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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).

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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.

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