Explain the agonist-to-antagonist spectrum of action of psychopharmacologic agents.

Post a response to each of the following:

Explain the agonist-to-antagonist spectrum of action of psychopharmacologic agents.
Compare and contrast the actions of g couple proteins and ion gated channels.
Explain the role of epigenetics in pharmacologic action.
Explain how this information may impact the way you prescribe medications to clients. Include a specific example of a situation or case with a client in which the psychiatric mental health nurse practitioner must be aware of the medication’s action.

G-protein-linked receptors

Structure and function

Another major target of psychotropic drugs is the class of receptors linked to G proteins. These receptors all have the structure of seven transmembrane regions, meaning that they span the membrane seven times ( ). Each of the transmembrane regions clusters around a centralFigure 2-1 core that contains a binding site for a neurotransmitter. Drugs can interact at this neurotransmitter binding site or at other sites (allosteric sites) on the receptor. This can lead to a wide range of modifications of receptor actions due to mimicking or blocking, partially or fully, the neurotransmitter function that normally occurs at this receptor. These drug actions can thus change downstream molecular events such as which phosphoproteins are activated or inactivated and therefore which enzymes, receptors, or ion channels are modified by neurotransmission. Such drug actions can also change which genes are expressed, and thus which proteins are synthesized and which functions are amplified, from synaptogenesis, to receptor and enzyme synthesis, to communication with downstream neurons innervated by the neuron with the G-protein-linked receptor.

These actions on neurotransmission by G-protein-linked receptors are described in detail in Chapter on signal transduction and chemical neurotransmission. The reader should have a good command1

of the function of G-protein-linked receptors and their role in signal transduction from specific neurotransmitters, as described in , in order to understand how drugs acting atChapter 1 G-protein-linked receptors modify the signal transduction that arises from these receptors. This is important to understand because such drug-induced modifications in signal transduction from G-protein-linked receptors can have profound actions on psychiatric symptoms. In fact, the single most common action of psychotropic drugs utilized in clinical practice is to modify the actions of G-protein-linked receptors, resulting in either therapeutic actions or side effects. Here we will describe how various drugs stimulate or block these receptors, and throughout the textbook we will show how specific drugs acting at specific G-protein-linked receptors have specific actions on specific psychiatric disorders.

G-protein-linked receptors as targets of psychotropic drugs

G-protein-linked receptors are a large superfamily of receptors that interact with many neurotransmitters and with many psychotropic drugs ( ). There are numerous ways toFigure 2-1B subtype these receptors, but pharmacologic subtypes are perhaps the most important to understand for clinicians who wish to target specific receptors with psychotropic drugs utilized in clinical practice. That is, the natural neurotransmitter interacts at all of its receptor subtypes, but many drugs are more selective than the neurotransmitter itself for certain receptor subtypes and thus define a pharmacologic subtype of receptor at which they specifically interact. This is not unlike the concept of the neurotransmitter being a master key that opens all the doors, and a drug that interacts at pharmacologically specific receptor subtypes functioning as a specific key opening only one door. Here we will develop the concept that drugs have many different ways of interacting at pharmacologic subtypes of G-protein-linked receptors, which occur across an agonist spectrum (

).Figure 2-3

No agonist

An important concept for the agonist spectrum is that the absence of agonist does not necessarily mean that nothing is happening with signal transduction at G-protein-linked receptors. Agonists are thought to produce a conformational change in G-protein-linked receptors that leads to full receptor activation, and thus full signal transduction. In the absence of agonist, this same conformational change may still be occurring at some receptor systems, but only at very low frequency. This is referred to as , which may be present especially in receptor systems and brainconstitutive activity areas where there is a high density of receptors. Thus, when something occurs at very low frequency but among a high number of receptors, it can still produce detectable signal transduction output. This is represented as a small – but not absent – amount of signal transduction in .Figure 2-4

Agonists

An agonist produces a conformational change in the G-protein-linked receptor that turns on the synthesis of second messenger to the greatest extent possible (i.e., the action of a ). Thefull agonist full agonist is generally represented by the naturally occurring neurotransmitter itself, although some

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drugs can also act in as full a manner as the natural neurotransmitter. What this means from the perspective of chemical neurotransmission is that the full array of downstream signal transduction is triggered by a full

Figure 2-3. . Shown here is the agonist spectrum. Naturally occurring neurotransmittersAgonist spectrum stimulate receptors and are thus agonists. Some drugs also stimulate receptors and are therefore agonists as well. It is possible for drugs to stimulate receptors to a lesser degree than the natural neurotransmitter; these are called partial agonists or stabilizers. It is a common misconception that antagonists are the opposite of agonists because they block the actions of agonists. However, although antagonists prevent the actions of agonists, they have no activity of their own in the absence of the agonist. For this reason, antagonists are sometimes called “silent.” Inverse agonists, on the other hand, do have opposite actions compared to agonists. That is, they not only block agonists but can also reduce activity below the baseline level when no agonist is present. Thus, the agonist spectrum reaches from full agonists to partial agonists through to “silent” antagonists and finally inverse agonists.

Figure 2-4. . The absence of agonist does not mean that there is no activity related toConstitutive activity G-protein-linked receptors. Rather, in the absence of agonist, the receptor’s conformation is such that it leads to a low level of activity, or constitutive activity. Thus, signal transduction still occurs, but at a low frequency. Whether this constitutive activity leads to detectable signal transduction is affected by the receptor density in that brain region.

agonist ( ). Thus, downstream proteins are maximally phosphorylated, and genes areFigure 2-5 maximally impacted. Loss of the agonist actions of a neurotransmitter at G-protein-linked receptors, due to deficient neurotransmission of any cause, would lead to the loss of this rich downstream chemical tour de force. Thus, agonists that restore this natural action would be potentially useful in states where reduced signal transduction leads to undesirable symptoms.

There are two major ways to stimulate G-protein-linked receptors with full agonist action. First, several drugs bind to the neurotransmitter site and produce the same array of signaldirectly transduction effects as a full agonist ( ). These are direct-acting agonists. Second, manyTable 2-4 drugs can act to boost the levels of the natural full agonist neurotransmitter ( ).indirectly Table 2-5 This happens when neurotransmitter inactivation mechanisms are blocked. The most prominent examples of indirect full agonist actions have already been discussed above, namely inhibition of the monoamine transporters SERT, NET, and DAT and the GABA transporter GAT1. Another way to accomplish indirect full agonist action is to block the enzymatic destruction of neurotransmitters (

). Two examples of this are inhibition of the enzymes monoamine oxidase (MAO) and Table 2-5 acetylcholinesterase.

Antagonists

On the other hand, it is also possible that full agonist action can be too much of a good thing and that maximal activation of the signal transduction cascade is not always desirable, as in states of overstimulation by neurotransmitters. In such cases, blocking the action of the natural neurotransmitter agonist may be desirable. This is the property of an antagonist. Antagonists produce a conformational change in the G-protein-linked receptor that causes no change in signal transduction – including no change in whatever amount of any constitutive activity that may have been present in the absence of agonist (compare with ). Thus, true antagonistsFigure 2-4 Figure 2-6 are “neutral” and, since they have no actions of their own, are also called “silent.”

There are many more examples in clinical practice of important antagonists of G-protein-linked receptors than there are of direct-acting full agonists ( ). Antagonists are well known both asTable 2-4 the mediators of therapeutic actions in psychiatric disorders and as the cause of undesirable side effects ( ). Some of these may prove to be inverse agonists (see below), but mostTable 2-4 antagonists utilized in clinical practice are characterized simply as “antagonists.”

Antagonists block the actions of everything in the agonist spectrum ( ). In the presence ofFigure 2-3 an agonist, an antagonist will block the actions of that agonist but does nothing itself ( ).Figure 2-6 The antagonist simply returns the receptor conformation back to the same state as exists when no agonist is present ( ). Interestingly, an antagonist will also block the actions of a partialFigure 2-4 agonist. Partial agonists are thought to produce a conformational change in the G-protein-linked receptor that is intermediate between a full agonist and the baseline conformation of the receptor in the absence of

Figure 2-5. . When a full agonist binds to G-protein-linkedFull agonist: maximum signal transduction receptors, it causes conformational changes that lead to maximum signal transduction. Thus, all the downstream effects of signal transduction, such as phosphorylation of proteins and gene activation, are maximized.

agonist ( and ). An antagonist reverses the action of a partial agonist by returning theFigures 2-7 2-8 G-protein-linked receptor to the same conformation ( ) as exists when no agonist is presentFigure 2-6 ( ). Finally, an antagonist reverses an inverse agonist. Inverse agonists are thought toFigure 2-4 produce a conformational state of the receptor that totally inactivates it and even removes the baseline constitutive activity ( ). An antagonist reverses this back to the baseline state thatFigure 2-9 allows constitutive activity ( ), the same as exists for the receptor in the absence of theFigure 2-6 neurotransmitter agonist ( ).Figure 2-4

By themselves, therefore, it is easy to see that true antagonists have no activity, and why they are sometimes referred to as “silent.” Silent antagonists return the entire spectrum of drug-induced conformational changes in the G-protein-linked receptor ( and ) to the same place (Figures 2-3 2-10

) – i.e., the conformation that exists in the absence of agonist ( ).Figure 2-6 Figure 2-4

Partial agonists

It is possible to produce signal transduction that is something more than an antagonist yet something less than a full agonist. Turning down the gain a bit

Table 2-4 Key G-protein-linked receptors directly targeted by psychotropic drugs

Table 2-5 Key G-protein-linked receptors indirectly targeted by psychotropic drugs

DAT, dopamine transporter; MAO, monoamine oxidase; NET, norepinephrine transporter; SERT, serotonin transporter; VMAT, vesicular monoamine transporter.

Figure 2-6. . An antagonist blocks agonists (both full and partial) from binding to”Silent” antagonist G-protein-linked receptors, thus preventing agonists from causing maximum signal transduction and instead changing the receptor’s conformation back to the same state as exists when no agonist is present. Antagonists also reverse the effects of inverse agonists, again by blocking the inverse agonists from binding and then returning the receptor conformation to the baseline state. Antagonists do not have any impact on signal transduction in the absence of an agonist.

from full agonist actions, but not all the way to zero, is the property of a partial agonist ( ).Figure 2-7 This action can also be seen as turning up the gain a bit from silent antagonist actions, but not all the way to a full agonist. Depending upon how close this partial agonist is to a full agonist or to a silent antagonist on the agonist spectrum will determine the impact of a partial agonist on downstream signal transduction events.

The amount of “partiality” that is desired between agonist and antagonist – that is, where a partial agonist should sit on the agonist spectrum – is a matter of debate as well as trial and error. The ideal therapeutic agent may have signal transduction through G-protein-linked receptors that is not too “hot,” yet not too “cold,” but “just right,” sometimes called the “Goldilocks” solution. Such an ideal state may vary from one clinical situation to another, depending upon the balance between full agonism and silent antagonism that is desired.

In cases where there is unstable neurotransmission throughout the brain, such as when pyramidal neurons in the prefrontal cortex are out of “tune,” it may be desirable to find a state of signal transduction that stabilizes G-protein-linked receptor output somewhere between too much and too little downstream action. For this reason, partial agonists are also called “stabilizers,” since they have the theoretical capacity to find a stable solution between the extremes of too much full agonist action and no agonist action at all ( ).Figure 2-7

Since partial agonists exert an effect less than that of a full agonist, they are also sometimes called “weak,” with the implication that partial agonism means partial clinical efficacy. That is certainly possible in some cases, but it is more sophisticated to understand the potential stabilizing and “tuning” actions of this class of therapeutic agents, and not to use terms that imply clinical actions for the entire class of drugs that may only apply to some individual agents. A few partial agonists are utilized in clinical practice ( ) and more are in clinical development.Table 2-4

Light and dark as an analogy for partial agonists

It was originally conceived that a neurotransmitter could only act at receptors like a light switch, turning things on when the neurotransmitter is present and turning things off when the neurotransmitter is absent. We now know that many receptors, including the G-protein-linked

receptor family, can function rather more like a rheostat. That is, a full agonist will turn the lights all the way on ( ), but a partial agonist will only turn the light on partially ( ). IfFigure 2-8A Figure 2-8B neither full agonist nor partial agonist is present, the room is dark ( ).Figure 2-8C

Each partial agonist has its own set point engineered into the molecule, such that it cannot turn the lights on brighter even with a higher dose. No matter how much partial agonist is given, only a certain degree of brightness will result. A series of partial agonists will differ one from the other in the degree

Figure 2-7. . Partial agonists stimulate G-protein-linked receptors to enhance signal transductionPartial agonist but do not lead to maximum signal transduction the way full agonists do. Thus, in the absence of a full agonist, partial agonists increase signal transduction. However, in the presence of a full agonist, the partial agonist will actually turn down the strength of various downstream signals. For this reason, partial agonists are sometimes referred to as stabilizers.

Figure 2-8. . A useful analogy for the agonist spectrum is a light controlled by aAgonist spectrum: rheostat rheostat. The light will be brightest after a full agonist turns the light switch fully on (A). A partial agonist will also act as a net agonist and turn the light on, but only partially, according to the level preset in the partial agonist’s rheostat (B). If the light is already on, a partial agonist will “dim” the lights, thus acting as a net antagonist. When no full or partial agonist is present, the situation is analogous to the light being switched off (C).

of partiality, so that theoretically all degrees of brightness can be covered within the range from “off” to “on,” but each partial agonist has its own unique degree of brightness associated with it.

What is so interesting about partial agonists is that they can appear as a net agonist, or as a net antagonist, depending upon the amount of naturally occurring full agonist neurotransmitter that is present. Thus, when a full agonist neurotransmitter is absent, a partial agonist will be a net agonist. That is, from the resting state, a partial agonist initiates somewhat of an increase in the signal transduction cascade from the G-protein-linked second-messenger system. However, when full agonist neurotransmitter is present, the same partial agonist will become a net antagonist. That is, it will decrease the level of full signal output to a lesser level, but not to zero. Thus, a partial agonist can simultaneously deficient neurotransmitter activity yet excessive neurotransmitterboost block activity, another reason that partial agonists are called stabilizers.

Returning to the light-switch analogy, a room will be dark when agonist is missing and the light switch is off ( ). A room will be brightly lit when it is full of natural full agonist and the light switchFigure 2-8C is fully on ( ). Adding partial agonist to the dark room where there is no natural full agonistFigure 2-8A neurotransmitter will turn the lights up, but only as far as the partial agonist works on the rheostat (

). Relative to the dark room as a starting point, a partial agonist acts therefore as a netFigure 2-8B agonist. On the other hand, adding a partial agonist to the fully lit room will have the effect of turning the lights down to the intermediate level of lower brightness on the rheostat ( ). This is aFigure 2-8B net antagonistic effect relative to the fully lit room. Thus, after adding partial agonist to the dark room and to the brightly lit room, both rooms will be equally light. The degree of brightness is that of being partially turned on, as dictated by the properties of the partial agonist. However, in the dark room, the partial agonist has acted as a net agonist, whereas in the brightly lit room, the partial agonist has acted as a net antagonist.

An agonist and an antagonist in the same molecule is quite a new dimension to therapeutics. This concept has led to proposals that partial agonists could treat not only states that are theoretically deficient in full agonist, but also those that have a theoretical excess of full agonist. A partial agonist may even be able to treat simultaneously states that are mixtures of both excess and deficiency in neurotransmitter activity.

Figure 2-9. . Inverse agonists produce conformational change in the G-protein-linked receptorInverse agonist that renders it inactive. This leads to reduced signal transduction as compared not only to that associated with agonists but also to that associated with antagonists or the absence of an agonist. The impact of an inverse agonist is dependent on the receptor density in that brain region. That is, if the receptor density is so low that constitutive activity does not lead to detectable signal transduction, then reducing the constitutive activity would not have any appreciable effect.

Inverse agonists

Inverse agonists are more than simple antagonists, and are neither neutral nor silent. These agents have an action that is thought to produce a conformational change in the G-protein-linked receptor that stabilizes it in a totally inactive form ( ). Thus, this conformation produces a functionalFigure 2-9 reduction in signal transduction ( ) that is even less than that produced when there is eitherFigure 2-9 no agonist present ( ) or a silent antagonist present ( ). The result of an inverseFigure 2-4 Figure 2-6 agonist is to shut down even the constitutive activity of the G-protein-linked receptor system. Of

course, if a given receptor system has no constitutive activity, perhaps in cases when receptors are present in low density, then there will be no reduction in activity and the inverse agonist will look like an antagonist.

In many ways, therefore, inverse agonists do the of agonists. If an agonist increases signalopposite transduction from baseline, an inverse agonist decreases it, even below baseline levels. In contrast to agonists and antagonists, therefore, an neither increases signal transduction likeinverse agonist an agonist ( ) nor merely blocks the agonist from increasing signal transduction like anFigure 2-5 antagonist ( ); rather, an inverse agonist binds the receptor in a fashion so as to provoke anFigure 2-6 action opposite to that of the agonist, namely causing the receptor to its baseline signaldecrease transduction level ( ). It is unclear from a clinical point of view what the relevant differencesFigure 2-9 are between an inverse agonist and a silent antagonist. In fact, some drugs that have long been considered to be silent antagonists may turn out in some areas of the brain to be

Figure 2-10. . This figure summarizes the implications of the agonist spectrum. Full agonistsAgonist spectrum cause maximum signal transduction, while partial agonists increase signal transduction compared to no agonist but decrease it compared to full agonist. Antagonists allow constitutive activity and thus, in the absence of an agonist, have no effects themselves; in the presence of an agonist, antagonists lead to reduced signal transduction. Inverse agonists are the functional opposites of agonists and actually reduce signal transduction beyond that produced in the absence of an agonist.

inverse agonists. Thus, the concept of an inverse agonist as clinically distinguishable from a silent antagonist remains to be proven. In the meantime, inverse agonists remain an interesting pharmacological concept.

In summary, G-protein-linked receptors act along an agonist spectrum, and drugs have been described that can produce conformational changes in these receptors to create any state from full agonist, to partial agonist, to silent antagonist, to inverse agonist ( ). When one considersFigure 2-10 signal transduction along this spectrum ( ), it is easy to understand why agents at eachFigure 2-10 point along the agonist spectrum differ so much from each other, and why their clinical actions are so different.

Epigenetics

Genetics is the DNA code for what a cell can transcribe into specific types of RNA or translate into specific proteins. However, just because there are over 20 000 genes in the human genome, it does not mean that every gene is expressed, even in the brain. Epigenetics is a parallel system that determines whether any given gene is actually made into its specific RNA and protein, or if it is instead ignored or silenced. If the genome is a lexicon of all protein “words,” then the epigenome is a “story” resulting from arranging the “words” into a coherent tale. The genomic lexicon of all potential proteins is the same in every one of the 10+ billion neurons in the brain, and indeed is the same in all of the 200+ types of cells in the body. So, the plot of how a normal neuron becomes a malfunctioning neuron in a psychiatric disorder, as well as how a neuron becomes a neuron instead of a liver cell, is the selection of which specific genes are expressed or silenced. In addition, malfunctioning neurons are impacted by inherited genes that have abnormal nucleotide sequences, which if expressed contribute to mental disorders. Thus, the story of the brain depends not only on which genes are inherited but also on whether any abnormal genes are expressed or even whether normal genes are expressed when they should be silent or silenced when they should be expressed. Neurotransmission, genes themselves, drugs, and the environment all regulate which genes are expressed or silenced, and thus all affect whether the story of the brain is a compelling narrative such as learning and memory, a regrettable tragedy such as drug abuse, stress reactions, and psychiatric disorders, or therapeutic improvement of a psychiatric disorder by medications or psychotherapy.

What are the molecular mechanisms of epigenetics?

Epigenetic mechanisms turn genes on and off by modifying the structure of chromatin in the cell nucleus ( ). The character of a cell is fundamentally determined by its chromatin, aFigure 1-30 substance composed of nucleosomes ( ). Nucleosomes are an octet of proteins calledFigure 1-30 histones around which DNA is wrapped ( ). Epigenetic control over whether a gene is readFigure 1-30 (i.e., expressed) or is not read (i.e., silenced), is achieved by modifying the structure of chromatin. Chemical modifications that can do this include not only methylation, but also acetylation, phosphorylation, and other processes that are regulated by neurotransmission, drugs, and the environment ( ). For example, when DNA or histones are methylated, this compacts theFigure 1-30 chromatin and acts to close off access of molecular transcription factors to the promoter regions of DNA, with the consequence that the gene in this region is silenced, and not expressed, so no RNA or protein is manufactured ( ). Silenced DNA means molecular features that are not part of aFigure 1-30 given cell’s personality.

Histones are methylated by enzymes called histone methyl-transferases, and this is reversed by enzymes called histone demethylases ( ). Methylation of histones can silence genes,Figure 1-30 whereas demethylation of histones can activate genes. DNA can also be methylated, and this also silences genes. Demethylation of DNA reverses this. Methylation of DNA is regulated by DNA methyl-transferase (DNMT) enzymes, and demethylation of DNA by DNA demethylase enzymes (

). There are many forms of methyl-transferase enzymes, and they all tag their substratesFigure 1-30 with methyl groups donated from methylfolate via S-adenosyl-methionine (SAMe) ( ).L- Figure 1-30 When neurotransmission, drugs, or the environment affect methylation, this regulates whether genes are epigenetically silenced or expressed.

Methylation of DNA can eventually lead to deacetylation of histones as well, by activating enzymes called histone deacetylases (HDACs). Deacetylation of histones also has a silencing action on gene expression ( ). Methylation and deacetylation compress chromatin, as though a molecularFigure 1-30 gate has been closed. This prevents transcription factors from accessing the promoter regions that activate genes; thus, the genes are silenced and not transcribed into RNA or translated into proteins ( ). On the other hand, demethylation and acetylation do just the oppostite: theyFigure 1-30 decompress chromatin as though a molecular gate has been opened, and thus transcription factors can get to the promoter regions of genes and activate them ( ). Activated genes thusFigure 1-30 become part of the molecular personality of a given cell.

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Figure 1-30. . Molecular gates are opened by acetylation and/or demethylationGene activation and silencing of histones, allowing transcription factors access to genes, thus activating them. Molecular gates are closed by deacetylation and/or methylation provided by the methyl donor SAMe derived from methylfolate. This preventsL- access of transcription factors to genes, thus silencing them. Ac, acetyl; Me, methyl; DNMT, DNA methyl-transferase; TF, transcription factor; SAMe, S-adenosyl-methionine; L-MF, methylfolate.L-

How epigenetics maintains or changes the status quo

Some enzymes try to maintain the status quo of a cell, such as DNMT1 (DNA methyl-transferase 1), which maintains the methylation of specific areas of DNA and keeps various genes quiet for a lifetime. That is, this process keeps a neuron a neuron and a liver cell a liver cell, including when a cell divides into another one. Presumably, methylation is maintained at genes that one cell does not need, even though another cell type might.

It used to be thought that, once a cell differentiated, the epigenetic pattern of gene activation and gene silencing remained stable for the lifetime of that cell. Now, however, it is known that there are various circumstances in which epigenetics may change in mature, differentiated neurons. Although the initial epigenetic pattern of a neuron is indeed set during neurodevelopment to give each neuron its own lifelong “personality,” it now appears that the storyline of some neurons is that they respond to their narrative experiences throughout life with a changing character arc, thus causing de novo alterations in their epigenome. Depending upon what happens to a neuron (such as child abuse, adult stress, dietary deficiencies, productive new encounters, psychotherapy, drugs of abuse, or psychotropic therapeutic medications), it now seems that previously silenced genes can become activated and/or previously active genes can become silenced ( ). When this happens,Figure 1-30 both favorable and unfavorable developments can occur in the character of neurons. Favorable epigenetic mechanisms may be triggered in order for one to learn (e.g., spatial memory formation) or to experience the therapeutic actions of psychopharmacologic agents. On the other hand,

unfavorable epigenetic mechanisms may be triggered in order for one to become addicted to drugs of abuse or to experience various forms of “abnormal learning,” such as when one develops fear conditioning, an anxiety disorder, or a chronic pain condition.

How these epigenetic mechanisms arrive at the scene of the crime remains a compelling neurobiological and psychiatric mystery. Nevertheless, a legion of scientific detectives is working on these cases and is beginning to show how epigenetic mechanisms are mediators of psychiatric disorders. There is also the possibility that epigenetic mechanisms can be harnessed to treat addictions, extinguish fear, and prevent the development of chronic pain states. It may even be possible to prevent disease progression of psychiatric disorders such as schizophrenia by identifying high-risk individuals before the “plot thickens” and the disorder is irreversibly established and relentlessly marches on to an unwanted destiny.

One of the mechanisms for changing the status quo of epigenomic patterns in a mature cell is via de novo DNA methylation by a type of DNMT enzyme known as DNMT2 or DNMT3 ( ).Figure 1-30 These enzymes target neuronal genes for silencing that were previously active in a mature neuron. Of course, deacetylation of histones near previously active genes would do the same thing, namely silence them, and this is mediated by the enzymes called histone deacetylases (HDACs). In reverse, demethylation or acetylation both activate genes that were previously silent. The real question is, how does a neuron know which genes among its thousands to silence or activate in response to the environment, including stress, drugs, and diet? How might this go wrong when a psychiatric disorder develops? This part of the story remains a twisted mystery, but some very interesting detective work has already been done by various investigators who hope to understand how some neuronal stories evolve into psychiatric tragedies. These investigations may set the stage for rewriting the narrative of various psychiatric disorders by therapeutically altering the epigenetics of key neuronal characters so that the story has a happy ending.

Explain the agonist-to-antagonist spectrum of action of psychopharmacologic agents.

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