, the TRP depletion paradigm is used at present as a specific and nontoxic method for evaluating effects
produced by a temporary reduction of 5-HT function in
humans. The TRP depletion method could be used to study
behavior in which the role of 5-HT is unknown. Finally, other
neurotransmitters may be influenced by diet (i.e., dopamine,
noradrenaline, and acetylcholine) by manipulating their precursors. Diets lacking phenylalanine or choline may be used
as a tool to study the physiological and behavioral effects
produced by a reduction of the respective neurotransmitters,
similarly to what is found for 5-HT.
I am most grateful to R. Stancampiano for precious collaboration and critical reading of the manuscript. I thank M. Ibba for help in constructing Fig. 1.
I apologize to the authors of many important contributions that could not be
cited due to space limitations.
References
1. Biggio G, Fadda F, Fanni P, Tagliamonte A, and Gessa GL. Rapid depletion
of serum tryptophan, brain tryptophan, serotonin and 5-hydroxyindolacetic acid by a tryptophan-free diet. Life Sci 14: 1321–1329, 1974.
2. Concu A, Fadda F, Blanco S, Congia S, and Lostia M. Mental changes
induced by the oral administration of tryptophan-free amino acid mixture
in man. IRCS Med Sci 5: 520, 1977.
3. Fernstrom JD. Role of precursor availability in control of monoamine
biosynthesis in brain. Physiol Rev 63: 484–546, 1983.
4. Fratta W, Biggio G, and Gessa GL. Homosexual mounting behavior
induced in male rats and rabbits by a tryptophan-free diet. Life Sci 21:
379–384, 1977.
5. Gessa GL, Biggio G, Fadda F, Corsini GU, and Tagliamonte A. Effect of
the oral administration of tryptophan-free amino acid mixtures on serum
tryptophan and serotonin metabolism. J Neurochem 22: 869–870, 1974.
News Physiol. Sci. • Volume 15 • October 2000
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pain sensitivity, and muricide behavior), confirmed that such
a diet increases aggressiveness in rats. Increased aggressiveness and irritability has also been observed in monkeys after
the administration of a TRP-free amino acid mixture. More
recently, a significant increase in aggressive response was
found in healthy human subjects with the use of an aggression paradigm, after the administration of a TRP-free amino
acid mixture (8). These results are consistent with the hypothesis that brain 5-HT neurons exert inhibitory control over
aggressive behavior.
Sleep. With the use of pharmacological manipulations, a
role of the serotonergic system has been demonstrated in
sleep, though the results are not univocal. The acute administration of a TRP-free amino acid mixture, prepared as
described in our previous report (2), causes in humans a
decrease in stage 4 sleep latency and an increase in stage 4
sleep, but REM sleep did not change significantly (7). In
rats, on the other hand, a significant decrease of REM sleep
was found (7). Although the total sleep duration in rat and
human did not significantly change, the different effect of
the diet in the rat and human may be due to a different role
of 5-HT in the regulation of sleep.
Sexual behavior. It has been well known since the middle
of 1960s that the pharmacological reduction of serotonergic
activity induces compulsive sexual activity in laboratory animals. On the basis of this finding, different research groups
have utilized diets either deficient in or lacking TRP to reveal
possible effects on sexual behavior. It has been demonstrated
that a TRP-free diet produced a significant increase in maleto-male mounting behavior both in rats and rabbits (4). Similarly, a TRP-deficient diet facilitates the copulatory behavior
of male rats with females in estrus. These results clearly
demonstrate that 5-HT plays an inhibitory role in sexual
behavior. Interestingly, food deficient in TRP, such as corn,
may have aphrodisiac properties.
Mood. Young et al. (14) first demonstrated that the ingestion
of a TRP-free amino acid mixture causes a rapid lowering of
mood in normal male subjects. This result has also been
observed in healthy men with a multigenerational family history
of major affective disorders. Moreover, the acute ingestion of a
TRP-free amino acid mixture may have a transient depressive
effect in drug-remitted depressed patients (see below). Other
studies performed on normal women confirm what was found
in men. However, women appear to be more susceptible than
men to the depressive effect induced by TRP depletion.
Memory and learning. Recently, we found that the TRP-free
diet does not affect avoidance learning nor spatial memory performance in rats, although it did diminish the release of 5-HT in
the hippocampus and cortex (11). In contrast to the results
obtained in animals, Riedel et al. (10) found an impairment of
memory consolidation in healthy volunteers with or without a
positive family history of depression. These researchers
observed a lowering mood effect in subjects with a positive
family history of depression but not in the other group. However, in mentally normal males with high levels of anxiety, the
acute ingestion of a TRP-free amino-acid mixture maintains
anxiety, which is reduced after a balanced diet is restored (2).
On the other hand, TRP depletion also causes a lowering of
6. Gessa GL, Biggio G, Fadda F, Corsini GU, and Tagliamonte A. Tryptophanfree diet: a new means for rapidly decreasing brain tryptophan content and
serotonin synthesis. Acta Vitamin Enzymol 29: 72–78, 1975.
7. Moja EA, Antinoro E, Cesa-Bianchi M, and Gessa GL. Increase in stage 4
sleep after ingestion of a tryptophan-free diet in humans. Pharm Res
Comm 16: 909–914, 1984.
8. Moeller FG, Dougherty DM, Swann AC, Collins D, Davis CM, and Cherek
DR. Tryptophan depletion and aggressive responding in healthy males.
Psychopharmacology 126: 97–103, 1996.
9. Nishizawa S, Benkelfat C, Young SN, Leyton M, Mzengeza S, De Montigny
C, Blier P, and Diksic M. Differences between males and females in rates
of serotonin synthesis in human brain. Proc Natl Acad Sci USA 94:
5308–5313, 1997.
10. Riedel WJ, Klaassen T, Deutz NEP, van Someren A, and van Praag HM.
Tryptophan depletion in normal volunteers produces selective impairment
in memory consolidation. Psychopharmacology 141: 362–369, 1999.
11. Stancampiano R, Cocco S, Melis F, Cugusi C, Sarais L, and Fadda F. The
decrease of serotonin release induced by a tryptophan-free amino acid
diet does not affect spatial and passive avoidance learning. Brain Res 762:
269–274, 1997.
12. Stancampiano R, Melis F, Sarais L, Cocco S, Cugusi C, and Fadda F. Acute
administration of a tryptophan-free amino-acid mixture decreases 5-HT
release in rat hippocampus in vivo. Am J Physiol Regulatory Integrative
Comp Physiol 272: R991–R994, 1997.
13. Young SN, Evin FR, Pihl RO, and Finn P. Biochemical aspects of tryptophan depletion in primates. Psychopharmacology 98: 508–511, 1989.
14. Young SN, Smith SE, Pihl R, and Ervin FR. Tryptophan depletion causes a
rapid lowering of mood in normal males. Psychopharmacology 87:
173–177, 1985.
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effect of lowering plasma tryptophan on food selection in normal males.
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David G. Parkes and Clive N. May
Urocortin is a potent regulator of cardiac function, with actions that are prolonged in experimental
animals. These changes are mediated via binding to corticotropin-releasing factor receptors found in
peripheral tissues. The effects of urocortin on behavior, appetite, inflammation, and the cardiovascular
system suggest that this peptide may be an endogenous factor mediating actions previously
attributed to corticotropin-releasing factor.
S
ince corticotropin-releasing factor (CRF) was isolated and
characterized by Vale and co-workers (13) at the Salk Institute, peripheral cardiovascular actions of CRF have been
observed across species ranging from rodents to humans.
However, scientists have been perplexed by the relevance of
these cardiovascular actions, since very low levels of CRF
normally circulate in peripheral blood and relatively low levels of CRF gene expression are observed in the heart. It is well
accepted that CRF is the primary hormone involved in the
mammalian response to stress (2, 14) and produces central
actions to increase blood pressure and stimulate pituitary
adrenocorticotropic hormone (ACTH) and adrenal steroid
release in all species studied. CRF belongs to a family of
structurally related peptides that includes fish urotensin 1
and amphibian sauvagine, which also possess bioactivity
similar to CRF in several mammalian systems. In 1993, the
discovery of a high-affinity receptor for CRF (1) added to the
acceptance of CRF as a physiologically relevant hormone
present in the central nervous system and pituitary blood supply. However, lack of any significant expression of this CRF
type 1 receptor (CRF-R1) in peripheral tissues relevant to control of the cardiovascular system did not support the hypothesis that circulating CRF may be directly controlling the heart
or vasculature. In 1994, a second CRF receptor was cloned
and characterized, and tissue expression of this type 2 receptor (CRF-R2) was reported soon thereafter. A splice variant of
D. G. Parkes is at Amylin Pharmaceuticals, 9373 Towne Centre Dr., San
Diego, California 92121, and C. N. May is at the Howard Florey Institute
of Physiology and Medicine, University of Melbourne, Parkville, Victoria,
3052 Australia.
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News Physiol. Sci. • Volume 15 • October 2000
this type 2 receptor, CRF receptor type 2β (CRF-R2β), is present in both brain and peripheral tissues, including the heart,
testis, and gastrointestinal tract. Recently, a third splice variant of the CRF-R2 was isolated, CRF-R2γ, and this receptor is
expressed in human brain regions, including the hippocampus and septum (Fig. 1).
Isolation and characterization of urocortin
In 1995, Vaughan and colleagues (15) described the discovery of a CRF-related peptide expressed in rat brain known
as urocortin (Ucn), named after its peptide homology to both
the teleost hormone urotensin and to mammalian CRF and
because it possesses biological activity exhibited by both of
these peptides. Rat Ucn is a 40 amino acid peptide with 45%
homology to rat/human CRF, 63% homology to teleost
urotensin 1, and 35% homology to frog sauvagine (Fig. 2)
(15). The urotensin-like immunoreactivity possessed by Ucn
enabled its initial identification within a discrete region of the
rat midbrain known as the Edinger-Westphal nucleus, a
region that lacks expression of CRF mRNA. Ucn cDNA was
isolated from an mRNA library derived from rat midbrain,
which was screened with a urotensin probe. The full-length
cDNA encodes a protein deduced to be 122 amino acids in
length. The carboxy terminus contains Ucn, a putatively
cleaved 40 amino acid peptide with a carboxy terminal amidation. Recently, the sequence of ovine Ucn was published
and is identical to that for the rat peptide.
Vaughan and colleagues also reported Ucn to have marked
cardiovascular actions in rats to lower blood pressure and
increase heart rate, with a greater potency and duration of
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Urocortin: A Novel Player in Cardiac Control