DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

5-HT receptor families linked to different signaling pathways can
elicit a common neurophysiological action. Yet another receptor, the
5-HT 1P
receptor, elicits a slow depolarization. This receptor, which
couples to activation of adenylyl cyclase, is restricted to the enteric
nervous system (Gershon and Tack, 2007). The unique pharmacological
profile of the 5-HT 1P
receptor is most consistent with the 5-HT 7
receptor.
The fast depolarization elicited by 5-HT 3
receptors reflects
direct gating of an ion channel intrinsic to the receptor structure
itself. The 5-HT 3
receptor–induced inward current has the characteristics
of a cation-selective, ligand-operated channel. Membrane
depolarization is mediated by simultaneous increases in Na + and
K + conductance, comparable to the nicotinic cholinergic receptor.
5-HT 3
receptors have been characterized in the CNS and in sympathetic
ganglia, primary afferent parasympathetic and sympathetic
nerves, and enteric neurons. The pharmacological properties
of 5-HT 3
receptors, which are different from those of other 5-HT
receptors, suggest that multiple 5-HT 3
receptor subtypes may exist
and may correspond to different combinations of subunits (Jensen
et al., 2008).
Behavior. The behavioral alterations elicited by drugs that interact
with 5-HT receptors are extremely diverse. Many animal behavioral
models for initial assessment of agonist and antagonist properties of
drugs depend on aberrant motor or reflex responses, such as startle
reflexes, hind-limb abduction, head twitches, and other stereotypical
behaviors. Operant behavioral paradigms, such as drug discrimination,
provide models of specific 5-HT receptor activation and are
useful for exploring the action of CNS-active drugs, including agents
that interact with 5-HT. For example, investigations of the mechanism
of action of hallucinogenic drugs have relied heavily on drug
discrimination (Winter, 2009). The following discussion focuses on
animal models that may relate to pathological conditions in humans
and will not attempt to cover the voluminous literature dealing with
5-HT and behavior. See King and associates (2008), Lesch and
coworkers (2003), Lucki (1998), and Swerdlow and colleagues
(2000) for excellent reviews on this topic.
Sleep-Wake Cycle. Control of the sleep-wake cycle is one of the first
behaviors in which a role for 5-HT was identified. Following pioneering
work in cats (Jouvet, 1999), many studies showed that depletion
of 5-HT with p-chlorophenylalanine, a tryptophan hydroxylase
inhibitor, elicits insomnia that is reversed by the 5-HT precursor, 5-
hydroxytryptophan. Conversely, treatment with L-tryptophan or with
nonselective 5-HT agonists accelerates sleep onset and prolongs total
sleep time. 5-HT antagonists reportedly can increase and decrease
slow-wave sleep, probably reflecting interacting or opposing roles
for subtypes of 5-HT receptors. One relatively consistent finding in
humans and in laboratory animals is an increase in slow-wave sleep
following administration of a selective 5-HT 2A/2C
-receptor antagonist
such as ritanserin.
Aggression and Impulsivity. Studies in laboratory animals and in
humans suggest that 5-HT serves a critical role in aggression and
impulsivity. Many human studies reveal a correlation between low
cerebrospinal fluid 5-HIAA and violent impulsivity and aggression. As
with many effects of 5-HT, pharmacological studies of aggressive
behavior in laboratory animals are not definitive, but suggest a role
for 5-HT. Two genetic studies have reinforced and amplified this
notion. Knockout mice lacking the 5-HT 1B
receptor exhibited extreme
aggression (Saudou et al., 1994), suggesting either a role for 5-HT 1B
receptors in the development of neuronal pathways important in
aggression or a direct role in the mediation of aggressive behavior. A
human genetic study identified a point mutation in the gene encoding
MAO-A, which was associated with extreme aggressiveness and mental
retardation (Brunner et al., 1993), and this has been confirmed in
knockout mice lacking MAO-A (Cases et al., 1995).
Anxiety and Depression. The effects of 5-HT–active drugs in anxiety
and depressive disorders, like the effects of selective serotonin reuptake
inhibitors (SSRIs), strongly suggest a role for 5-HT in the neurochemical
mediation of these disorders. Mutant mice lacking the 5-HT
transporter display anxiety and a “depressive-like” phenotype (Fox et
al., 2007). 5-HT-related drugs with clinical effects in anxiety and
depression have varied effects in classical animal models of these disorders,
depending on the experimental paradigm, species, and strain.
For example, the anxiolytic buspirone (Chapter 15), a partial agonist at
5-HT 1A
receptors, does not reduce anxiety in classical approachavoidance
paradigms that were instrumental in development of anxiolytic
benzodiazepines. However, buspirone and other 5-HT 1A
receptor
agonists are effective in other animal behavioral tests used to predict
anxiolytic effects. Furthermore, studies in 5-HT 1A
receptor knockout
mice suggest a role for this receptor in anxiety, and possibly
depression. Agonists of certain 5-HT receptors, including 5-HT 2A
and 5-HT 2C
receptors (e.g., m-chlorophenylpiperazine), have anxiogenic
properties in laboratory animals and in human studies. Similarly,
these receptors have been implicated in the animal models of depression,
such as learned helplessness.
An impressive finding in humans with depression is the
abrupt reversal of the antidepressant effects of drugs such as SSRIs
by manipulations that rapidly reduce the amount of 5-HT in the
brain. These approaches include administration of p-chlorophenylalanine
or a tryptophan-free drink containing large quantities of
neutral amino acids (Delgado et al., 1990). Curiously, this kind of
5-HT depletion has not been shown to worsen or to induce depression
in nondepressed subjects, suggesting that the continued presence
of 5-HT is required to maintain the effects of these drugs. This
clinical finding adds credence to somewhat less convincing neurochemical
findings that suggest a role for 5-HT in the pathogenesis
of depression.
Pharmacological Manipulation of the
Amount of 5-HT in Tissues
A highly specific mechanism for altering synaptic availability
of 5-HT is inhibition of presynaptic reaccumulation
of neuronally released 5-HT. Selective serotonin
reuptake inhibitors (SSRIs), such as fluoxetine (PROZAC,
others), potentiate and prolong the action of 5-HT
released by neuronal activity. When co-administered
with L-5-hydroxytryptophan, SSRIs elicit a profound
activation of serotonergic responses. SSRIs (citalopram
[CELEXA], escitalopram [LEXAPRO], fluoxetine, fluvoxamine,
paroxetine [PAXIL], and sertraline [ZOLOFT]) are
the most widely used treatment for endogenous depression
(Chapter 15). Sibutramine (MERIDIA), an inhibitor of the
reuptake of 5-HT, NE, and DA, is used as an appetite
343
CHAPTER 13
5-HYDROXYTRYPTAMINE (SEROTONIN) AND DOPAMINE