Long established as the preeminent source in its field, the eagerly anticipated fifth edition of Dr Stahl's essential textbook of psychopharmacology is here! With its use of icons and figures that form Dr Stahl's unique 'visual language', the book is the single most readable source of information on disease and drug mechanisms for all students and mental health professionals seeking to understand and utilize current therapeutics, and to anticipate the future for novel medications. Every aspect of the book has been updated, with the clarity of explanation that only Dr Stahl can bring.
Transporters, Receptors, and Enzymes as Targets of Psychopharmacological Drug Action
Psychotropic drugs have many mechanisms of action, but they all target specific molecular sites that have profound effects upon neurotransmission. It is thus necessary to understand the anatomical infrastructure and chemical substrates of neurotransmission (Chapter 1) in order to grasp how psychotropic drugs work. Although there are over 100 essential psychotropic drugs utilized in clinical practice today (see Stahl’s Essential Psychopharmacology: the Prescriber’s Guide), there are only a few sites of action for all these therapeutic agents (Figure 2-1). Specifically, about a third of psychotropic drugs target one of the transporters for a neurotransmitter; another third target receptors coupled to G proteins; and perhaps only 10% target enzymes. All three of these sites of action will be discussed in this chapter. The balance of psychotropic drugs target various types of ion channels, which will be discussed in Chapter 3. Thus, mastering how just a few molecular sites regulate neurotransmission allows the psychopharmacologist to understand the theories about the mechanisms of action of virtually all psychopharmacological agents.
In fact, these molecular targets form the basis of how psychotropic drugs are now named. That is, there is a modern movement afoot to name psychotropic drugs for their pharmacological mechanism of action (e.g., serotonin transport inhibitor, dopamine D2, and serotonin 5HT2A antagonist) rather than for their therapeutic indication (e.g., antidepressant, antipsychotic, etc.). Naming drugs for therapeutic indication has led to endless confusion, because many drugs are used for indications far beyond their original use (e.g., so-called antipsychotics that are used for depression). Thus, throughout this textbook we will use the new nomenclature for drugs (neuroscience-based nomenclature), which is based upon mechanism of action and not therapeutic indication, wherever possible. This chapter and the next will explain all known mechanisms targeted by psychotropic drugs that form the basis for how they are named.
Finally, since there are genetic variants known for many targets of psychotropic drugs, there is an ongoing effort to determine to what extent such genetic variants may increase or decrease the odds that a patient will have a good clinical response or side effects to drugs that engage that target, in a process called pharmacogenomics. The scientific foundation for clinical application of genetic variants of psychotropic drug targets is still evolving, but current insights will be mentioned briefly when the specific target is described throughout this textbook.
Neuronal membranes normally serve to keep the internal milieu of the neuron constant by acting as barriers to the intrusion of outside molecules and to the leakage of internal molecules. However, selective permeability of the membrane is required to allow discharge as well as uptake of specific molecules to respond to the needs of cellular functioning. Good examples of this are neurotransmitters, which are released from neurons during neurotransmission, and in many cases are also transported back into presynaptic neurons as a recapture mechanism following their release. This recapture – or reuptake – is done in order for neurotransmitter to be reused in a subsequent neurotransmission. Also, once inside the neuron, most neurotransmitters are transported again into synaptic vesicles for storage, protection from metabolism, and immediate use during a volley of future neurotransmission.
Both types of neurotransmitter transport – presynaptic reuptake as well as vesicular storage – utilize a molecular transporter belonging to a “superfamily” of 12-transmembrane-region proteins (Figures 2-1A and 2-2). That is, neurotransmitter transporters have in common the structure of going in and out of the membrane 12 times (Figure 2-1A). These transporters are a type of receptor that binds to the neurotransmitter prior to transporting that neurotransmitter across the membrane.
Recently, details of the structures of neurotransmitter transporters have been determined and this has led to a proposed subclassification of neurotransmitter transporters. That is, there are two major subclasses of plasma membrane transporters for neurotransmitters (Tables 2-1 and 2-2). Some of these transporters are presynaptic and others are on glial membranes. The first subclass is comprised of sodium/chloride-coupled transporters, called the solute carrier SLC6 gene family, and includes transporters for the monoamines serotonin, norepinephrine, and dopamine (Table 2-1 and Figure 2-2A) as well as for the neurotransmitter GABA (γ-aminobutyric acid) and the amino acid glycine (Table 2-2 and Figure 2-2A). The second subclass is comprised of high-affinity glutamate transporters, also called the solute carrier SLC1 gene family (Table 2-2 and Figure 2-2A).
|Transporter||Common abbreviation||Gene family||Endogenous substrate||False substrate|
|Serotonin transporter||SERT||SLC6||Serotonin||Eecstacy (MDMA)|
MDMA = 3.4-methylenedioxymethamphetamine
|Transporter||Common abbreviation||Gene family||Endogenous substrate|
|GABA transporter 1 (neuronal and glial)||GAT1||SLC6||GABA|
|GABA transporter 2 (neuronal and glial)||GAT2||SLC6||GABA beta-alanine|
|GABA transporter 3 (mostly glial)||GAT3||SLC6||GABA beta-alanine|
|GABA transporter 4 also called betaine transporter (neuronal and glial)||GAT4 BGT1||SLC6||GABA betaine|
|Glycine transporter 1 (mostly glial)||GlyT1||SLC6||Glycine|
|Glycine tranporter 2 (neuronal)||GlyT2||SLC6||Glycine|
|Excitatory amino acid transporters 1–5||EAAT1–5||SLC1||L-glutamate L-aspartate|
In addition, there are three subclasses of intracellular synaptic vesicle transporters for neurotransmitters: the SLC18 gene family comprised both of vesicular monoamine transporters (VMATs) for serotonin, norepinephrine, dopamine, and histamine and the vesicular acetylcholine transporter (VAChT); the SLC32 gene family and their vesicular inhibitory amino acid transporters (VIAATs); and finally the SLC17 gene family and their vesicular glutamate transporters, such as vGluT1–3 (Table 2-3 and Figure 2-2B).
|Transporter||Common abbreviation||Gene family||Endogenous substrate|
|Vesicular monoaminetransporters 1 and 2Norepinephrine||VMAT1VMAT2||SLC18||
|Vesicular acetylcholine transporter||VAChT||SLC18||Acetylcholine|
Reuptake mechanisms for monoamines utilize unique presynaptic transporters (Figure 2-2A) in each different monoamine neuron but the same vesicular transporter (Figure 2-2B) in the synaptic vesicle membranes of all three monoamine neurons plus histamine neurons. That is, the unique presynaptic transporter for the monoamine serotonin is known as SERT, for norepinephrine is known as NET, and for dopamine, DAT (Table 2-1 and Figure 2-2A). All three of these monoamines are then transported into synaptic vesicles of their respective neurons by the same vesicular transporter, known as VMAT2 (vesicular monoamine transporter 2) (Figure 2-2B and Table 2-3).
Although the presynaptic transporters for these three neurotransmitters – SERT, NET, and DAT – are unique in their amino acid sequences and binding affinities for monoamines, each presynaptic monoamine transporter nevertheless has appreciable affinity for amines other than the one matched to its own neuron (Table 2-1). Thus, if other transportable neurotransmitters or drugs are in the vicinity of a given monoamine transporter, they may also be transported into the presynaptic neuron by hitchhiking a ride on certain transporters that can carry them into the neuron.
For example, the norepinephrine transporter NET has high affinity for the transport of dopamine as well as for norepinephrine; the dopamine transporter DAT has high affinity for the transport of amphetamines as well as for dopamine; the serotonin transporter SERT has high affinity for the transport of “Ecstasy” (the drug of abuse MDMA or 3,4-methylenedioxymethamphetamine) as well as for serotonin (Table 2-1).
How are neurotransmitters transported? Monoamines are not passively shuttled into the presynaptic neuron, because it requires energy to concentrate monoamines into a presynaptic neuron. That energy is provided by transporters in the SLC6 gene family coupling the “downhill” transport of sodium (down a concentration gradient) with the “uphill” transport of the monoamine (up a concentration gradient) (Figure 2-2A). Thus, the monoamine transporters are really sodium-dependent cotransporters; in most cases, this involves the additional cotransport of chloride, and in some cases the countertransport of potassium. All of this is made possible by coupling monoamine transport to the activity of a sodium–potassium ATPase (adenosine triphosphatase), an enzyme sometimes called the “sodium pump” that creates the downhill gradient for sodium by continuously pumping sodium out of the neuron (Figure 2-2A).
The structure of a monoamine neurotransmitter transporter from the SLC6 family has recently been proposed to have binding sites not only for the monoamine, but also for two sodium ions (Figure 2-2A). In addition, these transporters may exist as dimers, or two copies working together with each other, but the manner in which they cooperate is not yet well understood and is not shown in the figures. There are other binding sites on this transporter – not well defined – for several drugs such as the many selective serotonin reuptake inhibitors (known as SSRIs) and other related agents used to treat unipolar depression. When these drugs bind to the transporter, they inhibit reuptake of monoamines. These drugs do not bind to the substrate site (where the monoamine itself binds to the transporter) and are not transported into the neuron, and thus are said to be allosteric (i.e., “other site”).
In the absence of sodium, there is low affinity of the monoamine transporter for its monoamine substrate, and in this case, there is binding of neither sodium nor monoamine. An example of this is shown for the serotonin transporter SERT in Figure 2-2A where the transport “wagon” has flat tires indicating no binding of sodium, as well as absence of binding of serotonin to its substrate binding site since the transporter has low affinity for serotonin in the absence of sodium. The allosteric site for a drug that inhibits this transporter is also empty (the front seat in Figure 2-2A). However, in Figure 2-2A in the presence of sodium ions, the tires are now “inflated” by sodium binding and serotonin can now also bind to its substrate site on SERT. The situation is now primed for serotonin transport back into the serotonergic neuron, along with cotransport of sodium and chloride down the gradient and into the neuron and countertransport of potassium out of the neuron (Figure 2-2A). If a drug binds to an inhibitory allosteric site, namely the front seat on the SERT transporter wagon in Figure 2-2A (i.e., drugs such as the selective serotonin reuptake inhibitor fluoxetine [Prozac]), this reduces the affinity of the serotonin transporter SERT for its substrate serotonin, and serotonin binding is prevented.
Why does this matter? Blocking the presynaptic monoamine transporter has a huge impact on neurotransmission at any synapse that utilizes that neurotransmitter. The normal recapture of neurotransmitter by the presynaptic neurotransmitter transporter in Figure 2-2A keeps the levels of this neurotransmitter from accumulating in the synapse. Normally, following release from the presynaptic neuron, neurotransmitters only have time for a brief dance on their synaptic receptors, and the party is soon over because the monoamines climb back into the presynaptic neuron on their transporters (Figure 2-2A). If one wants to enhance normal synaptic activity of these neurotransmitters, or restore their diminished synaptic activity, this can be accomplished by blocking these transporters in Figure 2-2A. Although this might not seem to be a very dramatic thing, the fact is that this alteration in chemical neurotransmission – namely the enhancement of synaptic monoamine action – is thought to underlie the clinical effects of all the agents that block monoamine transporters, including most drugs that treat ADHD (attention deficit hyperactivity disorder). “Stimulants” for ADHD, such as methylphenidate and amphetamine, as well as the drug of abuse cocaine, all act on DAT and NET. Also, most drugs that treat unipolar depression act at SERT, NET, DAT, or some combination of these transporters. However, it is a misnomer to call these agents simply “antidepressants,” since they are not first-line treatments for all forms of depression, and they are used for many, many other indications in addition to unipolar depression. Specifically, many drugs that block monoamine transporters are not only effective in the treatment of unipolar depression. They are also used to treat many forms of anxiety, from generalized anxiety disorder to social anxiety disorder to panic disorder; for reducing neuropathic pain in fibromyalgia, postherpetic neuralgia, diabetic peripheral neuropathic pain, and other pain conditions; for improving eating disorders, impulsive–compulsive disorders, obsessive–compulsive disorder, and trauma- and stress-related disorders such as posttraumatic stress disorder. They have additional therapeutic actions as well. Furthermore, some forms of depression, notably bipolar depression and depression with mixed features, are not treated first-line with drugs that block monoamine transporters. No wonder we don’t call agents that block monoamine transporters simply “antidepressants” anymore!
Given the high prevalence of disorders that inhibitors of monoamine transporters treat, it may come as no surprise that these drugs are among the most frequently prescribed psychotropic drugs. In fact, some estimates are that a monoamine transport inhibitor is prescribed every second of every minute of every hour of every day in the US alone (many millions of prescriptions a year)! Also, about a third of the currently prescribed essential 100 psychotropic drugs act by targeting one or more of the three monoamine transporters. Thus, the reader can see why understanding monoamine transporters and how various drugs act at these transporters is so important to grasping how one of the critical classes of agents in psychopharmacology works.
In addition to the three transporters for monoamines discussed in detail above, there are several other transporters for various different neurotransmitters or their precursors. Although this includes a dozen additional transporters, there is only one psychotropic drug used clinically that is known to bind to any of these transporters. Thus, there is a presynaptic transporter for choline, the precursor to the neurotransmitter acetylcholine, but no known drugs target this transporter. There are also several transporters for the ubiquitous inhibitory neurotransmitter GABA, known as GAT1–4 (Table 2-2). Although debate continues about the exact localization of these subtypes to presynaptic neurons, neighboring glia, or even postsynaptic neurons, it is clear that a key presynaptic transporter of GABA is the GAT1 transporter, which is selectively blocked by the anticonvulsant tiagabine, thereby increasing synaptic GABA concentrations. In addition to anticonvulsant actions, this increase in synaptic GABA may have therapeutic actions in anxiety, sleep disorders, and pain. No other inhibitors of this transporter are available for clinical use.
Finally, there are multiple transporters for two amino acid neurotransmitters, glycine and glutamate (Table 2-2). There are no drugs utilized in clinical practice that are known to block glycine transporters although new agents are in clinical trials for treating schizophrenia and other disorders. The glycine transporters, along with the choline and GABA transporters, are all members of the SLC6 gene family, the same family to which the monoamine transporters belong and have a similar structure (Figure 2-2A and Tables 2-1 and 2-2). However, the glutamate transporters belong to a unique family, SLC1, and have a somewhat unique structure and somewhat different functions compared to those transporters of the SLC6 family (Table 2-2).
Specifically, there are several transporters for glutamate, known as excitatory amino acid transporters 1–5 (EAAT1–5; Table 2-2). The exact localization of these various transporters to presynaptic neurons, postsynaptic neurons, or glia is still under investigation, but the uptake of glutamate into glia is well known to be a key system for recapturing glutamate for re-use once it has been released. Transport into glia results in conversion of glutamate into glutamine, and then glutamine enters the presynaptic neuron for reconversion back into glutamate. No drugs utilized in clinical practice are known to block glutamate transporters.
One difference between transport of neurotransmitters by the SLC6 gene family and transport of glutamate by the SLC1 gene family is that glutamate does not seem to cotransport chloride with sodium when it also cotransports glutamate. Also, glutamate transport is almost always characterized by the countertransport of potassium, whereas this is not always the case with SLC6 gene family transporters. Glutamate transporters may work together as trimers rather than dimers, as the SLC6 transporters seem to do. The functional significance of these differences remains obscure, but may become more apparent if clinically useful psychopharmacological agents that target glutamate transporters are discovered. Since it may often be desirable to diminish rather than enhance glutamate neurotransmission, the future utility of glutamate transporters as therapeutic targets is also unclear.
It is an interesting observation that apparently not all neurotransmitters are regulated by reuptake transporters. The central neurotransmitter histamine apparently does not have a transporter for it presynaptically (although it is transported into synaptic vesicles by VMAT2, the same transporter used by the monoamines – see Figure 2-2B). Histamine’s inactivation is thus thought to be entirely enzymatic. The same can be said for neuropeptides, since reuptake pumps and presynaptic transporters have not been found for them, and are thus thought to be lacking for this class of neurotransmitter. Inactivation of neuropeptides is apparently by diffusion, sequestration, and enzymatic destruction, but not by presynaptic transport. It is always possible that a transporter will be discovered in the future for some of these neurotransmitters, but at the present time there are no known presynaptic transporters for either histamine or neuropeptides.
Vesicular transporters for the monoamines (VMATs) are members of the SLC18 gene family and have already been discussed above. They are shown in Figure 2-2B and listed in Table 2-3. The vesicular transporter for acetylcholine – also a member of the SLC18 gene family but known as VAChT – is shown in Figure 2-2B and listed in Table 2-3. The GABA vesicular transporter is a member of the SLC32 gene family and is called VIAAT (vesicular inhibitory amino acid transporter; shown in Figure 2-2B and Table 2-3). Finally, vesicular transporters for glutamate, called vGluT1–3 (vesicular glutamate transporters 1, 2, and 3), are members of the SLC17 gene family and are also shown in Figure 2-2B and listed in Table 2-3. A novel 12-transmembrane-region synaptic vesicle transporter of uncertain mechanism and with unclear substrates, called the SV2A transporter and localized within the synaptic vesicle membrane, binds the anticonvulsant levetiracetam, perhaps interfering with neurotransmitter release and thereby reducing seizures.
How do neurotransmitters get inside synaptic vesicles? In the case of vesicular transporters, storage of neurotransmitters is facilitated by a proton ATPase, known as the “proton pump” that utilizes energy to pump positively charged protons continuously out of the synaptic vesicle (Figure 2-2B). The neurotransmitters can then be concentrated against a gradient by substituting their own positive charge inside the vesicle for the positive charge of the proton being pumped out. Thus, neurotransmitters are not so much transported as they are “antiported” – i.e., they go in while the protons are actively transported out, keeping charge inside the vesicle constant. This concept is shown in Figure 2-2B for the VMAT transporting dopamine, in exchange for protons. Contrast this with Figure 2-2A where a monoamine transporter on the presynaptic membrane is cotransporting a monoamine along with sodium and chloride, but with the help of a sodium–potassium ATPase (sodium pump) rather than a proton pump.
Vesicular transporters for acetylcholine (SLC18 gene family), GABA (SLC32 gene family), and glutamate (SLC17 gene family) are not known to be targeted by any drug utilized by humans. However, vesicular transporters for monoamines in the SLC18 gene family (VMATs), particularly those in dopamine neurons, are targeted by several drugs, including amphetamine (as a transported substrate) and tetrabenazine and its derivatives deutetrabenazine and valbenazine (as inhibitors, see Chapter 5) . Amphetamine thus has two targets: monoamine transporters discussed above as well as VMATs discussed here. In contrast, other drugs for ADHD, such as methylphenidate, and the so-called “stimulant” drug of abuse cocaine, target only the monoamine transporters, and in much the same manner as described for SSRIs at the serotonin transporter.