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Chapter 1. Neurotransmitters, Receptors, Signal Transduction, and Second Messengers in Psychiatric Disorders

Steven T. Szabo, Ph.D.; Todd D. Gould, M.D.; Husseini K. Manji, M.D., F.R.C.P.C.
DOI: 10.1176/appi.books.9781585623860.407001

Sections

Excerpt

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.

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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.

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.

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.

FIGURE 1–5. The noradrenergic system.This figure depicts the noradrenergic projections throughout the brain (A) and the various regulatory processes involved in norepinephrine (NE) neurotransmission (B). NE neurons innervate nearly all parts of the neuroaxis, with neurons in the locus coeruleus being responsible for most of the NE in the brain (90% of NE in the forebrain and 70% of total NE in the brain). The amino acid l-tyrosine is actively transported into presynaptic NE nerve terminals, where it is ultimately converted into NE. 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. Aromatic amino acid decarboxylase (AADC) converts l-dopa to dopamine (DA). l-dopa then becomes decarboxylated by decarboxylase to form dopamine (DA). DA is then taken up from the cytoplasm into vesicles, by vesicle monoamine transporters (VMATs), and hydroxylated by dopamine -hydroxylase (DBH) in the presence of O2 and ascorbate to form NE. Normetanephrine (NM), which is formed by the action of COMT (catechol-O-methyltransferase) on NE, can be further metabolized by monoamine oxidase (MAO) and aldehyde reductase to 3-methoxy-4-hydroxyphenylglycol (MHPG). Reserpine causes a depletion of NE in vesicles by interfering with uptake and storage mechanisms (depressive-like symptoms have been reported with this hypertension). Once released from the presynaptic terminal, NE can interact with a variety of presynaptic and postsynaptic receptors. Presynaptic regulation of NE neuron firing activity and release occurs through somatodendritic (not shown) and nerve-terminal 2 adrenoreceptors, respectively. Yohimbine potentiates NE neuronal firing and NE release by blocking these 2 adrenoreceptors, thereby disinhibiting these neurons from a negative feedback influence. Conversely, clonidine attenuates NE neuron firing and release by activating these receptors. Idazoxan is a relatively selective 2 adrenoreceptor antagonist primarily used for pharmacological purposes. The binding of NE to G protein receptors (Go, Gi, etc.) that are coupled to adenylyl cyclase (AC) and phospholipase C– (PLC-b) produces a cascade of second-messenger and cellular effects (see diagram and later sections of the text). NE has its action terminated in the synapse by rapidly being taken back into the presynaptic neuron via NE transporters (NETs). Once inside the neuron, it can either be repackaged into vesicles for reuse or undergo enzymatic degradation. The selective NE reuptake inhibitor and antidepressant reboxetine and older-generation tricyclic antidepressant desipramine are able to interfere/block the reuptake of NE. On the other hand, amphetamine is able to facilitate NE release by altering NET function. Green spheres represent DA neurotransmitters; blue spheres represent NE neurotransmitters. DAG = diacylglycerol; 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 1–6. The cholinergic system.This figure depicts the cholinergic pathways in the brain (A) and various regulatory processes involved in cholinergic neurotransmission (B). Choline crosses the blood–brain barrier to enter the brain and is actively transported into cholinergic presynaptic terminals by an active uptake mechanism (requiring ATP). This neurotransmitter is produced by a single enzymatic reaction in which acetyl coenzyme A (AcCoA) donates its acetyl group to choline by means of the enzyme choline acetyltransferase (ChAT). AcCoA is primarily synthesized in the mitochondria of neurons. Upon its formation, acetylcholine (ACh) is sequestered into secretory vesicles by vesicle ACh transporters (VATs), where it is stored. Vesamicol effectively blocks the transport of ACh into vesicles. An agent such as -bungarotoxin or AF64A is capable of increasing synaptic concentration of ACh by acting as a releaser and a noncompetitive reuptake inhibitor, respectively. In turn, agents such as botulinum toxin are able to attenuate ACh release from nerve terminals. Once released from the presynaptic terminals, ACh can interact with a variety of presynaptic and postsynaptic receptors. In contrast to many other monoaminergic neurotransmitters, the ACh signal is terminated primarily by degradation by the enzyme acetylcholinesterase (AChE) rather than by reuptake. Interestingly, AChE is present on both presynaptic and postsynaptic membranes and can be inhibited by physostigmine (reversible) and soman (irreversible). Currently, AChE inhibitors such as donepezil and galantamine are the only classes of agents that are FDA approved for the treatment of Alzheimer's disease. ACh receptors are of two types: muscarinic (G protein–coupled) and nicotinic (ionotropic). Presynaptic regulation of ACh neuron firing activity and release occurs through somatodendritic (not shown) and nerve terminal M2 autoreceptors, respectively. The binding of ACh to G protein–coupled muscarinic receptors that are negatively coupled to adenylyl cyclase (AC) or coupled to phosphoinositol hydrolysis produces a cascade of second-messenger and cellular effects (see diagram). ACh also activates ionotropic nicotinic receptors (nAChRs). ACh has it action terminated in the synapse through rapid degradation by AChE, which liberates free choline to be taken back into the presynaptic neuron through choline transporters (CTs). Once inside the neuron, it can be reused for the synthesis of ACh, can be repackaged into vesicles for reuse, or undergoes enzymatic degradation. There are some relatively new agents that selectively antagonize the muscarinic receptors, such as CI-1017 for M1, methoctramine for M2, 4-DAMP for M3, PD-102807 for M4, and scopolamine (hardly a new agent) for M5 (although it also has affinity for M3 receptor). nAChR or nicotine receptors are activated by nicotine and the specific alpha(4)beta(2*) agonist metanicotine. Mecamylamine is an AChR antagonist. DAG = diacylglycerol; 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 1–7. The glutamatergic system.This figure depicts the various regulatory processes involved in glutamatergic neurotransmission. The biosynthetic pathway for glutamate involves synthesis from glucose and the transamination of -ketoglutarate; however, a small proportion of glutamate is formed more directly from glutamine by glutamine synthetase. The latter is actually synthesized in glia and, via an active process (requiring ATP), is transported to neurons, where in the mitochondria glutaminase is able to convert this precursor to glutamate. Furthermore, in astrocytes glutamine can undergo oxidation to yield -ketoglutarate, which can also be transported to neurons and participate in glutamate synthesis. Glutamate is either metabolized or sequestered and stored in secretory vesicles by vesicle glutamate transporters (VGluTs). Glutamate can then be released by a calcium-dependent excitotoxic process. Once released from the presynaptic terminal, glutamate is able to bind to numerous excitatory amino acid (EAA) receptors, including both ionotropic (e.g., NMDA [N-methyl-d-aspartate]) and metabotropic (mGluR) receptors. Presynaptic regulation of glutamate release occurs through metabotropic glutamate receptors (mGluR2 and mGluR3), which subserve the function of autoreceptors; however, these receptors are also located on the postsynaptic element. Glutamate has its action terminated in the synapse by reuptake mechanisms utilizing distinct glutamate transporters (labeled VGT in figure) that exist on not only presynaptic nerve terminals but also astrocytes; indeed, current data suggest that astrocytic glutamate uptake may be more important for clearing excess glutamate, raising the possibility that astrocytic loss (as has been documented in mood disorders) may contribute to deleterious glutamate signaling, but more so by astrocytes. It is now known that a number of important intracellular proteins are able to alter the function of glutamate receptors (see diagram). Also, growth factors such as glial-derived neurotrophic factor (GDNF) and S100 secreted from glia have been demonstrated to exert a tremendous influence on glutamatergic neurons and synapse formation. Of note, serotonin1A (5-HT1A) receptors have been documented to be regulated by antidepressant agents; this receptor is also able to modulate the release of S100. AKAP = A kinase anchoring protein; CaMKII = Ca2+/calmodulin–dependent protein kinase II; ERK = extracellular response kinase; GKAP = guanylate kinase–associated protein; Glu = glutamate; Gly = glycine; GTg = glutamate transporter glial; GTn = glutamate transporter neuronal; Hsp70 = heat shock protein 70; MEK = mitogen-activated protein kinase/ERK; mGluR = metabotropic glutamate receptor; MyoV = myosin V; NMDAR = NMDA receptor; nNOS = neuronal nitric oxide synthase; PKA = phosphokinase A; PKC = phosphokinase C; PP-1, PP-2A, PP-2B = protein phosphatases; RSK = ribosomal S6 kinase; SHP2 = src homology 2 domain–containing tyrosine phosphatase.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 Nicholls 1994.

FIGURE 1–8. The GABAergic system.This figure depicts the various regulatory processes involved in GABAergic neurotransmission. The amino acid (and neurotransmitter) glutamate serves as the precursor for the biosynthesis of -aminobutyric acid (GABA). The rate-limiting enzyme for the process is glutamic acid decarboxylase (GAD), which utilizes pyridoxal phosphate as an important cofactor. Furthermore, agents such as l-glutamine--hydrazide and allylglycine inhibit this enzyme and, thus, the production of GABA. Once released from the presynaptic terminal, GABA can interact with a variety of presynaptic and postsynaptic receptors. Presynaptic regulation of GABA neuron firing activity and release occurs through somatodendritic (not shown) and nerve-terminal GABAB receptors, respectively. Baclofen is a GABAB receptor agonist. The binding of GABA to ionotropic GABAA receptors and metabotropic GABAB receptors mediates the effects of this receptor. The GABAB receptors are thought to mediate their actions by being coupled to Ca2+ or K+ channels via second-messenger systems. Many agents are able to modulate GABAA receptor function. Benzodiazepines, such as diazepam, increase Cl permeability, and there are numerous available antagonists directed against this site. There is also a distinctive barbiturate binding site on GABAA receptors, and many psychotropic agents are capable of influencing the function of this receptor (see blown-up diagram). GABA is taken back into presynaptic nerve endings by a high-affinity GABA uptake transporter (GABAT) similar to that of the monoamines. Once inside the neuron, GABA can be broken down by GABA transaminase (GABA-T), which is localized in the mitochondria; GABA that is not degraded is sequestered and stored into secretory vesicles by vesicle GABA transporters (VGTs), which differ from VMATs in their bioenergetic dependence. The metabolic pathway that produces GABA, mostly from glucose, is referred to as the GABA shunt. The conversion of -ketoglutarate into glutamate by the action of GABA-T and GAD catalyzes the decarboxylation of glutamic acid to produce GABA. GABA can undergo numerous transformations, of which the simplest is the reduction of succinic semialdehyde (SS) to -hydroxybutyrate (GHB). On the other hand, when SS is oxidized by succinic semialdehyde dehydrogenase (SSADH), the production of succinic acid (SA) occurs. GHB has received attention because it regulates narcoleptic episodes and may produce amnestic effects. The mood stabilizer and antiepileptic drug valproic acid is reported to inhibit SSADH and GABA-T. TBPS = t-butylbicyclophosphorothionate.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.

FIGURE 1–9. Neurotrophic cascades.Cell survival is dependent on neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) and nerve growth factor, and the expression of these factors can be induced by synaptic activity. Phosphorylation of tyrosine receptor kinase (Trk) receptors activates a critical signaling pathway, the Ras/MAP kinase pathway (see Figure 1–15). Phosphorylated Trk receptors also recruit the phosphoinositide-3 kinase (PI3K) pathway through at least two distinct pathways, the relative importance of which differs between neuronal subpopulations. In many neurons, Ras-dependent activation of PI3K is the most important pathway through which neurotrophins promote cell survival (not shown; see text). In some cells, as shown in the figure, PI3K can also be directly activated through adaptor proteins (Shc, Grb-2, and Gab-1). PI3K directly regulates certain cytoplasmic apoptotic pathways. Akt phosphorylates the pro-apoptotic Bcl-2 family member BAD (Bcl-xl/Bcl-2–associated death promoter), thereby inhibiting BAD's pro-apoptotic functions (Datta et al. 1997). Akt may also promote survival in an indirect fashion by regulating another major signaling enzyme: glycogen synthase kinase–3 (GSK-3) (Woodgett 2001). Interestingly, lithium is an inhibitor of GSK-3. Phosphorylated Trk receptors also recruit phospholipase C–1 (PLC-1). The Trk kinase then phosphorylates and activates PLC-1, which acts to hydrolyze phosphatidylinositides to generate diacylglycerol (DAG) and inositol-1,4,5-triphosphate (IP3). Antidepressant medication and mood stabilizers increase levels of BDNF and other neurotrophic factors, suggesting a therapeutic relevance.

FIGURE 1–10. Nitric oxide as a signaling molecule.This figure depicts the various regulatory processes involved in nitric oxide (NO) signaling. Reactive oxygen species, in particular several gases, represent yet another means by which the brain is able to transmit messages. NO is formed via NO synthase (NOS), an enzyme that is generally activated by Ca2+-calmodulin. As such, Ca2+ entry into cells via NMDA (N-methyl-d-aspartate) receptor activation is an important means of activating NOS. NOS yields NO by converting arginine to citrulline using O2. NO then converts GTP to cGMP, which then is able to target soluble guanylyl cyclases (GCs) (enzymes that are similar to adenylyl cyclases but are activated by cGMP rather than cAMP). cGMP then activates the protein kinase (PKG) and, through the conversion of ATP to ADP, phosphorylates many proteins to bring about the physiological effects of NO. Once produced, NO is then able to diffuse out of the neuron and act on other cells as a signaling molecule. Interestingly, NO is able to also diffuse back to the presynaptic terminal, acting as a retrograde transmitter, and is thought to be important in reshaping synaptic connections (i.e., it has been linked to long-term potentiation). NO is labeled in yellow; glutamate is labeled in purple. GTg = glial transporter for glutamate; GTn = neuronal transporter for glutamate; 5-HT1A = serotonin1A receptor; S100 = calcium-binding protein expressed primarily by astrocytes.Source. Adapted from Girault J-A, Greengard P: "Principles of Signal Transduction," in Neurobiology of Mental Illness. Edited by Charney DS, Nestler EJ, Bunney BS. New York, Oxford University Press, 1999. Copyright 1999, Oxford University Press. Used with permission.

FIGURE 1–11. Principles of signal transduction.As described in the text, neurons regulate signaling pathways through multiple mechanisms and at multiple levels. Neuronal circuits possess a large number of extracellular neuroactive molecules (1; labeled A, B, and C) that can interact with multiple receptors (2). Binding of neuroactive molecules to receptors can result in stimulation and/or attenuation of multiple cellular signaling pathways (3), depending on the type of receptor, location in the central nervous system, and activity of other signaling pathways within the cell. Thus, the potential is there to greatly amplify the signals. This signaling can then converge on one signaling pathway (4) or diverge into many signaling pathways (5). Activation of signaling pathways alters gene transcription and activity of proteins such as ion channels and other signaling molecules (6). Additionally, activation of signaling pathways can both positively (7) and negatively (8) regulate the function of extracellular receptors. Bcl-2 = an anti-apoptotic protein; BDNF = brain-derived neurotrophic factor; CREB = cAMP response element–binding protein.

FIGURE 1–12. cAMP signaling pathway.Receptors can be positively (e.g., -adrenergic, D1) or negatively (e.g., 5-HT1A, D2) coupled to adenylyl cyclase (AC) to regulate cAMP levels. 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). After activation, the phosphorylated CREB binds to the cAMP response element (CRE), a gene sequence found in the promoter of certain genes; data suggest that antidepressants may activate CREB, thereby bringing about increased expression of a major target gene, BDNF. Phosphodiesterase is an enzyme that breaks down cAMP to AMP. Some antidepressant treatments have been found to upregulate phosphodiesterase. Drugs like rolipram, which inhibit phosphodiesterase, may be useful as adjunct treatments for depression. Forskolin is an agent used in preclinical research to stimulate adenylyl cyclase.

FIGURE 1–13. Phosphoinositide (PI) signaling pathway.A number of receptors in the CNS (including M1, M3, M5, 5-HT2C) are coupled, via Gq/11, to activation of PI hydrolysis. Activation of these receptors induces phospholipase C (PLC) hydrolysis of phosphoinositide-4,5-bisphosphate (PIP2) to sn-1,2-diacylglycerol (DAG) and inositol-1,4,5-triphosphate (IP3). DAG activates protein kinase C (PKC), an enzyme that has many effects, including the activation of phospholipase A2 (PLA2), an activator of arachidonic acid signaling pathways. IP3 binds to the IP3 receptor, which results in the release of intracellular calcium from intracellular stores, most notably the endoplasmic reticulum. Calcium is an important signaling molecule and initiates a number of downstream effects such as activation of calmodulins and calmodulin-dependent protein kinases (see Figure 1–15). IP3 is recycled back to PIP2 by the enzymes inositol monophosphatase (IMPase) and inositol polyphosphatase (IPPase; not shown), both of which are targets of lithium. Thus, lithium may initiate many of its therapeutic effects by inhibiting these enzymes, thereby bringing about a cascade of downstream effects involving PKC and gene expression changes.Source. Adapted from Gould TD, Chen G, Manji HK: "Mood Stabilizer Pharmacology." Clinical Neuroscience Research 2:193–212, 2003. Copyright 2003, Elsevier. Used with permission.

FIGURE 1–14. Calcium-mediated signaling.In neurons, Ca2+-dependent processes represent an intrinsic nonsynaptic feedback system that provides competence for adaptation to different functional tasks. Ca2+ is generally mobilized in one of two ways in the cells: either by mobilization from intracellular stores (e.g., from the endoplasmic reticulum) or from outside of the cell via plasma membrane ion channels and certain receptors (e.g., NMDA [N-methyl-d-aspartate]). The external concentration of Ca2+ is approximately 2 mM, yet resting intracellular Ca2+ concentrations are in the range of 100 nM (2 x 104 lower). Local high levels of calcium result in activation of enzymes, signaling cascades, and, at extremes, cell death. Release of intracellular stores of calcium is primarily regulated by inositol-1,4,5-triphosphate (IP3) receptors that are activated upon generation of IP3 by phospholipase C (PLC) activity, and the ryanodine receptor that is activated by the drug ryanodine. Many proteins bind Ca2+ and are classified as either "buffering" or "triggering." These include calcium pumps, calbindin, calsequestrin, calmodulin, PKC, phospholipase A2, and calcineurin. Once stability of intracellular calcium is accomplished, transient low-magnitude changes can serve an important signaling function. Calcium action is local. Because of the high concentration of calcium-binding proteins, it is estimated that the free Ca2+ ion diffuses only approximately 0.5 M and is free for about 50 sec before encountering a Ca2+-binding protein. Ca2+ is sequestered in the endoplasmic reticulum (which serves as a vast web and framework for Ca2+-binding proteins to capture and sequester Ca2+). Ca2+ buffering/triggering proteins are nonuniformly distributed, so there is considerable subcellular variation of Ca2+ concentrations (e.g., near a Ca2+ channel). The primary mechanism for Ca2+ calcium exit from the cell is either via sodium-calcium exchange or by means of a calcium pump.

FIGURE 1–15. MAP (mitogen-activated protein) kinase signaling pathway.The influence of neurotrophic factors on cell survival is mediated by activation of the MAP kinase cascade and other neurotrophic cascades. Activation of neurotrophic factor receptors referred to as tyrosine receptor kinases (Trks) results in activation of the MAP kinase cascade via several intermediate steps, including phosphorylation of the adaptor protein Shc and recruitment of the guanine nucleotide exchange factor Sos. This results in activation of the small guanosine triphosphate–binding protein Ras, which leads to activation of a cascade of serine/threonine kinases. This includes Raf, MAP kinase kinase (MEK), and MAP kinase (also referred to as extracellular response kinase, or ERK). One target of the MAP kinase cascade is the ribosomal S6 kinases, known as RSK, which influences cell survival in at least two ways. RSK phosphorylates and inactivates the pro-apoptotic factor BAD (Bcl-xl/Bcl-2–associated death promoter). RSK also phosphorylates cAMP response element–binding protein (CREB) and thereby increases the expression of the anti-apoptotic factor Bcl-2 and brain-derived neurotrophic factor (BDNF). Ras also activates the phosphoinositol–3 kinase (PI3K) pathway, a primary target of which is the enzyme glycogen synthase kinase (GSK-3). Activation of the PI3 kinase pathway deactivates GSK-3. GSK-3 has multiple targets in cells, including transcription factors (-catenin and c-Jun) and cytoskeletal elements such as tau. Many of the targets of GSK-3 are pro-apoptotic when activated. Thus, deactivation of GSK-3 via activation of the PI3K pathway results in neurotrophic effects. Lithium inhibits GSK-3, an effect that may be, at least in part, responsible for lithium's therapeutic effects. These mechanisms underlie many of the long-term effects of neurotrophins, including neurite outgrowth, cytoskeletal remodeling, and cell survival.Source. Adapted from Gould TD, Chen G, Manji HK: "Mood Stabilizer Psychopharmacology." Clinical Neuroscience Research 2:193–212, 2002. Copyright 2002, Elsevier. Used with permission.
Table Reference Number
TABLE 1–1. Key features of G protein subunits
Table Reference Number
TABLE 1–2. Selected peptides and their presumed relevance to psychiatric disorders and treatment

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