The Role of Serotonin in Depression and OCD
James M.
By Ronald F. Borne, Ph.D., Department of Medicinal Chemistry, School of
Pharmacy, University of Mississippi
Introduction
Serotonin (5-hydroxytryptamine, 5-HT) is widely distributed in animals
and plants, occurring in
vertebrates, fruits, nuts, and venoms. A number of congeners of
serotonin are also found in nature
and have been shown to possess a variety of peripheral and central
nervous system activities.
Of particular interest over the years is the psychotomimetic activity
displayed by several
serotonin-related compounds such as N,N-dimethyl tryptamine,
5-hydroxy-N,N-dimethyltryptamine (bufotenine), and
4-phosyphoryloxy-N,N-dimethyl-tryptamine (psilocybin).
Although serotonin may be obtained from a variety of dietary sources,
endogenous 5-HT is
synthesized in situ from tryptophan through the actions of the enzymes
tryptophan hydroxylase
and aromatic L-amino acid decarboxylase. Both dietary and endogenous
5-HT are rapidly
metabolized and inactivated by monoamine oxidase and aldehyde
dehydrogenase to the major
metabolite, 5-hydroxyindoleacetic acid (5-HIAA).
Of the chemical neurotransmitter substances, serotonin is perhaps the
most implicated in the
etiology or treatment of various disorders, particularly those of the
central nervous system,
including anxiety, depression, obsessive-compulsive disorder,
schizophrenia, stroke, obesity, pain,
hypertension, vascular disorders, migraine, and nausea. A major factor
in our understanding of the
role of 5-HT in these disorders is the recent rapid advance made in
understanding the
physiological role of various serotonin receptor subtypes. This review
will summarize the
physiological functions of serotonin--those drugs currently available
that act by mimicking or
antagonizing the actions of serotonin--and the future development of
serotonergic agents.
Serotonin was first isolated from blood in 1948 by Page and coworkers
and was later identified in
the central nervous system. As is the case for most neurotransmitters,
it has a relatively simple
chemical structure but displays complex pharmacological properties.
Based on the similarity of this
structure to the structures of norepinephrine and dopamine, it is not
surprising that serotonin, like
its catecholamine counterparts, possesses a diversity of pharmacological
effects, both centrally and
peripherally. It is found in three main areas of the body: the
intestinal wall (where it causes
increased gastrointestinal motility); blood vessels (where large vessels
are constricted); and the
central nervous system (CNS).
The most widely studied effects have been those on the CNS. The
functions of serotonin are
numerous and appear to involve control of appetite, sleep, memory and
learning, temperature
regulation, mood, behavior (including sexual and hallucinogenic
behavior), cardiovascular function,
muscle contraction, endocrine regulation, and depression. Peripherally,
serotonin appears to play a
major role in platelet homeostasis, motility of the GI tract, and
carcinoid tumor secretion. This
represents quite a broad spectrum of pharmacological and psychological
effects, considering the
fact that the average human adult possesses only about 10 mg of 5-HT.
Subsequent to his
discovery of serotonin, Page commented that no physiological substance
known possesses such
diverse actions in the body as does 5-HT.
Chemical neurotransmitters (CNTs) produce their effects as a consequence
of interactions with
appropriate receptors. As is the case with all the CNTs, serotonin is
synthesized in brain neurons
and stored in vesicles. Upon a nerve impulse, it is released into the
synaptic cleft, where it interacts
with various postsynaptic receptors.
The actions of 5-HT are terminated by three major mechanisms: diffusion;
metabolism; and uptake
back into the synaptic cleft through the actions of specific amine
membrane transporter systems.
These events are summarized in Figure 1. Thus, the actions of 5-HT can
be theoretically
modulated by agents that stimulate or inhibit its biosynthesis (step 1);
agents that block its storage
(step 2); agents that stimulate or inhibit its release (step 3); agents
that mimic or inhibit its actions at
its various postsynaptic receptors (step 4); agents that inhibit its
uptake back into the nerve
terminal (step 5); agents that affect its matabolism (step 6).
Of all the CNTs, 5-HT presents the most perplexing array of receptor
interactions. In 1957,
Gaddum suggested that 5-HT interacted on two different receptors in
isolated tissues, one on
smooth muscle and one on nervous tissue. Since dibenzyline selectively
antagonized smooth
muscle, and morphine was selective for nervous tissue, these receptors
were named "D" and "M"
receptors, respectively. Since that time, and especially in the past
decade, there has been
tremendous progress in 5-HT receptor identification. It now appears that
there are at least four
populations of receptors for serotonin: 5-HT1, 5-HT2, 5-HT3, and 5-HT4.
Recent cloning
studies suggest the existence of 5-HT5, 5-HT6, and 5-HT7 subtypes as
well. To complicate
matters further, evidence has been presented that five distinct subtypes
of the 5-HT2 (one of
which was formerly named the 5-HT1C receptor, a name that still appears
in the literature) and
three subtypes of the 5-HT3 receptors exist.
The physiological function of each receptor subtype has not been
established and is currently the
subject of intensive investigation. With the exception of the 5-HT3
receptor, which is a
ligand-gated ion channel related to NMDA, GABA and nicotinic receptors,
all of the 5-HT
receptor subtypes belong to the group of G-protein linked receptors.
The design of specific agonists and antagonists for each receptor system
offers much promise for
new drug development. The greatest current interest involves the
modulation of 5-HT at receptors
in the CNS. The following briefly summarizes our understanding of the
function of the most widely
studied 5-HT receptors.
5-HT1 receptors
These receptors appear to be involved in the processes of smooth muscle
relaxation, contraction
of some cardiac and vascular smooth muscle, rejunctional inhibition of
neurotransmitter release,
and effects in the CNS. Five subtypes have been proposed, four of which
appear to play a major
role in humans:
5-HT1A
This represents perhaps the most widely studied 5-HT receptor
subtype. These receptors
are located primarily in the CNS. Agonists facilitate male sexual
behavior in rats,
hypotension, increase food intake, produce hypothermia, and act as
anxiolytics. This
receptor has also been widely implicated in depression.
5-HT1B
These may serve as autoreceptors; thus, activation causes an
inhibition of neurotransmitter
release. Agonists inhibit aggressive behavior and food intake in
rodents. These receptors,
which have been identified only in rodents and are apparently
absent in humans, are thus
only of theoretical interest at present. These receptors may be the
counterpart of the
5-HT1D receptor found in other species.
5-HT1C
These receptors belong to the same receptor subfamily as the 5-HT2
receptor and have
been recently renamed as 5-HT2C receptors. This receptor is located
in high density in the
choroid plexus and may regulate cerebrospinal fluid production and
cerebral circulation.
This subtype is speculated to be involved in the regulation of
analgesia, sleep, and
cardiovascular function.
5-HT1D
Located primarily in the CNS, this receptor may play a role as a
presynaptic heteroreceptor
or as a terminal autoreceptor, being thus involved in the
inhibition of neurotransmitter release
by mediating a negative feedback effect on transmitter release.
This subtype is the most
abundant 5-HT1 receptor in the CNS but is also found in vascular
smooth muscle mediating
contraction. While the role of activation of this receptor subtype
is not fully understood,
agonists at this site are effective in treating acute migraine
headaches. The development of
selective antagonists of this receptor should clarify the
functional role of 5-HT1D receptors
in the CNS.
5-HT2 receptors
Located primarily in the vascular smooth muscle, platelets, lung, CNS,
and the GI tract, these
appear to be involved in gastointestinal and vascular smooth muscle
contraction, platelet
aggregation, hypertension, migraine, and neuronal depolarization.
Antagonists have potential use as
antipsychotic agents. Because these receptors belong to the same
receptor subfamily as the former
5-HT1C receptors, they have been recently renamed as 5-HT2A receptors.
5-HT3 receptors
Located primarily in peripheral and central neurons, these receptors
appear to be involved in the
depolarization of peripheral neurons, pain, and the emesis reflex.
Potential use of agents acting at
this site include migraine, anxiety, and cognitive and psychotic
disorders.
5-HT4 receptors
These receptors are found in the CNS, the heart, and the Gi tract. Their
activation produces an
increase in cyclic andenosine monophosphate (AMP) and appears to involve
activation of
neurotransmitter release. The gastric prokinetic activity of
metoclopramide has been attributed, in
part, to its ability to activate 5-HT4 receptors.
Drugs acting by serotonergic mechanisms
Drugs affecting serotonin synthesis and metabolism
Although an inviting target for drug design, stimulators or inhibitors
of the biosynthesis of 5-HT
have not been marketed to date. Administration of tryptophan can
increase endogenous levels of
serotonin and thus has potential value in the treatment of
phenylketonuria. An investigational drug,
p-chlorophenylalanine, has been shown to decrease serotonin levels by
90% as a result of
inhibition of the rate-limiting step in 5-HT synthesis, tryptophan
hydroxylase, but no therapeutic
applications have been suggested, because of its inherent toxicity.
Other inhibitors such as
6-fluorotryptophan and p-chloroamphetamine have also been investigated,
but no clinical
applications have been uncovered.
Inhibitors of monoamine oxidase, as one would expect, have been shown to
increase levels of
5-HT.
Serotonin depletors or releasing agents
Fenfluramine (Pondimin), marketed as an appetite suppressant, is a
fairly selective and long-acting
5-HT depleting agent, singling it out from the other phenethylamine
anorectic drugs. An
increasingly popular "recreational" drug of abuse,
3,4-methylenedioxymethamphetamine (MDMA,
Ecstasy, ADAM) has caused widespread concern as a neurotoxin because of
its ability to
produce long-term depletion of 5-HT from neurons in rat and primate
brains. Similar effects have
been noted for several illegal analogs related to MDMA, such as the
N-ethyl analog known as
EVE.
Prior to its classification as a Schedule 1 controlled substance, MDMA
and its predecessor MDA
(3,4-methylenedioxyamphetamine) were synthesized by "street chemists" as
designer drugs and
were used for various unapprovd purposes and made available to
psychotherapists. MDMA was
originally synthesized in 1914 as an appetite suppressant but was never
marketed because of toxic
side effects noted early in testing. MDMA has been used as an adjunct to
psychotherapy and was
popular among psychotherapists because of its ability to reduce anxiety
and facilitate
communication by giving the patient a calmer understanding of his or her
problems. MDMA
promotes a significant release of 5-HT from presynaptic vesicles,
producing a profound decrease
in brain levels of serotonin. The long-term psychological and physical
consequences of this
depletion has yet to be fully explored.
Inhibitors of serotonin uptake
The major mechanism by which the action of serotonin is terminated is by
uptake through
presynaptic membranes. After 5-HT acts on its various postsynaptic
receptors, it is removed from
the synaptic cleft back into the nerve terminal through an uptake
mechanism involving a specific
membrane transporter in a manner similar to that of other biogenic
amines. Agents that selectively
inhibit this uptake increase the concentration of 5-HT at the
postsynaptic receptors and have been
found to be quite useful in treating various psychiatric disorders,
particularly depression.
Approximately 5% of the U.S. population experience a depressive episode
requiring
psychopharmacological treatment; in any one year, 10-12 million
Americans are affected by
depression, with the condition twice as common in females than in males.
It has been estimated
that 15% of patients hospitalized for depression will commit suicide.
However, 80-90% of
individuals suffering from depression can be successfully treated.
Depression is an affective disorder, the pathogenesis of which cannot be
explained by any single
cause or theory. The most widely accepted hypothesis involves abnormal
function of the
catecholamine (primarily norepinephrine) and/or serotonin transmitter
systems. In this hypothesis,
most forms of depression are associated with a deficiency of
norepinephrine and/or serotonin at
functionally important adrenergic or serotonergic receptors. Hence drugs
that enhance the
concentrations of norepinephrine and/or serotonin at these receptors
should alleviate to an extent
the symptoms of depression. Approaches to the treatment of depression
over the years have
involved the use of agents (stimulants) that mimic norepinephrine;
agents (MAOIs) that increase
the levels of NE and 5-HT by inhibiting their metabolism; and drugs that
increase these levels at
the receptor by inhibiting the uptake of NE and 5-HT.
The classical tricyclic antidepressants (TCAs) currently available block
primarily the uptake of
norepinephrine and also, to varying degrees, the uptake of
5-HT--depending on whether they are
secondary or tertiary amines. Tertiary amines such as imipramine and
amitriptyline are more
selective inhibitors of 5-HT than catecholamines, compared with
secondary amines such as
desipramine. More recently, selective 5-HT reuptake inhibitors (SSRIs)
have been investigated as
potential antidepressants with the anticipation that these agents,
unlike the first-generation TCAs,
would possess fewer side effects, such as anticholinergic actions and
cardiotoxicity, and would be
less likely to cause sedation and weight gain.
Clomipramine (Anafranil) is structurally related to the classical TCAs
and was the first medication
approved in the United States for the treatment of obsessive-compulsive
disorder. It is a potent
inhibitor of 5-HT uptake, but effectively inhibits NE uptake as well. In
addition, climipramine has
affinity for central dopamine D2, histamine H1, and adrenergic alpha-1
receptors and possesses
anticholinergic effects.
Three selective 5-HT uptake inhibitors, also referred to as
second-generation antidepressants,
have been introduced on the U.S. market. Fluoxetine (Prozac), sertraline
(Zoloft), and paroxetine
(Paxil) have gained immediate acceptance, each appearing in the most
recent listing of the top 200
prescription drugs. Fluoxetine recently was approved also for the
treatment of
obsessive-compulsive disorder. These agents do not appear to possess
greater efficacy than the
TCAs, nor do they generally possess a faster onset of action; however,
they do have the
advantage of a lower side-effect profile. Of these three SSRIs,
paroxetine is the most potent
inhibitor of 5-HT uptake, fluoxetine the least. Sertaline is the most
selective for 5-HT versus NE
uptake, fluoxetine the lese selective. Fluoxetine and sertraline produce
active metabolites, while
paroxetine is metabolized to inactive metabolites. The SSRIs, in
general, affect only the uptake of
serotonin and display little or no affinity for various receptor systems
including muscarinic,
adrenergic, dopamine, histamine, or 5-HT receptors.
In addition to treating depression, several other potential therapeutic
applications for SSRIs have
been investigated. They include treatment of Alzheimer's disease;
modulation of aggressive
behavior; treatment of premenstrual syndrome, diabetic neuropathy, and
chronic pain; and
suppression of alcohol intake. Of particular significance is the
observation that 5-HT reduces food
consumption by increasing meal-induced satiety and reducing hunger,
without producing the
behavioral effects of abuse liability associated with amphetamine-like
drugs; thus, there is interest
in the possible use of SSRIs in the treatment of obesity.
Venlafaxine (Effexor) is a recently introduced antidepressant, differing
from the classical TCAs and
the SSRIs chemically and pharmacologically in that it acts as a potent
inhibitor of both 5-HT and
norepinephrine uptake, as well as weakly inhibiting dopamine uptake. Its
major metabolite,
O-desmethylvenlafaxine, shares a similar profile. Neither venlafaxine
nor its major metabolite have
significant affinity for muscarinic, histaminergic, benzodiazephine, mu
opioid, or adrenergic alpha-1
receptors. It is administered as a recemic mixture. Both enantiomers
inhibit 5-HT and NE uptake,
but the (S)(+)-isomer is more selective for 5-HT uptake. Venlafaxine
possesses an efficacy
equivalent to that of the TCAs and a benign side effect profile similar
to the SSRIs.
Agents acting at serotonin receptors
Serotonin agonists. Despite the large number of serotonin analogs that
have been prepared and
investigated, few have reached the marketplace. Trazodone (Desyrel), a
second-generation
antidepressant, possesses a complex mechanism of action. It may act as a
presynaptic alpha-2
norepinephrine receptor antagonist, selectively blocking 5-HT uptake as
well as possessing 5-HT
receptor antagonist properties. Interestingly, it is metabolized to
m-chlorophenylpiperazine, a
known agaonist at 5-HT receptors and an inhibitor of 5-HT uptake. The
anxiolytic agent
buspirone (BuSpar) is a partial agonist at 5-HT1A receptors and
interacts with other receptor
systems as well.
The recent introduction of sumatriptan (Imitrex) as the first 5-HT1D
receptor agonist represents a
major advance in the treatment of acute migraine attacks. Migraine
headaches affect nearly one in
11 Americans, occurring usually in adults 35-45 years of age.
Many factors have been implicated as initiators of migraine attacks,
including stress, smoking,
fatigue, glaring lights, weather, hormonal fluctuations, various foods
(including those which contain
nitrate and nitrate preservatives), caffeine-containing beverages,
alcohol (especially red wine), and
drugs that cause blood vessels to dilate. Migraine represents a disorder
of cerebral vascular
regulation and may be the result of a marked, prolonged phase of cranial
vasodilation. During an
attack, extravasation of plasma proteins and development of localized
inflammation in intracranial
vessels also occur. The trigeminal (fifth cranial) nerve has been
implicated. Migraines may be
initiated by afferent and/or efferent nerves to affected blood vessels.
Chemical mediators including serotonin, thromboxane A2, prostaglandins
and kinins appear to be
involved. 5-HT receptors predominate in cranial blood vessels and are
widely distributed in the
CNS, where they play an important role in controlling cranial
circulation and pain. During the
prodromal phase of an attack, 5-HT is spontaneously released from
platelets. It enters the vessel
wall, causing arterial vasoconstriction and lowering the pain threshold.
In the absence of 5-HT,
extracranial arteries dilate and distend, resulting in a headache.
Serotonin is released during migraine attacks, and the major metabolite
of 5-HT,
5-hydroxyindoleacetic acid (5-HIAA), is exreted in increased amounts. Of
all the 5-HT receptors,
the 5-HT1 subtype has been most widely implicated, since these receptors
are mainly located in
certain cranial blood vessels.
Sumatriptan selectively constricts carotid arterial circulation
supplying blood to extracranial and
intracranial tissues such as meninges, dilation of which is thought to
contribute to migraines; it binds
with high affinity to 5-HT1D receptors and, to a lesser extent, to
5-HT1A sites. Sumatriptan also
may activate a prejunctional inhibitor receptor, which resembles the
5-HT1D receptor on
perivascular fibers, resulting in an inhibition of the release of
inflammatory neuropeptides that
mediate pain. It is highly selective for 5-HT1 receptors and lacks
affinity for 5-HT2, 5-HT3,
adrenergic, dopamine, acetylcholine, or benzodiazepine receptor sites.
The ergot alkaloids such as dihydroergotamine, on the other hand, bind
to a number of differnet
neurotransmitter receptor systems.
Sumatriptan is administerd subcutaneously and has been reported to
provide complete relief in
86%-96% of patients within 20-60 minutes of injection. There is
considerable interest in
developing rapid-acting, orally effective 5-HT1D agonists for the
treatment of migraines.
Recently, cisapride (Propulsid) was introduced as a new-generation
prokinetic agent indicated for
the symptomatic treatment of patients with nocturnal heartburn from
gastroesophageal reflux
disease (GERD). An estimated 44% of adult Americans experience heartburn
at least once a
month. Of these, 7%-10% have heartburn on a weekly or more frequent
basis, to such an extent
that there is a disruption of lifestyle. Treatment generally involves
behavioral modification;
nonprescription drug therapy, including antacids and alginic
acid-antacid combinations; and
prescription drug therapy involving acid release inhibitors
(H2-antagonists and proton pump
inhibitors) and prokinetic agents that increase motility of the GI
tract.
Cisapride is a substituted piperidyl benzamide derivative somewhat
structurally related to the
prototype prokinetic agent metoclopramide. It acts as a 5-HT4 agonist in
vitro, resulting in
increased GI motility and cardiac rate.
Cisapride is less potent than metoclopramide as a dopamine receptor
antagonist and possesses a
specific action on the postganglionic nerves of the myenteric plexas of
Gi smooth muscles,
enhancing the local release of acetylcholine. It has no effect on
muscarinic or nicotinic receptor
stimulation, nor does it inhibit acetylcholinesterase.
Serotonin antagonists. The ergot alkaloids (ergolines) generally display
a high affinity but low
selectivity for 5-HT binding sites; many also display a high affinity
for dopamine and
norepinephrine binding sites as well. methysergide, used to prevent
migraine headaches, is a potent
5-HT2 antagonist, while the related alkaloid ergotamine, which is used
to treat existing migraines,
is a 5-HT1 agonist/partial agonist.
Many hallucinogenic substances such as LSD and psilocin are thought to
block serotonin, but,
obviously, not all central 5-HT antagonists are hallucinogens. A
clinically investigated 5-HT2
antagonist, ketaserin, has been found to be an effective
anti-hypertensive agent but is not selective
since it may also block alpha1-andrenoreceptors.
Two 5-HT3 receptor antagonists, ondansetron (zofran) and granisetron
(Kytril), have been
marketed to treat nausea associated with radiation and chemotherapy in
cancer patients. Nausea
and vomiting have consistently appeared among the severe side effects
most frequently reported
by patients as a result of cancer chemotherapy and radiotherapy. The
intensity of these effects
varies with the nature of the chemotherapeutic agent, ranging from those
with very high emetogenic
potential such as cisplatin, dacarbazine, mechlorethamine, and high
doses of cytarabine and
melphalan to those with a low potential, such as vincristine,
chlorambucil, and the androgens and
estrogens.
Innervation of the chemoreceptor trigger zone in the CNS may occur along
a number of pathways,
including peripheral receptor stimulation in the GI tract, vestibular
stimulation, and anticipatory
stimulation involving the cerebral cortex.
A number of different classes of antiernetic agents have been explored
over the years. Among
them are anticholinergics; antihistaminics; benzodiazepines and
barbiturates; cannabinoids; and
dopamine antagonists such as the phenothiazines, butyrophenones, and
benzamides. Within the
latter class, metoclopramide is perhaps the standard of comparison
because of its effectiveness in
treating nausea associated with high doses of cisplatin. Until recently,
metoclopramide was
considered the most effecting single agent in treating cisplatin-induced
emesis, but its use has been
associated with a high incidence of extrapyramidal effects.
5-HT3 receptors have been proposed to play a major role in the
physiology of emesis. These
receptors are found in high concentrations peripherally in the gut and
centrally in the cortical and
limbic regions and in or near the chemoreceptor trigger zone, and have
been implicated in the
vomiting reflex induced by serotonin as a result of chemotherapy.
During the course of these therapies, mucosal enterochromaffin cells
release 5-HT; this stimulates
5-HT3 receptors, evoking vagal efferent discharge and inducing emesis.
Both ondansetron and
granisetron are potent and selective inhibitors of 5-HT3 receptors both
centrally and peripherally.
Ondansetron has 100 times greater affinity for 5-HT3 receptors than does
metoclopramide, while
metoclopramide has 50 times greater affinity for dopamine D2 receptors
than for 5-HT3
receptors. Granisetron possesses 4,000 to 40,000 times greater affinity
for 5-HT3 receptors in the
brain than for other receptors, including 5-HT1, 5-HT2, dopamine D2,
histamine H1, opioid,
benzodiazepine, or adrenergic alpha-1, alpha-2 or beta. Therefore, these
selective 5-HT3
receptor antagonists lack many of the side effects associated with other
antiemetic agents,
particularly lacking the extrapyramidal side effects associated with the
dopamine antagonists.
Ondansetron is available in both injectable and oral formulations, while
granisetron is available only
in an injectable formulation at the present time.
The future
The future therapeutic applications of receptor-selective serotonin
agents are potentially numerous,
thus explaining the tremendous investment the pharmaceutical industry is
currently making in
serotonin research. Some of these potential applications include the
following:
Neuroleptics. The mechanism of action of current neuroleptics primarily
involves antagonism of
dopaminergic receptors, but 5-HT2 sites may also be involved since many
currently marked
neuroleptics have been also shown to antagonize 5-HT2 receptors.
For example, clozapine (Clozaril) possesses higher affinity for 5-HT2
sites than for dopamine
receptors. the role of 5-HT2 receptors in the mechanism of action of the
neuroleptics is unclear
but may offer a potential area for the development of newer agents. Of
particular interest are
behavioral studies in the rodent and primates indicating that 5-HT3
antagonist potently antagonize
dopamine activity suggesting an important role in controlling limbic
dopamine function. These
studies suggest a potentially novel approach to the treatment of
schizophrenia.
Antidepressants. In addition to the continued search for inhibitors of
5-HT and/or NE uptake,
5-HT2 receptors may be attractive targets for new agents in this area.
Chronic antidepressant
treatment leads to a decrease in the number of 5-HT2 receptors in
cortical brain tissue from
animals and suicide victims. The potential use of 5-HT2 antagonists as
antidepressants is currently
being explored. The use of selective inhibitors of 5-HT uptake in the
treatment of depression has
been previously discussed. Fluvoxamine, a potent and selective 5-HT
uptake inhibitor, recently
was recommended for approval by an FDA advisory committee for the
treatment of
obsessive-compulsive disorder and has been shown to be effective in
depression.
Anxiolytics. "Second-generation" anxiolytics such as buspirone bind with
high affinity to 5-HT1A
receptors, while benzodiazepines have very low affinity for 5-HT sites
(primarily affecting
GABAminergic function). The development of 5-HT1A agents as potential
"anxioselective" drugs
may thus provide anxiolytics that lack some of the side effects of
benzodiazepine therapy, such as
muscle relaxation, sedation, ataxia, and memory impairment. In addition,
5-HT3 antagonists have
shown great promise in animal models.
Cardiaovascular agents. Antagonists of 5-HT2 sites are being explored as
antihypertensive
agents and for use in peripheral vascular disease, thrombic or embolic
episodes, and
cardiopulmonary emergencies, but they may present clinical problems.
Flesinoxan, a 5-HT1A
agonist, is currently undergoing clinical trials, and many other
agonists at this site are bring explored
as antihypertensives.
Analgesics. The selective 5-HT uptake inhibitor fluoxetine has been
shown to produce analgesia in
mice following intrathecal administration. The role of 5-HT in pain
perception is being explored.
Migraines. Two experimental "5-HT1-like" agonists (AH 25086 and GR
43175) are being
clinically investigated for the treatment of acute migrains. These
agents act by activating 5-HT1
receptors that mediate localized vasoconstriction within the carotid
vascular bed and appear to be
more selective than ergotamine. In addition, 5-HT3 antagonists have been
shown to possess
effectiveness in migraines.
Anorectics. Serotonin is believe to reduce the consumption of food.
Selective 5-HT uptake
inhibitors (as discussed earlier) and 5-HT releasing agents have been
suggested as antiobesity
agents. Partial agonists at 5-HT1A receptors have been shown to increase
food uptake, so it is of
interest to speculate that selective antagonists at these sites may be
potentially useful appetite
suppressants. Agents acting selectively on serotonergic mechanisms would
have the advantage
over those agents acting by noradrenergic mechanisms (e.g.,
amphetamine), because the potential
for abuse would be significantly decreased. 5-HT uptake inhibitors have
also been shown to be
effective in treating bulimia and such other eating disorders as
anorexia nervosa.
Antiemetics. Several pharmaceutical firms are testing additional
antagonists of 5-HT3 receptors as
agents that can reduce the distressing vomiting syndrome associated with
cancer chemotherapy.
Orally effective agents with a rapid onset of action would be highly
desirable.
Senile demantias. Alzheimer's diseas (AD) is the most common form of
senile dementia. While the
pathogenesis of AD has not been totally clarified, the role of chemical
neurotransmitters has been
an active area of investigation. Although the involvement of the
cholinergic system has received the
greatest attention, serotonin appears to also play a major role in the
disease. 5-HT function
appears to be significantly reduced in Alzheimer's disease as indicated
by post-mortem
examination of brains of AD patients, which reviealed a reduction in
receptors of both the 5-HT1
and 5-HT2 type. The role of 5-HT1A receptors in the onset of senile
dementia disorders such as
Alzheimer's disease is being explored by several groups. The finding
that 5-HT1A binding sites are
reduced 50% post-mortem in patients with known Alzheimer's-type
dementias, coupled with the
observation that 5-HT1A receptors are present in large numbers on
cholinergic terminals, suggests
that binding to these receptors may offer a potential means for
identifying early neuronal changes
that lead to Alzheimer's-type dementias. The early diagnosis of the
onset of these dementias may
allow more effective therapeutic utilization of agents, such as
cholinergic drugs, for the treatment of
these disorders.
5-HT2 receptors also appear to be decreased in Alzheimer's disease.
Overall, there is much
evidence to suggest that 5-HT transmission is impaired in sinile
dementia of the Alzheimer's type
and that enhancement of 5-HT function may offer new treatment
approaches. Interestingly, 5-HT3
receptor antagonists posess the ability to modify cognitive events and
to improve impaired
performance in animal models. Ondansetron, for example, possesses a
dose-related effect on
learning and memory in age-associated memory immpairment, suggesting a
role for 5-HT3
antagonists in the treatment of cognitive disorders.
Prokinetic agents. As stated earlier, the prokinetic activity of
metoclopramide has been attributed
to its ability to activate 5-HT4 receptors. The recently introduced
prokinetic agent cisapride has
also been shown, in vitro, to activate 5-HT4 receptors, suggesting that
other agents of this class
may be introduced in the near future.
Substance abuse. In a number of animal studies, 5-HT uptake inhibitors
have been shown to
decrease the ingestion of alcohol as well as suppressing the
self-administration of other abused
substances, such as cocaine. Although the clinical usefulness of 5-HT
uptake inhibitors has not
been established to date, these agents have also been shown to decrease
alcohol intake in humans,
suggesting an important potential role in treating substance abuse.
While the present data are
inconclusive, 5-HT3 receptor antagonists appear to reduce the "reward"
effects of systemically
administered morphine; however, it is not known if they block
self-administration of morphine. The
anxiety-related consequences of drug withdrawal appear to be improved by
5-HT3 receptor
antagonists.
Nociception. 5-HT3 receptors have been demonstrated on peripheral
sensory neurons, and they
appear to induce pain and sensitize nociceptive neurons when they are
activated. It is interesting to
speculate on the potential role of 5-HT3 receptor antagonists in the
treatment of pain.
Conclusion
Exciting times are ahead for serotonin research. For example, just
within the past six months,
isolation of genomic clones has been reported for the 5-HT1A, 5-HT1C,
and 5-HT2 receptors.
One 5-HT3 receptor subunit from neuroblastoma cells has been cloned.
Also, recent cloning
studies have identified two human gene products of the 5-HT1D receptor,
which have been
designated as 5-HT1Da and 5-HT1Db receptors. The tremendous recent
interst and advances in
serotonin receptors, coupled with the intensive research programs in
industry and academia for
selective agonists at the various 5-HT receptors and subtypes, offer
great promise for the
development of important new therapeutic agents. Analysts project a
greater than $10 billion
market for serotonin-related drugs in the 1990s.
Classification and functional responses mediated by major
5-HT receptors
Receptor type
5-HT1-like 5-HT2 5-HT3
-----------------------------------------------------------------------------
Cardiovascular actions Platelet aggregation Reflex
bradycardia
Hyperphagia Vasoconstriction Provocation of
pain
Hyperalgesia SM contraction Nausea and
vomiting
Anxiety Behavioral effects Migraine
Depression Sexual Activity Antipsychotic
activity
Sleep Muscle contraction Anxiolytic
activity
Aggression Hallucinogenic activity
Migraine Antipsychotic activity
Marketed drugs acting by serotonergic mechanisms
Primary Indication
Serotonin depletors or releasing agents
Fenfluramine (Pondimin) Appetite Suppressant
Selective inhibitors of serotonin uptake
Fluoxetine (Prozac) Antidepressant, OCD
Sertraline (Zoloft) Antidepressant
Paroxetine (Paxil) Antidepressant
Inhibitors of serotonin/norepinephrine uptake
Classical tricyclic antidepresssants Antidepressant
Clomipramine (Anafranil) OCD
Venlafaxine (Effexor) Antidepressant
Serotonin receptor agonists
Buspirone (BuSpar) Anxiolytic
Sumatriptan (Imitrex) Migraine headaches
Cisapride (Propulside) Prokinetic agent
Serotonin receptor antagonists
Methysergide Migraine headaches
Ondansetron (Zofran) Antiemetic
Granisetreon (Kytril) Antiemetic
This article taken from Drug Topics, October 10, 1994, p.108
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