The American Psychiatric Publishing Textbook of Psychopharmacology

1858 Pages·2009·16.69 MB·English

by  Alan F. Schatzberg

Psychopharmacology has developed as a medical discipline over approximately the past five decades. The discoveries
of the earlier effective antidepressants, antipsychotics, and mood stabilizers were invariably based on serendipitous
observations. The repeated demonstration of efficacy of these agents then served as an impetus for considerable
research into the neurobiological bases of their therapeutic effects and of emotion and cognition themselves, as well
as the biological basis of the major psychiatric disorders. Moreover, the emergence of an entire new multidisciplinary
field, neuropsychopharmacology, which has led to newer specific agents to alter maladaptive central nervous system
processes or activity, was another by-product of these early endeavors. The remarkable proliferation of information in
this area—coupled with the absence of any comparable, currently available text—led us to edit the first edition of The
American Psychiatric Press Textbook of Psychopharmacology, published in 1995. The response to that edition was
overwhelmingly positive. In the second edition, published in 1998, we expanded considerably on the first edition,
covering a number of areas in much greater detail, adding several new chapters, and updating all of the previous
material. Again, the response was positive. We then presented a third edition in 2004 with virtually all new material,
and now this fourth edition has updated the previous material and added several chapters on important (often
emerging) areas not previously covered.
In order for the reader to appreciate and integrate the rich amount of information about pharmacological agents, we
have attempted in all editions to provide sufficient background material to understand more easily how drugs work
and why, when, and in whom they should be used. For this fourth edition, we have updated all the material, often
adding new contributors as well as adding several new chapters, and thus expanding the scope and length of the
text. The textbook consists of five major parts. The first section, “Principles of Psychopharmacology,” was edited by
Robert Malenka and provides a theoretical background for the ensuing parts. It includes chapters on
neurotransmitters; signal transduction and second messengers; molecular biology; chemical neuroanatomy;
electrophysiology; animal models of psychiatric disorders; psychoneuroendocrinology, pharmacokinetics; and
pharmacodynamics; psychoneuroimmunology; brain imaging in psychopharmacology; and statistics/clinical trial
design.
The second part, “Classes of Psychiatric Treatments: Animal and Human Pharmacology,” presents information by
classes of drugs and is coedited by K. Ranga Rama Krishnan and Dennis Charney. For each drug within a class, data
are reviewed on preclinical and clinical pharmacology, pharmacokinetics, indications, dosages, and cognate issues.
This section is pharmacopoeia-like. Individual chapters are now generally dedicated to individual agents (e.g.,
paroxetine, venlafaxine). We include data not only on currently available drugs in the United States but also on
medications that will in all likelihood become available in the near future. We have not only updated all the material
but invited new authors on many chapters to provide fresh insights.
The third part, “Clinical Psychobiology and Psychiatric Syndromes,” edited by David Kupfer, reviews data on the
biological underpinnings of specific disorders—for example, major depression, bipolar disorder, and panic disorder.
The chapter authors in this section comprehensively review the biological alterations described for each of the major
psychiatric disorders, allowing the reader to better understand current psychopharmacological approaches as well as
to anticipate future developments.
The fourth part, “Psychopharmacological Treatment,” edited by David Dunner, reviews state-of-the-art therapeutic
approaches to patients with major psychiatric disorders as well as to those in specific age groups or circumstances:
childhood disorders, emergency psychiatry, pregnancy and postpartum, and so forth. Here, too, new contributors
provide fresh looks at important clinical topics. This section provides the reader with specific information about drug
selection and prescription. We have added a new chapter on chronic pain syndromes.
Last, we have added a new chapter on ethical considerations in psychopharmacological treatment and research,
providing the reader with a thoughtful overview of this important area.
This textbook would not have been possible without the superb editorial work of the section editors—as well as, of
course, the authors of the chapters, who so generously gave of their time. In addition, we wish to thank Editorial
Director John McDuffie of American Psychiatric Publishing and his staff for their editorial efforts. In particular, we
appreciate the major efforts of Bessie Jones, Acquisitions Coordinator; Greg Kuny, Managing Editor; Tammy J.
Cordova, Graphic Design Manager; Susan Westrate, Prepress Coordinator; Judy Castagna, Manufacturing Manager;
Melissa Coates, Assistant Editor; and Rebecca Richters, Senior Editor. Finally, we extend our thanks to Tina Coltri-
Marshall at the University of California–Davis, Rebecca Wyse at Stanford University, and Janice Dell at Emory
University for their invaluable editorial assistance.
y
Alan F. Schatzberg, M.D.
Charles B. Nemeroff, M.D., Ph.D.
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Steven T. Szabo, Todd D. Gould, Husseini K. Manji: Chapter 1. Neurotransmitters, Receptors, Signal Transduction, and Second Messengers in Psychiatric Disorders, in The American
Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition. Edited by Alan F. Schatzberg, Charles B. Nemeroff. Copyright ©2009 American Psychiatric Publishing, Inc. DOI:
10.1176/appi.books.9781585623860.407001. Printed 5/12/2009 from www.psychiatryonline.com
Textbook of Psychopharmacology >
Chapter 1. Neurotransmitters, Receptors, Signal Transduction, and Second Messengers in Psychiatric
Disorders
NEUROTRANSMITTERS, RECEPTORS, SIGNAL TRANSDUCTION, AND SECOND MESSENGERS IN PSYCHIATRIC
DISORDERS: INTRODUCTION
This chapter serves as a primer on the recent advances in our understanding of neural function both in health and in disease. It is beyond the scope of this
chapter to cover these important areas in extensive detail, and readers are referred to outstanding textbooks that are entirely devoted to the topic (Cooper
et al. 2001; Kandel et al. 2000; Nestler et al. 2001; Squire et al. 2003). Here, we focus on the principles of neurotransmission and second-messenger
generation that we believe are critical for an understanding of the biological bases of major psychiatric disorders, as well as the mechanisms by which
effective treatments may exert their beneficial effects. In particular, it is our goal to lay the groundwork for the subsequent chapters, which focus on
individual disorders and their treatments.
Although this chapter is intended to provide a general overview on neurotransmitter and second-messenger function, whenever possible we emphasize the
neuropsychiatric relevance of specific observations. In the chapter proper, we outline principles that are of utmost importance to the study and practice of
psychopharmacology; in the figure legends, we provide additional details for the interested reader.
[The work presented in this chapter was undertaken under the auspices of the National Institute of Mental Health Intramural Program. Dr. Manji is now at
Johnson & Johnson Pharmaceutical Research & Development.
The authors thank Ioline Henter for assistance in the preparation of this chapter.]
WHAT ARE NEUROTRANSMITTERS?
Several criteria have been established for a neurotransmitter, including 1) it is synthesized and released from neurons; 2) it is released from nerve
terminals in a chemically or pharmacologically identifiable form; 3) it interacts with postsynaptic receptors and brings about the same effects as are seen
with stimulation of the presynaptic neuron; 4) its interaction with the postsynaptic receptor displays a specific pharmacology; and 5) its actions are
terminated by active processes (Kandel et al. 2000; Nestler et al. 2001). However, our growing appreciation of the complexity of the central nervous system
(CNS) and of the existence of numerous molecules that exert neuromodulatory and neurohormonal effects has blurred the classical definition of
neurotransmitters somewhat, and even well-known neurotransmitters do not meet all these criteria under certain situations (Cooper et al. 2001).
Most neuroactive compounds are small polar molecules that are synthesized in the CNS via local machinery or are able to permeate the blood–brain barrier.
To date, more than 50 endogenous substances have been found to be present in the brain that appear to be capable of functioning as neurotransmitters.
There are many plausible explanations for why the brain would need so many transmitters and receptor subtypes to transmit messages. Perhaps the
simplest explanation is that the sheer complexity of the CNS results in many afferent nerve terminals impinging on a single neuron. This requires a neuron
to be able to distinguish the multiple information conveying inputs. Although this can be accomplished partially by spatial segregation, it is accomplished in
large part by chemical coding of the inputs—that is, different chemicals convey different information. Moreover, as we discuss in detail later, the evolution
of multiple receptors for a single neurotransmitter means that the same chemical can convey different messages depending on the receptor subtypes it acts
on. Additionally, the firing pattern of neurons is also a means of conveying information; thus, the firing activities of neurons in the brain differ widely, and a
single neuron firing at different frequencies can even release different neuroactive compounds depending on the firing rate (e.g., the release of peptides
often occurs at higher firing rates than that which is required to release monoamines). These multiple mechanisms to enhance the diversity of responses
—chemical coding, spatial coding, frequency coding—are undoubtedly critical in endowing the CNS with its complex repertoire of physiological and
behavioral responses (Kandel et al. 2000; Nestler et al. 2001). Finally, the existence of multiple neuroactive compounds also provides built-in safeguards to
ensure that vital brain circuits are able to partially compensate for loss of function of particular neurotransmitters.
RECEPTORS
An essential property of any living cell is its ability to recognize and respond to external stimuli. Cell surface receptors have two major functions:
recognition of specific molecules (neurotransmitters, hormones, growth factors, and even sensory signals) and activation of "effectors." Binding of the
appropriate agonist (i.e., neurotransmitter or hormone) externally to the receptor alters the conformation (shape) of the protein. Cell surface receptors use
a variety of membrane-transducing mechanisms to transform an agonist's message into cellular responses. In neuronal systems, the most typical
responses ultimately (in some cases rapidly, in others more slowly) involve changes in transmembrane voltage and hence neuronal changes in excitability.
Collectively, the processes are referred to as transmembrane signaling or signal transduction mechanisms. These processes are not restricted to neurons.
For example, astrocytes, which were once thought to be unrelated to neurotransmission, have recently been demonstrated to possess voltage-regulated
anion channels (VRAC), which not only transport Cl– but also allow efflux of amino acids such as taurine, glutamate, and aspartate (Mulligan and MacVicar
2006).
Interestingly, although increasing numbers of potential neuroactive compounds and receptors continue to be identified, it has become clear that translation
of the extracellular signals (into a form that can be interpreted by the complex intracellular enzymatic machinery) is achieved through a relatively small
number of cellular mechanisms. Generally speaking, these transmembrane signaling systems, and the receptors that utilize them, can be divided into four
major groups (Figure 1–1):
Those that are relatively self-contained in structure and whose message takes the form of transmembrane ion fluxes (ionotropic)
Those that are multicomponent in nature and generate intracellular second messengers (G protein–coupled)
Those that contain intrinsic enzymatic activity (receptor tyrosine kinases and phosphatases)
Those that are cytoplasmic and translocate to the nucleus to directly regulate transcription (gene expression) after they are activated by lipophilic molecules (often
hormones) that enter the cell (nuclear receptors)
FIGURE 1–1. Major receptor subtypes in the central nervous system.
This figure depicts the four major classes of receptors in the CNS. (A) Ionotropic receptors. These receptors comprise multiple protein subunits that are combined in such a
way as to create a central membrane pore through this complex, allowing the flow of ions. This type of receptor has a very rapid response time (milliseconds). The
consequences of receptor stimulation (i.e., excitatory or inhibitory) depend on the types of ions that the receptor specifically allows to enter the cell. Thus, for example, Na+
entry through the NMDA (N-methyl-D-aspartate) receptor depolarizes the neuron and brings about an excitatory response, whereas Cl– efflux through the -aminobutyric acid
type A (GABAA) receptor hyperpolarizes the neuron and brings about an inhibitory response. Illustrated here is the NMDA receptor regulating a channel permeable to Ca2+,
Na+, and K+ ions. The NMDA receptors also have binding sites for glycine, Zn2+, phencyclidine (PCP), MK801/ketamine, and Mg2+; these molecules are able to regulate the
function of this receptor. (B) G protein–coupled receptors (GPCRs). The majority of neurotransmitters, hormones, and even sensory signals mediate their effects via seven
transmembrane domain–spanning receptors that are G protein–coupled. The amino terminus of the G protein is on the outside of the cell and plays an important role in the
recognition of specific ligands; the third intracellular loop and carboxy terminus of the receptor play an important role in coupling to G proteins and are sites of regulation of
receptor function (e.g., by phosphorylation). All G proteins are heterotrimers (consisting of , , and subunits). The G proteins are attached to the membrane by isoprenoid
moieties (fatty acid) via their subunits. Compared with the ionotropic receptors, GPCRs mediate a slower response (on the order of seconds). Detailed depiction of the
activation of G protein–coupled receptors is given in Figure 1–2. Here we depict a receptor coupled to the G protein Gs (the s stands for stimulatory to the enzyme adenylyl
cyclase [AC]). Activation of such a receptor produces activation of AC and increases in cAMP levels. G protein–coupled pathways exhibit major amplification properties, and,
for example, in model systems researchers have demonstrated a 10,000-fold amplification of the original signal. The effects of cAMP are mediated largely by activation of
protein kinase A (PKA). One major downstream target of PKA is CREB (cAMP response element–binding protein), which may be important to the mechanism of action of
antidepressants. (C) Receptor tyrosine kinases. These receptors are activated by neurotrophic factors and are able to bring about acute changes in synaptic function, as well
as long-term effects on neuronal growth and survival. These receptors contain intrinsic tyrosine kinase activity. Binding of the ligand triggers receptor dimerization and
transphosphorylation of tyrosine residues in its cytoplasmic domain, which then recruits cytoplasmic signaling and scaffolding proteins. The recruitment of effector molecules
generally occurs via interaction of proteins with modular binding domains SH2 and SH3 (named after homology to the src oncogenes–src homology domains); SH2 domains
are a stretch of about 100 amino acids that allows high-affinity interactions with certain phosphotyrosine motifs. The ability of multiple effectors to interact with
phosphotyrosines is undoubtedly one of the keys to the pleiotropic effects that neurotrophins can exert. Shown here is a tyrosine kinase receptor type B (TrkB), which upon
activation produces effects on the Raf, MEK (mitogen-activated protein kinase/ERK), extracellular response kinase (ERK), and ribosomal S6 kinase (RSK) signaling pathway.
Some major downstream effects of RSK are CREB and stimulation of factors that bind to the AP-1 site (c-Fos and c-Jun). (D) Nuclear receptors. These receptors are
transcription factors that regulate the expression of target genes in response to steroid hormones and other ligands. Many hormones (including glucocorticoids, gonadal
steroids, and thyroid hormones) are able to rapidly penetrate into the lipid bilayer membrane, because of their lipophilic composition, and thereby directly interact with these
cytoplasmic receptors inside the cell. Upon activation by a hormone, the nuclear receptor–ligand complex translocates to the nucleus, where it binds to specific DNA
sequences, referred to as hormone responsive elements (HREs), and regulates gene transcription. Nuclear receptors often interact with a variety of coregulators that promote
transcriptional activation when recruited (coactivators) and those that attenuate promoter activity (corepressors). However, nongenomic effects of neuroactive steroids have
also been documented, with the majority of evidence suggesting modulation of ionotropic receptors. This figure illustrates both the genomic and the nongenomic effects. ATF1
= activation transcription factor 1; BDNF = brain-derived neurotrophic factor; CaMKII = Ca2+/calmodulin–dependent protein kinase II; CREM = cyclic adenosine
5'-monophosphate response element modulator; D1 = dopamine1 receptor; D5 = dopamine5 receptor; ER = estrogen receptor; GR = glucocorticoid receptor; GRK = G
protein–coupled receptor kinase; P = phosphorylation; PR = progesterone receptor.
Ionotropic Receptors
The first class of receptors contains in their molecular complex an intrinsic ion channel. Receptors of this class include those for a number of amino acids,
including glutamate (e.g., the NMDA [N-methyl-D-aspartate] receptor) and GABA ( -aminobutyric acid via the GABAA receptor), as well as the nicotinic
acetylcholine (ACh) receptor and the serotonin3 (5-HT3) receptor. Ion channels are integral membrane proteins that are directly responsible for the
electrical activity of the nervous system by virtue of their regulation of the movement of ions across membranes. Receptors containing intrinsic ion channels
have been called ionotropic and are generally composed of four or five subunits that open transiently when neurotransmitter binds, allowing ions to flow
into (e.g., Na+, Ca2+, Cl–) or out of (e.g., K+) the neuron, thereby generating synaptic potential (see Figure 1–1).
Often, the ionotropic receptors can be composed of different compositions of the different subunits, thereby providing the system with considerable
flexibility. For example, there is extensive research into the potential development of an anxiolytic that is devoid of sedative effects by targeting GABAA
receptor subunits present in selected brain regions. In general, neurotransmission that is mediated by ionotropic receptors is very fast, with ion channels
opening and closing within milliseconds, and regulates much of the tonic excitatory (e.g., glutamate-mediated) and inhibitory (e.g., GABA-mediated)
activity in the CNS; as we discuss below, many of the classical neurotransmitters (e.g., monoamines) exert their effects on a slower time scale and are
therefore often considered to be modulatory in their effects.
G Protein–Coupled Receptors
Most receptors in the CNS do not have intrinsic ionic conductance channels within their structure but instead regulate cellular activity by the generation of
various "second messengers." Receptors of this class do not generally interact directly with the various second-messenger-generating enzymes but instead
transmit information to the appropriate "effector" by the activation of interposed coupling proteins. These are the G protein–coupled receptor families. The
G protein–coupled receptors (GPCRs, which constitute more than 80% of all known receptors in the body, and number about 300) all span the plasma
membrane seven times (see Figure 1–1). GPCRs have been the focus of extensive research in psychiatry in recent years (Catapano and Manji 2007). The
amino terminus is on the outside of the cell and plays a critical role in recognition of the ligand; the carboxy terminus and third intracellular loop are inside
the cell and regulate not only coupling to different G proteins but also "cross talk" between receptors and desensitization (see Figure 1–1).
G proteins are so named because of their ability to bind the guanine nucleotides guanosine triphosphate (GTP) and guanosine diphosphate (GDP).
Receptors coupled to G proteins include those for catecholamines, serotonin, ACh, various peptides, and even sensory signals such as light and odorants
(Table 1–1). As we discuss later in the chapter, multiple subtypes of G proteins are known to exist, and they play critical roles in amplifying and integrating
signals.
TABLE 1–1. Key features of G protein subunits
G protein class Members Effector(s)/Functions Examples of receptors
i G i1–3, G o AC (+) 2, D2, A1, , M2, 5-HT1A
Ligand-type Ca2+ channels (+) Olfactory signals
G z, G t1–2 K+ channels (+)
Ca2+ channels (–)a GABAB
Cyclic GMP Retinal rods, cones (rhodopsins)
Phosphodiesterase (+) (G t1–2)
q G q, G 11, G 14, G 15, G 16 PLC- (+) TxA2, 5-HT2C, M1, M3, M5, 1
12 G 12,G 13 RGS domain–containing rho exchange factors TxA2, thrombin
b (x5) AC type I (–); AC types II, IV (potentiation)
PLC (+)
Receptor kinases (+)
Inactivates s
(x12) required for interaction of subunit with receptor
Note. AC = adenylyl cyclase; A1, A2 = adenosine receptor subtypes; 1, 1, 2 = adrenergic receptor subtypes; C = cholera toxin; D1, D2 = dopamine receptor subtypes; G t
= olfactory, but also found in limbic areas; G s = stimulatory; G t = transducin; GABAB = -aminobutyric acid receptor subtype; 5-HT1A, 5-HT2C = serotonin receptor
subtypes; M1, M2, M3, M5 = muscarinic receptor subtypes; = opioid receptor; P = pertussis toxin; PLC = phospholipase C; RGS = regulators of G protein signaling; TxA2 =
thromboxane A2 receptor.
aAlthough regulation of Na+/H+ exchange and Ca2+ channels by G 1–2 and G 1–3 has been demonstrated in artificial systems in vitro, these findings await definitive
confirmation.
bEffectors are regulated by subunits as a dimer.
Autoreceptors and Heteroreceptors
Autoreceptors are receptors located on neurons that produce the endogenous ligand for that particular receptor (e.g., a serotonergic receptor on a
serotonergic neuron). By contrast, heteroreceptors are receptor subtypes that are present on neurons that do not contain an endogenous ligand for that
particular receptor subtype (e.g., a serotonergic receptor located on a dopaminergic neuron).
Two major classes of autoreceptors play very important roles in fine-tuning neuronal activity. Somatodendritic autoreceptors are present on cell bodies and
dendrites and exert critical roles in regulating the firing rate of neurons. In general, activation of somatodendritic autoreceptors (e.g., 2-adrenergic
receptors for noradrenergic neurons, serotonin1A [5-HT1A] receptors for serotonergic neurons, dopamine2 [D2] receptors for dopaminergic neurons)
inhibits the firing rate of the neurons by opening K+ channels and by reducing cyclic adenosine monophosphate (cAMP) levels, both of which may be
important in psychiatric disease. For example, TREK-1 is a background K+ channel regulator protein important in 5-HT transmission and potentially in
mood-like behavior regulation in mice (Heurteaux et al. 2006). Fundamental mechanisms of neuronal transmission—such as K+ channels, which regulate
membrane potentials—may relate to global alterations in brain functioning relevant to psychiatry.
The second major class of autoreceptors, nerve terminal autoreceptors, play an important role in regulating the amount of neurotransmitter released per
nerve impulse, generally by closing nerve terminal Ca2+ channels. Both of these types of autoreceptors are typically members of the G protein–coupled
receptor family. Neurotransmitter release is known to be triggered by influx and alterations of intracellular calcium, with the functioning of three types of
SNARE (soluble N-ethylmaleimide–sensitive factor attachment protein [SNAP] receptor) proteins exerting critical roles. Recent advances in our
understanding of the distinct kinetics of neurotransmitter release modulators, such as botulinum and tetanus neurotoxins, suggest that these induce
prominent alterations in synaptobrevin and syntaxin, leading to calcium-independent mechanisms of neurotransmitter regulation (Sakaba et al. 2005). Most
synapses are dependent on influx of Ca2+ through voltage-gated calcium channels for presynaptic neurotransmitter release; in the retina, however, this
influx of calcium occurs via glutamatergic AMPA receptors (Chavez et al. 2006). Beyond the receptor level, presynaptic SAD, an intracellular serine
threonine kinase, is associated with the active zone cytomatrix that regulates neurotransmitter release (Inoue et al. 2006). These recent data further
exemplify the dynamic nature and ongoing advancement of our knowledge pertaining to basic processes involved in neurotransmitter regulation that may
possibly aid in advancing treatment of psychopathology.
G Protein–Coupled Receptor Regulation and Trafficking
The mechanism by which GPCRs translate extracellular signals into cellular changes was once envisioned as a simple linear model. It is now known,
however, that the activity of GPCRs is subject to at least three additional principal modes of regulation: desensitization, downregulation, and trafficking
(Carman and Benovic 1998) (Figure 1–2). Desensitization, the process by which cells rapidly adapt to stimulation by agonists, is generally believed to occur
by two major mechanisms: homologous and heterologous.
FIGURE 1–2. G protein–coupled receptors and G protein activation.
All G proteins are heterotrimers consisting of , , and subunits. The receptor shuttles between a low-affinity form that is not coupled to a G protein and a high-affinity form
that is coupled to a G protein. (A) At rest, G proteins are largely in their inactive state, namely, as heterotrimers, which have GDP (guanosine diphosphate) bound to the
subunit. (B) When a receptor is activated by a neurotransmitter, it undergoes a conformational (shape) change, forming a transient state referred to as a high-affinity
ternary complex, comprising the agonist, receptor in a high-affinity state, and G protein. A consequence of the receptor interaction with the G protein is that the GDP comes
off the G protein subunit, leaving a very transient empty guanine nucleotide binding domain. (C) Guanine nucleotides (generally GTP) quickly bind to this nucleotide binding
domain; thus, one of the major consequences of active receptor–G protein interaction is to facilitate guanine nucleotide exchange—this is basically the "on switch" for the G
protein cycle. (D) A family of GTPase-activating proteins for G protein–coupled receptors has been identified, and they are called regulators of G protein signaling (RGS)
proteins. Since activating GTPase activity facilitates the "turn off" reaction, these RGS proteins are involved in dampening the signal. Binding of GTP to the subunit of G
proteins results in subunit dissociation, whereby the -GTP dissociates from the subunits. Although not covalently bound, the and subunits remain tightly associated and
generally function as dimers. The -GTP and subunits are now able to activate multiple diverse effectors, thereby propagating the signal. While they are in their active
states, the G protein subunits can activate multiple effector molecules in a "hit and run" manner; this results in major signal amplification (i.e., one active G protein subunit
can activate multiple effector molecules; see Figure 1–11). The activated G protein subunits also dissociate from the receptor, converting the receptor to a low-affinity
conformation and facilitating the dissociation of the agonist from the receptor. The agonist can now activate another receptor, and this also results in signal amplification.
Together, these processes have been estimated to produce a 10,000-fold amplification of the signal in certain models. (E) Interestingly, the subunit has intrinsic GTPase
activity, which cleaves the third phosphate group from GTP (G-P-P-P) to GDP (G-P-P). Since -GDP is an inactive state, the GTPase activity serves as a built-in timing
mechanism, and this is the "turn off" reaction. (F) The reassociation of -GDP with is thermodynamically favored, and the reformation of the inactive heterotrimer ( )
completes the G protein cycle.
Homologous desensitization is receptor specific; that is, only the receptor actively being stimulated becomes desensitized. This form of desensitization
occurs via a family of kinases known as G protein–coupled kinases (GRKs). When a receptor activates a G protein and causes dissociation of the subunit
from the subunits (discussed in detail later), the subunits are able to provide an "anchoring surface" for the GRKs to allow them to come into the
proximity of the activated receptor and phosphorylate it. This phorphorylation then recruits another family of proteins known as arrestins, which physically
interfere with the coupling of the phosphorylated receptor and the G protein, thereby dampening the signal. This form of desensitization is very rapid and
usually transient (i.e., the receptors get dephosphorylated and return to the baseline state). However, if the stimulation of the receptor is excessive and
prolonged, it leads to an internalization of the receptor, and often its degradation, a process referred to as downregulation.
Heterologous desensitization is not receptor specific and is mediated by second-messenger kinases such as protein kinase A (PKA) and protein kinase C
(PKC). Thus, when a receptor activates PKA, the activated PKA is capable of phosphorylating (and thereby desensitizing) not only that particular receptor
but also other receptors that are present in proximity and have the correct phosphorylation motif, thereby producing heterologous desensitization.
Upon prolonged or repeated activation of receptors by agonist ligands, the process of receptor downregulation is observed. Downregulation is associated
with a reduced number of receptors detected in cells or tissues, thereby leading to attenuation of cellular responses (Carman and Benovic 1998). The
process of GPCR sequestration is mediated by a well-characterized endocytic pathway involving the concentration of receptors in clathrin-coated pits and
subsequent internalization and recycling back to the plasma membrane (Tsao and von Zastrow 2000). Endocytosis can thus clearly serve as a primary
mechanism to attenuate signaling by rapidly and reversibly removing receptors from the cell surface. However, emerging evidence suggests additional
functions of endocytosis and receptor trafficking in mediating GPCR signaling by way of certain effector pathways, most notably mitogen-activated protein
(MAP) kinase cascades (discussed in greater detail later). There is also evidence that endocytosis of GPCRs may be required for certain signal transduction
pathways leading to the nucleus (Tsao and von Zastrow 2000). These diverse functions of GPCR endocytosis and trafficking are leading to unexpected
insights into the biochemical and functional properties of endocytic vesicles. Indeed, there is considerable excitement about our growing understanding of
the diverse molecular mechanisms for signaling specificity and receptor trafficking, and the possibility that this knowledge could lead to highly selective
therapeutics.
Receptor Tyrosine Kinases
The receptor tyrosine kinases, as their name implies, contain intrinsic tyrosine kinase activity and are generally utilized by growth factors, such as
neurotrophic factors, and cytokines. Binding of an agonist initiates receptor dimerization and transphosphorylation of tyrosine residues in its cytoplasmic
domain (Patapoutian and Reichardt 2001) (see Figure 1–1). The phosphotyrosine residues of the receptor function as binding sites for recruiting specific
cytoplasmic signaling and scaffolding proteins. The ability of multiple effectors to interact with phosphotyrosines is undoubtedly one of the keys to the
pleiotropic effects that neurotrophins can exert. These pleiotropic and yet distinct effects of growth factors are mediated by varying degrees of activation of
three major signaling pathways: the MAP kinase pathway, the phosphoinositide-3 (PI3) kinase pathway, and the phospholipase C (PLC)– 1 pathway (see
Figure 1–9 later in this chapter).
Nuclear Receptors
Nuclear receptors are transcription factors that regulate the expression of target genes in response to steroid hormones and other ligands. Many hormones
(including glucocorticoids, gonadal steroids, and thyroid hormones) are able to rapidly penetrate into the lipid bilayer membrane, because of their lipophilic
composition, and thereby directly interact with these cytoplasmic receptors inside the cell (see Figure 1–1). Upon activation by a hormone, the nuclear
receptor–ligand complex translocates to the nucleus, where it binds to specific DNA sequences referred to as hormone-responsive elements (HREs), and
subsequently regulates gene transcription (Mangelsdorf et al. 1995; Truss and Beato 1993). Nuclear receptors often interact with a variety of coregulators
that promote transcriptional activation when recruited (coactivators) and those that attenuate promoter activity (corepressors).
With this overview of neurotransmitters and receptor subtypes, we now turn to a discussion of selected individual neurotransmitters and neuropeptides
before discussing the intricacies of cellular signal transduction systems.
NEUROTRANSMITTER AND NEUROPEPTIDE SYSTEMS
Serotonergic System
Largely on the basis of the observation that most current effective antidepressants and antipsychotics target these systems, the monoaminergic systems
(e.g., serotonin, norepinephrine, dopamine) have been extensively studied. Serotonin (5-HT) was given that name because of its activity as an endogenous
vasoconstrictor in blood serum (Rapport et al. 1947). It was later acknowledged as being the same molecule (secretin) found in the intestinal mucosa and
that is "secreted" by chromaffin cells (Brodie 1900). Following these findings, 5-HT soon became characterized as being a neurotransmitter in the CNS
(Bogdansky et al. 1956).
5-HT-producing cell bodies in the brain are localized in the central gray, in the surrounding reticular formation, and in cell clusters located in the center, and
thus the name raphe (from Latin, meaning midline) was adopted (Figure 1–3A) (discussed more extensively in Chapter 4, "Chemical Neuroanatomy of the
Primate Brain"). The dorsal raphe (DR), the largest brain stem 5-HT nucleus, contains approximately 50% of the total 5-HT neurons in the mammalian CNS;
in contrast, the medial raphe (MR) comprises 5% (Descarries et al. 1982; Wiklund and Bjorklund 1980). Serotonergic neurons project widely throughout
the CNS rather than to discrete anatomical locations (as the dopaminergic neurons appear to do; see Figure 1–4A later in this chapter), leading to the
suggestion that 5-HT exerts a major modulatory role throughout the CNS (Reader 1980). Interestingly, evidence suggests that infralimbic and prelimbic
regions of the ventral medial prefrontal cortex (mPFCv) in rats are responsible for detecting whether a stressor is under the organism's control. When a
stressor is controllable, stress-induced activation of the dorsal raphe nucleus is inhibited by the mPFCv, and the behavioral sequelae of the uncontrollable
stress response are blocked (Amat et al. 2005). The organism's ability to regulate 5-HT neuron activity and function has been a major ongoing focus of
psychiatric disorder research and treatments.
FIGURE 1–3. The serotonergic system.
This figure depicts the location of the major serotonin (5-HT)–producing cells (raphe nuclei) innervating brain structures (A), and various cellular regulatory processes
involved in serotonergic neurotransmission (B). 5-HT neurons project widely throughout the CNS and innervate virtually every part of the neuroaxis. L-Tryptophan, an amino
acid actively transported into presynaptic 5-HT-containing terminals, is the precursor for 5-HT. It is converted to 5-hydroxytryptophan (5-HTP) by the rate-limiting enzyme
tryptophan hydroxylase (TrpH). This enzyme is effectively inhibited by the drug p-chlorophenylalanine (PCPA). Aromatic amino acid decarboxylase (AADC) converts 5-HTP to
5-HT. Once released from the presynaptic terminal, 5-HT can interact with a variety (15 different types) of presynaptic and postsynaptic receptors. Presynaptic regulation of
5-HT neuron firing activity and release occurs through somatodendritic 5-HT1A (not shown) and 5-HT1B,1D autoreceptors, respectively, located on nerve terminals.
Sumatriptan is a 5-HT1B,1D receptor agonist. (The antimigraine effects of this agent are likely mediated by local activation of this receptor subtype on blood vessels, which
results in their constriction.) Buspirone is a partial 5-HT1A agonist that activates both pre- and postsynaptic receptors. Cisapride is a preferential 5-HT4 receptor agonist that is
used to treat irritable bowel syndrome as well as nausea associated with antidepressants. The binding of 5-HT to G protein receptors (Go, Gi, etc.) that are coupled to
adenylyl cyclase (AC) and phospholipase C– (PLC- ) will result in the production of a cascade of second-messenger and cellular effects. Lysergic acid diethylamide (LSD)
likely interacts with numerous 5-HT receptors to mediate its effects. Pharmacologically this ligand is often used as a 5-HT2 receptor agonist in receptor binding experiments.
Ondansetron is a 5-HT3 receptor antagonist that is marketed as an antiemetic agent for chemotherapy patients but is also given to counteract side effects produced by
antidepressants in some patients. 5-HT has its action terminated in the synapse by rapidly being taken back into the presynaptic neuron through 5-HT transporters (5-HTT).
Once inside the neuron, it can either be repackaged into vesicles for reuse or undergo enzymatic catabolism. The selective 5-HT reuptake inhibitors (SSRIs) and older-
generation tricyclic antidepressants (TCAs) are able to interfere/block the reuptake of 5-HT. 5-HT is then metabolized to 5-hydroxyindoleacetic acid (5-HIAA) by monoamine
oxidase (MAO), located on the outer membrane of mitochondria or sequestered and stored in secretory vesicles by vesicle monoamine transporters (VMATs). Reserpine
causes a depletion of 5-HT in vesicles by interfering with uptake and storage mechanisms (depressive-like symptoms have been reported with this agent). Tranylcypromine is
an MAO inhibitor (MAOI) and an effective antidepressant. Fenfluramine (an anorectic agent) and MDMA ("Ecstasy") are able to facilitate 5-HT release by altering 5-HTT
function. DAG = diacylglycerol; 5-HTT = serotonin transporter; IP3 = inositol-1,4,5-triphosphate.
Source. Adapted from Cooper JR, Bloom FE, Roth RH: The Biochemical Basis of Neuropharmacology, 7th Edition. New York, Oxford University Press, 2001. Copyright 1970,
1974, 1978, 1982, 1986, 1991, 1996, 2001 by Oxford University Press, Inc. Used by permission of Oxford University Press, Inc. Modified from Nestler et al. 2001.
FIGURE 1–4. The dopaminergic system.
This figure depicts the dopaminergic projections throughout the brain (A) and various regulatory processes involved in dopaminergic neurotransmission (B). The amino acid
L-tyrosine is actively transported into presynaptic dopamine (DA) nerve terminals, where it is ultimately converted into DA. The rate-limiting step is conversion of L-tyrosine
to L-dihydroxyphenylalanine (L-dopa) by the enzyme tyrosine hydroxylase (TH). -Methyl-p-tyrosine (AMPT) is a competitive inhibitor of tyrosine hydroxylase and has been
used to assess the impact of reduced catecholaminergic function in clinical studies. The production of DA requires that L-aromatic amino acid decarboxylase (AADC) act on
L-dopa. Thus, the administration of L-dopa to patients with Parkinson's disease bypasses the rate-limiting step and is able to produce DA quite readily. DA has its action
terminated in the synapse by rapidly being taken back into the presynaptic neuron through DA transporters (DATs). DA is then metabolized to dihydroxyphenylalanine
(DOPAC) by intraneuronal monoamine oxidase (MAO; preferentially by the MAO-B subtype) located on the outer membrane of mitochondria, or is sequestered and stored in
secretory vesicles by vesicle monoamine transporters (VMATs). Reserpine causes a depletion of DA in vesicles by interfering and irreversibly damaging uptake and storage
mechanisms. -Hydroxybutyrate inhibits the release of DA by blocking impulse propagation in DA neurons. Pargyline inhibits MAO and may have efficacy in treating
parkinsonian symptoms by augmenting DA levels through inhibition of DA catabolism. Other clinically used inhibitors of MAO are nonselective and thus likely elevate the levels
of DA, norepinephrine, and serotonin. Once released from the presynaptic terminal (because of an action potential and calcium influx), DA can interact with five different G
protein–coupled receptors (D1–D5), which belong to either the D1 or D2 receptor family. Presynaptic regulation of DA neuron firing activity and release occurs through
somatodendritic (not shown) and nerve terminal D2 autoreceptors, respectively. Pramipexole is a D2/D3 receptor agonist and has been documented to have efficacy as an
augmentation strategy in cases of treatment-resistant depression and in the management of Parkinson's disease. The binding of DA to G protein receptors (Go, Gi, etc.)
positively or negatively coupled to adenylyl cyclase (AC) results in the activation or inhibition of this enzyme, respectively, and the production of a cascade of second-
messenger and cellular effects (see diagram). Apomorphine is a D1/D2 receptor agonist that has been used clinically to aid in the treatment of Parkinson's disease.
(SKF-82958 is a pharmacologically selective D1 receptor agonist.) SCH-23390 is a D1/D5 receptor antagonist. There are likely physiological differences between D1 and D5
receptors, but the current unavailability of selective pharmacological agents has precluded an adequate differentiation thus far. Haloperidol is a D2 receptor antagonist, and
clozapine is a nonspecific D2/D4 receptor antagonist (both are effective antipsychotic agents). Once inside the neuron, DA can either be repackaged into vesicles for reuse or
undergo enzymatic catabolism. Nomifensine is able to interfere/block the reuptake of DA. The antidepressant bupropion has affinity for the dopaminergic system, but it is not
known whether this agent mediates its effects through DA or possibly by augmenting other monoamines. DA can be degraded to homovanillic acid (HVA) through the
sequential action of catechol-O-methyltransferase (COMT) and MAO. Tropolone is an inhibitor of COMT. Evidence suggests that the COMT gene may be linked to schizophrenia
(Akil et al. 2003).
Source. Adapted from Cooper JR, Bloom FE, Roth RH: The Biochemical Basis of Neuropharmacology, 7th Edition. New York, Oxford University Press, 2001. Copyright 1970,
1974, 1978, 1982, 1986, 1991, 1996, 2001 by Oxford University Press, Inc. Used by permission of Oxford University Press, Inc.
The precursor for 5-HT synthesis is l-tryptophan, an amino acid that comes primarily from the diet and crosses the blood–brain barrier through a carrier for
large neutral amino acids. Tryptophan hydroxylase (TrpH) is the rate-limiting enzyme in serotonin biosynthesis (Figure 1–3B), and polymorphisms in this