Serotonin:
The Neurotransmitter for the '90s
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 [note from webmaster: apparently, this drug has now been taken off the market], 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 vomitingAnxiety
Behavioral effects MigraineDepression
Sexual Activity
Antipsychotic activitySleep
Muscle contraction Anxiolytic
activityAggression
Hallucinogenic activityMigraine
Antipsychotic activity
Marketed drugs acting by serotonergic mechanisms
Primary Indication
Serotonin
depletors or releasing agents
Fenfluramine (Pondimin)
Appetite Suppressant
[Note from webmaster: apparently this drug has now been take off the market]
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
Please note, this article
was not written by the webmasters of this site and we do not have a way of getting in touch with the authors.
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