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FIGURE14-1Overlap of MDD and anxiety disorders.

Although the core symptoms of anxiety disorders (anxiety
and worry ) differ from the core symptoms of major depression ( loss of interest and depressed mood ), there is
considerable overlap among the rest of the symptoms associated with these disorders ( compare the " anxiety
disorders " puzzle on the right to the " MDD " puzzle on the left). For example , fatigue, sleep difficulties, and
problems concentrating are common to both types of disorders.

the reader is referred to Chapter 12; for those anxiolytic agents used also as mood stabilizers for the treatment of
bipolar disorder (i.e.,certain anti convulsants ) , the reader is referred to Chapter 13 ;and for those anxiolytics
used as antipsychotics , the place to look is Chapter 10. The discussion in this chapter is at the conceptual level
,and not at the pragmatic level. The reader should consult standard drug handbooks (such as Essential
Psychopharmacology : Presenters Guide) for details of doses , side effects , drug interactions , and other issues
relevant to the prescribing of these drugs in clinical practice.

That is, in generalized anxiety disorder, malfunctioning in the amygdala and CST C loops may be persistent
and unremitting yet not severe (Figure14-2), where as malfunctioning may be intermittent but catastrophic in an
unexpected manner for panic disorder (Figure14-3) or in an expected manner for social anxiety (Figure14-4).
Circuit malfunctioning may be traumatic in origin in posttraumatic stress disorder (PTSD ) (Figur e14-5) or
trapped in a redundant , repetitive loop for obsessive compulsive disorder (OCD ) (Figure 14-6) .

FIGURE 14-12 Endocrine output of fear. The fear response may be characterized in part by endocrine effects
such as in creases in Cortisol, which occur because of amygdala activation of the hypothalamic-pituitary adrenal
(HPA ) axis. Prolonged HP A activation and Cortisol release can have significant health implications ,such as
increased risk of coronary artery disease, type 2 diabetes,and stroke.

FIGURE 14-13 Breathing output. Changes in respiration may occur during a fear response; these changes are
regulated by activation of the parabrachial nucleus(PBN) via the amygdala. Inappropriate or excessive
activation of the PBN can lead not only to increases in the rate of respiration but also to symptoms such as
shortness of breath,exacerbation of asthma,or a sense of beings mothered.

The amygdala and the neurobiology of fear

The amygdala, an almond-shaped brain center located near the hippocampus (see Figure 9-63), has important an
atomical connections that allow it to integrate sensory and cognitive information and then to determine whether
there will be afear response (see Figures 9-6 4 and 9-65 as well as Figures 7-12, 7-13 , and 7-19 through 7-20).
Figures14-9 through 14-15 illustrate how the amygdala's connections relate to the signs and symptoms
associated Avith the fear response. Specifically, th e affect or feeling of fear may be regulated via there ciprocal
connections the amygdala shares with key areas of prefrontal cortex that regulate emotions ,

FIGURE14-14 Autonomic output of fear. Autonomic responses are typically associated with feelings of fear
.These include in creases in heart rate (HR) and blood pressure (BP), which are• regulated by reciprocal
connections between the amygdala and the locus coeruleus (LC). Long-term activation of this circuit may lead
to increased risk of atherosclerosis, cardiac ischemia, change in BP, decreased HR variability, myocardial
infarction (Ml) ,or even sudden death.

FIGURE14-15 Reexperiencing . Anxiety can be triggered not only by an external stimulus but also by an
individual's memories.Traumatic memories stored in the hippocampus can activate the amygdala, causing the
amygdala, in turn,to activate other brain regions and gene rate a fear response .This is termed reexperiencing
and is a particular feature of post traumatic stress disorder .

namely the orbit of rontal cortex and the anterior cingulate cortex (Figur e14-10). However, fear is not just a
feeling . The fear response canal so include motor responses . Depending on the circumstances and one's
temperament ,those motor responses could be fight ,flight , or freezing in place. Motor responses of fear are
regulated in part by connections between the amygdala and the periaqueductal gray area of the brainstem(Figure
14-11) .

or a false sense of being smothered (Figure14-13)— all of which are common during anxiety and especially during attacks of anxiety such as panic attacks . What is known about these connections is that several neurotransmitters are in volved in the production of symptoms of anxiety at the level of the amygdala and that numero us anxiolytic drugs have actions on these specific neurotransmitter systems to relieve the symptoms of anxiety and fear (Figure14-16) FIGURE 14-17 Gamma-aminobutyric acid (GABA) is produced. especially in conditions such as post traumatic stressdisorder. however . Symptoms of anxiety/ fear are as sociated with malfunctioning of amygdala-centered circuits. anxiety . A quick boost of Cortisol may enhance survival when a person is encountering areal but short-term threat . voltage-gated ion channels are in volved in neurotransmission with in these circuits. is converted to GABA by the enzym e glutamic acid decarboxylase (GAD). gamma-amino butyric acid (GABA). The amino acid glutamate.There are also endocrine reactions that accompany fear. causing changes in the hypothalamic pituitary-adrenal (HPA) axis and thus of Cortisol levels. and stroke (Figur e14-12). glutamate . and even sudden death (Figur e14-15) . in cluding in creased rates of coronary artery disease. perhaps the best-known and most widely used anxiolytics. including those in the amygdala and in the CST C loops. Breathing canal so change during a fear response . the neurotransmitters that regulate these circuits include serotonin (5HT). To understand how GABA regulates brain circuits in anxiety and how benzodiazepines exert . home of the noradrenergic cell bodies (Figure 14-14 ) ( noradrenergic neurons are discussed in Chapters 7 and 11 and noradrenergic pathways are illustrated in Figure7-9) . this can lead to unwanted symptoms of shortness of breath . Each connection utilizes specific neurotransmitters acting at specific receptors (Figure14-16). hypertension . and norepinephrine (NE). These autonomic and cardiovascular responses are mediated by connections between the amygdala and the locus coeruleus. apre cursor to GABA.in part due to connections between the amygdala and the hypothalamus. Some of the key neurotransmitters acting at the amygdala are shown in Figure14-16 . among others . in excess . In addition . GABA. exacerbation of asthma . myocardial infarction. when they are inappropriately or chronically triggered as part of an anxiety disorder — this can eventually lead to increases in atherosclerosis . cardiac ischemia.type 2 diabetes. chronic and persistent activation of this aspect of the fear response can lead to in creased medical comorbidity . Benzodiazepines. GABA is transported in to synaptic vesicles via vesicular inhibitory amino acid transporters (VIAATs ) and store duntil its release in to the synapse during neurotransmission. After synthesis. "Scaredt odeath " may not always be anexaggeration or a figure of speech ! Finally . Processing of the fear response is regulated by the numero us neuronal connections flowing in to and out of the amygdala. although the exact anatomical connections with in the amygdala and the specific receptor subtypes for these various circuits are still being clarified. corticotrophin releasing factor (CRF). However. When autonomic responses are repetitive — that is . regulated in part by the connections between amygdala and the parabrachial nucleus in the brain stem FIGURE14-16 Linking anxiety symptoms to circuits to neurotransmitters . GABA is the principal inhibitory neurotransmitter in the brain and normally serves an importan tregulatory role in reducing the activity of many neurons. (Figure14-13) . An adaptive response to fear is to accelerate respiratory rate in the course of a fight / fligh treaction to enhance survival .and benzodiazepines GABA is one of the key neurotransmitters in volved in anxiety and in the anxiolytic action Of many drugs used to treat the spectrum of anxiety disorders. act by enhancing GABA actions at the level of the amygdala and the prefrontal cortex within CST Cloops to relieve anxiety. The autonomic nervous system is at tuned to fear and is able to trigger responses such as increased pulse and blood pressure for fight / flight reactions and survival during real threats-from the cardiovascular system .a nxiety can be triggered internally from traumatic memories stored in the hippocampus and activated by connections with the amygdala (Figure 14-15) .

As will be explained herein detail. theta. GABA-B. and C Gamma-amino butyric acid-A (GABA-A) receptors. (Figure14-21). This class of receptor. Benzodiazepine-sensitive GABA-Areceptors (middle two) contain gamma and . The physiological role of GABA-C receptors is not well clarified as yet. three different beta isoforms. varioussub types of GABA-A receptors are targets of benzodiazepines. G protein-linked receptors. An understanding of the properties of GABA recept or subtypes is the key to grasping the role of GABA in anxiety and the mechanism of action of benzodiazepine anxiolytics. Specifically . but they do not appear to be targets of benzodiazepines. Alternatively. including how GABA is synthesized. The molecular structure of GABA-A receptors is shown in FIGURE 14-20 A. by contrast. GABA is transported in to synaptic vesicles by vesicular inhibitory amino acid transporters (VIAATs).and especially the properties of GABA receptors (Figure s14-1 7 through 14-25). once GABA has be en transported back in to the cell. Once for medin presynaptic neurons. (C ) Different types of subunits (also called isoform so subtypes) can combinet of or ma GABA-A receptor. These in clude six different alpha isoforms. These include the GABA transporter (GAT) as well as three major types of post synaptic GABA receptors: GABA-A. GABA-B receptors may be coupled to calcium and / or potassium channels and may be involved in pain. Classification of numer ous GABA receptor subtypes has proceeded at a rapid pace. There are three major types of GABA receptors and numerous subtypes of GABA receptors. where GABA is stored until it is released into the synapse during inhibitory neurotransmission (Figur e14-17). it is important to understand the GABA neurotransmitter syste. delta. where it may be repackaged for future use. and / oral cohol (Figure14-20) and are in volved with either tonic or phasic inhibitory neurotransmission at GABA synapses FIGURE 14-19 Gamma-amino butyric acid (GABA) receptors. or synthesized. G protein-linked receptors are discussed in Chapter 4 and illustrated in Figures 4-16 through 4-28. pi. Shown here are receptors for GABA that regulate its neurotransmission.2 through 5-25. GABA-B receptors are G protein-linked receptors that may be coupled with calcium or potassium channels. GABA can be transported out of thesynaptic cleft and back in to the presynaptic neuron via the GABA transporter (GAT). The major types are GABA-A. from the amino acid glutamate (glutami cacid) via the action soft he enzyme glutamic acid decarboxylase (GAD ) (Figure 14-17). analogous to similar transporters for other neurotransmitters discussed through out this text. barbiturates. memory.GABA is produced. VIAAT sand GATs are introduced in Chapter 4 and illustrated in Figure 4-10. GABA- A receptors and GABA-C receptors are both ligand-gated ion channels. GABA-A and GABA-C receptors are ligand- gated ion channels. also known as ionotrophic receptors and as ion channel—linked receptors. which converts GABA in to an inactive substance (Figure14-18) . and GABA-C. and other CNS functions GABA-A receptor subtypes Given the critical roles of various subtypes of GABA-A receptors in mediating inhibitory neurotransmission and as target soft he anxiolytic benzodiazepines. and three different rho isoforms.B. at the center of which is a chloride channel. (A) Shown here are the four trans membrane regions that make up one subunit of a GABA-A receptor. FIGURE 14-18 Gamma-amino butyric acid (GABA) action is terminated. they are part of a macromolecular complex that forms an inhibitory chloride channel. GABA's action can also be terminated by the enzyme GABA transaminase (GABA-T). three different gamma isoforms. GABA-B receptors. are members of a different receptor class. namely. (B) There are five copies of these subunits in a fully constituted GABA-A receptor. it may be converted in to an inactive substance via the enzyme GABA transaminase (GABA-T). mood. The ultimate type and function of each GABA-A receptor subtype will depend on which subunits it contains. GABA's synaptic actions are terminated by the presynaptic GABA transporter (GAT). Both GABA-A receptors and GABA-C receptors are part of a macromolecular complex that forms an inhibitory chloride channel (Figure14-20). is discussed in Chapter 5 and illustrated in Figures 5. GABA's action can be terminated through multiple mechanisms. also known as the GABA reuptake pump (Figure14-18).their anxiolytic actions. how its actionis terminated at the synapse.B and GABA-C receptors (Figur e14-19). epsilon. this class of receptors will be discussed in further detail. GABA.

they are not likely to be involved in the anxiolyticactions of benzodiazepines invarious anxiety disorders. one site per receptor complex (Figure14-20C).A receptors (Figure14-21). alpha 6. gamma (with three isoforms. all osteric modulators. depending on which subunits are present (Figure 14-20C). such as the frequency of neuronal discharge in response to excitatory inputs.mediated by ambient levels of extra cellular GABA that has escaped from the synapse). delta. and the agents that bind there. epsilon. Benzodiazepine-sensitive GABA-A receptors containing alpha1 subunits are in volved in sleep (second from left). alpha 1to 6). rho 1 to 3) (Figure 14-20 C).e. Each subunit of a GABA-A recept or has four transmembrane regions (Figure 14-20A). gamma1. and it is possible that novel synthetic neurosteroids that also target benzodiazepine-insensitive GABA. where they capture not only GABA that diffuses a way from the synapse but also neurosteroids synthesized and released byglia (Figure14-21). Subunits of GABA-A receptors are sometimes also called isoform sand in clude alpha (with six isoforms. FIGURE 14-21 GABA-A mediation of tonic and phasic inhibition. theta. . These receptors mediate in hibition that is tonic (i. pi. Extrasynaptic. Figure 14-20 . beta 1 to 3). are located extrasynaptically. or delta subunits (farright) are benzodiazepine insensitive. novel hypnotics as well as anesthetics have targeted these extrasynaptic benzodiazepine-insensitive GABA-A receptors. which occurs in bursts triggered by peakc on centrations of synaptically released GABA. Since the site for the modulators is in adifferent location from the agonist sites for GABA. When five subunits cluster together. This molecular structure of ligand-gated ion channels is introduced in Chapter 5 and illustrated in Figures 5-3 and 5-4. The binding site for these non benzodiazepine modulators is located between the alpha and the delta subunits. gamma1. or delta subunits (Figure 14-20C). Since the GABA-A receptors that modulate this action are not sensitive to benzodiazepines. There are many different subtypes of GABA-A receptors. bet a (with three isoforms. namely the naturally occurring neurosteroids. naturally ccurring neurosteroids may be important in setting that inhibitoryt one incritical brain areas. benzodiazepine-insensitive GABA-A receptors are thought to mediate a type of inhibition at the postsynaptic neuron that istonicyin contrast to the phasic type of inhibition mediated by postsynaptic benzodiazepine-sensitive GABA. Benzodiazepines^sensitive GABA-A receptors are those with alpha 4.A receptor with a chloride channel in the center (Figure 14-20B).alpha (1 through 3) subun its and mediate phasic inhibition triggered by peak concentrations of synaptically released GABA. Two molecules of GABA bind perreceptor complex at Sites located between the alpha and the betasubunits.A receptor subtype scould some day be come novel anxiolytics. Benzodiazepine-insensitive GABA-A receptor subtypes (with delta subunits and alpha 4 or 6 subunits) are located extrasynaptically. and rho (witht hree isoforms. the functions of a GABA-A receptor can vary significantly. anxiety it self may in part be dependent on having the right a mount of tonic inhibition in key anatomi care as such as the amygdala and cortical areas of CST C loops . alpha 6. If thist one becomes dysregulated. Such GABA. they form an intact GABA. Benzodiazepine-insensitive GABA-A receptors (those containing alpha 4. gamma 1 to 3).A receptors do bind to other modulators. gamma 1. and regulatetonic inhibition. Important for this discussion is the fact that.or delta subunits) are extrasy naptic and capture GABA that diffuses a way from the synapse as well as neurosteroids that are synthesized and released by glia. Further more . it is possible that abnormal neuron alexcitability could be come af actorin the development of various anxiety disorders. alpha6. the modulatory site is of tencalled all osteric (literally"other site"). How ever. Benzodiazepine sensitive GABA-Areceptors (those that contain gamma and alpha 1 through alpha 3 subunits) are post synaptic receptors that mediate phasic inhibition. GABA-A receptors with adelta subunit rather than a gamma subunit plus either alpha 4 or alpha 6 subunits do not bind to benzodiazepines. Indeed. depending on which subunits are present. Thus tonic inhibition may be regulated by the ambient levels of extracellular GABA molecules that have escaped presynaptic reuptake and enzymatic destruction . as well as to alcohol and to some general anesthetics (Figure 14-20 C). while those that contain alpha 2 and or alpha 3 subunits are in volved in anxiety(second from right).. sometimes referred to as the GABA agonist site (Figur e14-20C). GABA-A receptors containing alpha 4. Tonic inhibition is thought to set the overall tone and excitability of the postsynaptic neuron and to be importan t for certain regulatory events.

However. the identity of any such substance remains elusive. The combination of . including both benzodiazepine and non benzodiazepine positive all osteric modulators of the GABA.A receptor (Figur e14-20C).A receptor. Acting alone. or alpha 3 subtype (Figure14-20C). These ide as are further developed in Figures 14-22 throug h 14-2 4 as applied to the modulation of GABA-A receptors by benzodiazepine anxiolytics.A receptors hypothetically would causelesse uphoria . GAB A can increase the frequency of opening of the chloride channel . it is now known that synthetic drugs that do not have a benzodiazepine structure also bind to the benzodiazepine receptor. Such agents are being investigated but have notyet be enintroduced into clinical practice. Partial agonists selective for alpha 2/ 3subunits of benzodiazepine sensitive GABA. it would the or etically cause anxiolytic actions.many experts nowcall the benzodiazepinesite the GABAA allosteric modulatory site and anything that binds tot his site 2 including benzodiazepines. Further more . Not ably. onsleep. Benzodiazepines as positive all osteric mdulators (PAMs) Since the benzodiazepine-sensitive GABA. particularly the alpha 2/ 3 subtypes clustered at postsynaptic GABA sites. benzodiazepine-sensitive GABA-Are ceptor swit halpha2 (and/or alpha3) subunits may b e most important for regulating anxiety and are the presumed targets of the anxiolytic benzodiazepines (Figur e1420C).belessrein for cingand thus less a busable.one benzodiazepine molecule perrecept or complex (Figur e14-20C). Th e concept of partial agonists for ligand-gated ionchannels was introduced in Chapter 5and is illustrated in Figures 5-9 through 5-15.there is an on going search for selective alpha 2/ 3agents that could be utilized to tre at anxiety disorders in man. should exertan anxiolytic effect due to enhancement of phasic postsynaptic inhibition. On the other hand. Receptor subtype expression can changein response to chronic benzodiazepine administration and withdrawal and could the or etically be altered in patients with various anxiety disorder subtypes .from positive all osteric modulation (PAM ) to neutral antagonism to negative all osteric mdulation (NAM). with are duction both of fearand worry. alpha 2 or delta subunits is associated with different types of epilepsy.A receptors . If this action occurs at overly active output neurons in the amygdala or in CSTC loops. Such agents would the or etically be anxiolytic with out being sedating . benzodiazepines acting at these receptors. there must be two beta units plus a gamma unit of either the gamma 2 or gamma 3subtype . and causefewer problems in withdrawal. All osteric modulationis known to occurover a broadspectrum . In contrast to benzodiazepine insensitive GABA.this has led to the notion that there may be an"endogenous "ornaturally occurring benzodiazepine synthesized in the brain (the brain's own Xanax!).Thus . plus two alpha unit so feither the alpha1. but only to a limite dextent (compare Figures 14-22 A and 14-22 B).A receptor to be sensitivet obenzodiazepines And thus to be a target for benzodiazepine anxiolytics.A receptors with alpha1subunits may be most important for regulating sleep and are the presumed targets of numerous sedative hypnoticagents. How ever. GABA it self binds with two molecules of GABA perrecept or complex to the GABA a gonist sites inthe regions of the receptor between the alpha and the betaunits (Figur e14-20C) . currently available benzodiazepines are non selective for GABA-A receptor swith different alpha subunits . those benzodiazepine-sensitive GABA. anall osteric modulator. alpha2. Benzodiazepines appear to bind to the region of the recep tor between the gamm a 2/ 3 sub unit and the alpha1/2/3subunit .Benzodiazepine-sensitive GABA-A receptors have several structural and functional features that make them distinct from benzodiazepine- insensitive GABA-A receptors . Some of these a gents are selective only for the alpha1subtype of GABA. causeless dependence. Benzodiazepine- sensitive GABA-A receptor subtypes (with gamma subunits and alpha 1/2/3 subunits ) are thought to be postsynaptic in location and to mediate a type of inhibition at the postsynaptic neuron that is phasic. Not all benzodiazepine-sensitive GABA-A receptors are the same . Abnormal expression of gamma 2.for a GABA. Theoretically. These developments have led to end lessconfusion with terminology! Thus . occurringin bursts of inhibition triggered by peak concentrations of synaptically released GABA (Figure14-21). The concepts of PAMs and NAM sand the agonist spectrum are introduced in Chapter 5 and illustrated in Figure5-2 1through Figure5-23. The alpha 1 subtype of GABA-A receptor and the drugs that bind to it are discussed further in Chapter 16.A receptor complex is regulated not only by GABA it self but also by benzodiazepines at a highly specificall osteric modulatory binding site(Figure14-22) .

consist of five subunits with a central chloride channel and have binding sites not only for GABA but also forpositive all osteric modulators (e. (A ) Benzodiazepine- sensitive GABA-A receptors.g.A receptor in the absence of GABA. and D Positive all osteric modulation of GABA.Areceptors. like the one shown here. it has no effect on the chloride channel. it increases the frequency of opening of the chloride channel and thus allows more chloride to pass through. it causes the channel to open even morefrequently than when GABA alone is present..benzodiazepines). . (B) When GABA binds to its sites on the GABA-A receptor. (C) When a positive all osteric modulator suc has abenzodiazepine binds to the GABA. BfC. (D ) When a positive all osteric modulator suc has a benzodiazepine binds to the GABA-A receptor in the presence of GABA .FIGUR E 14-22 A.