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.

Noradrenergic

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-HTia (not shown) and 5-HTib,id autoreceptors, respectively, located on nerve terminals. Sumatriptan is a 5-HTib,id 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-HTia 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, G¡, etc.) that are coupled to adenylyl cyclase (AC) and phospholipase C-B (PLC-15) 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.

Parkinson Disease

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-di hydroxy phenylalanine (L-dopa) by the enzyme tyrosine hydroxylase (TH). a-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. 7-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 Di 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, Gj, 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 Di receptor agonist.) SCH-23390 is a D1/D5 receptor antagonist. There are likely physiological differences between Di 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 enzyme have been extensively investigated in psychiatric disorders, with equivocal results to date. A more fruitful research strategy in humans has been tryptophan depletion via dietary restriction to study the role of serotonin in the pathophysiology and treatment of psychiatric disorders (Bell et al. 2001). These studies have indicated that tryptophan depletion produces a rapid depressive relapse in patients treated with selective serotonin reuptake inhibitors (SSRIs) but not in those treated with norepinephrine reuptake inhibitors; the data suggesting induction of depressive symptoms in remitted patients or individuals with family histories of mood disorders are more equivocal (Bell et al. 2001).

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