Copyrighted Material

General Principles of Psychopharmacology Thomas F. Murray

Creighton University, Omaha, NE, USA

Drug Action psychopharmacology, the largest group of receptors are proteins. These include recep Pharmacology is the science of drug action, tors for endogenous hormones, growth and a drug is defined as any agent (chemical, factors, and neurotransmitters; metabolic hormone, peptide, antibody, etc.) that, enzymes or signaling pathways; transporters because of its chemical properties, alters and pumps; and structural proteins. Usually the structure and/or function of a biological the drug effect is measured at a much more system. Psychopharmacology is a sub‐disci complex level than a cellular response, such pline of pharmacology focused on the study as the organism level (e.g. sedation or change of the use of drugs (medications) in treating in behavior). mental disorders. Most drugs used in ani Drugs often act at receptors for endoge mals are relatively selective. However, selec nous (physiologic) hormones and neuro tivity of drugs is not absolute inasmuch as transmitters, and these receptors have they may be highly selective but never com evolved to recognize their cognate signaling pletely specific. Thus, most drugs exert a molecules. Drugs that mimic physiologic multiplicity of effects. signaling molecules at receptors are agonists, Drug action is typically defined as the initial that is, they activate these receptors. Partial change in a biological system that results agonist drugs produce less than maximal from interaction with a drug molecule. This activation of activation of receptors, while change occurs at the molecular level through a drug that binds to the receptor without drug interaction with molecular target in the capacity to activate the receptor may the biologic system (e.g.COPYRIGHTED tissue, organ). The function MATERIAL as a receptor antagonist. Antagonists molecular target for a drug typically is a mac that bind to the receptor at the same site romolecular component of a cell (e.g. protein, as agonists are able to reduce the ability DNA). These cellular macromolecules that of agonists to activate the receptor. This serve as drug targets are often described as mutually exclusive binding of agonists and drug receptors, and drug binding to these antagonists at a receptor is the basis for receptors mediates the initial cellular competitive antagonism as a mechanism of response. Drug binding to receptors either drug action. One additional class of drugs enhances or inhibits a biological process or acting at physiologic receptors are inverse signaling system. Of relevance to the field of agonists. At physiologic receptors that

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250 curves describe in vitro drug action where 200 the actual concentration of the drug interact ing with a receptor is known. Inspection of 150 dose–response relationships reveals that for any drug, there is a threshold dose below 100 which no effect is observed, and at the oppo site end of the curve there is typically a ceil 50 Effect (arbitrary units) ing response beyond which higher doses do 0 not further increase the response. As shown –10 –9 –8 –7 –6 –5 –4 in Figure 1.2, these dose‐ or concentration‐ Log [drug] M response curves are typically plotted as a function of the log of the drug dose or con Agonist Antagonist centration. This produces an S‐shaped curve Partial agonist Inverse agonist that pulls the curve away from the ordinate Figure 1.1 Theoretical logarithmic concentration‐ and allows comparison of drugs over a wide response relationships for agonist, partial agonist, range of doses or concentrations. antagonist, and inverse agonist drugs acting at a A drug‐receptor interaction is typically common receptor. In this theoretical set of reversible and governed by the affinity of the concentration‐response curves, the agonist drug for the receptor. The affinity essentially produces a maximum response while the partial agonist is only capable of evoking a partial response. describes the tightness of the binding of the The antagonist binds to the receptor but is not drug to the receptor. The position of the capable of activating the receptor and therefore theoretical S‐shaped concentration‐response does not produce a response. Inverse agonists bind curves depicted in Figure 1.2 reveals the to an inactive form of the receptor and produce an potency of these drugs. The potency of a effect which is in the inverse direction of that produced by the agonist. drug is a function of its affinity for a receptor, the number of receptors, and the fraction of receptors that must be occupied to produce exhibit constitutive activity in the absence of a maximum response in a given tissue. In activation by an endogenous agonist, inverse Figure 1.2, Drug A is the most potent and agonists stabilize an inactive conformation Drug C is least potent. The efficacy of all and therefore reduce the activation of the three drugs in Figure 1.2, however, is identical receptor. Thus, inverse agonists produce in that they all act as full agonists and produce responses that are the inverse of the response to an agonist at a given receptor. Theoretical log concentration‐response curves for 110 these four classes of drugs are depicted in 100 Drug A 90 Figure 1.1. 80 Drug B 70 Drug C 60 Dose Dependence of Drug 50 40 Interaction with Receptors 30

% Maximum effect 20 10 Receptor occupancy theory assumes that drug 0 action is dependent on concentration (dose) –10 –9 –8 –7 –6 –5 –4 and the attendant quantitative relationships Log [drug] M are plotted as dose‐ or concentration‐ Figure 1.2 Theoretical logarithmic concentration‐ response curves. Dose–response analysis is response relationships for three agonists which typically reserved to describe whole animal differ in relative potency. Drug A is more potent than drug effects, whereas concentration‐response Drug B, which in turn is more potent than Drug C.

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100% of the maximal effect. As a general Structural Features principle in medicine, for drugs with similar of the Central Nervous margins of safety, we care more about efficacy System (CNS) than potency. The comparison of potencies and Neurotransmission of agonists is accomplished by determining the concentration (or dose) that produces 50% of the maximum response (Effective The cellular organization of the mammalian brain is more complex than any other biologic Concentration, 50% = EC50). In Figure 1.2, the −8 −7 −6 tissue or organ. To illustrate this complexity, EC50 values are 10 , 10 , and 10 M, respec consider that the human brain contains tively, for Drugs A, B and C; hence, the rank 12 13 15 order of potency is Drug A > Drug B > Drug C, 10 neurons, 10 glia, and 10 synapses. with Drug A being the most potent since its Understanding how this complex informa tion processor represents mental content and EC50 value is the lowest. Figure 1.3 depicts three additional theoretical concentration‐ directs behavior remains a daunting biomed response curves for drugs with identical ical mystery. Recent reconstruction of a potencies but different efficacies. In this volume of the rat neocortex found at least example, Drug A is a full agonist, producing a 55 distinct morphological types of neurons maximum response, whereas Drugs B and C (Makram et al. 2015). The excitatory to are partial agonists, producing responses, inhibitory neuron ratio was estimated to be respectively, of 50% and 25% of the maxi 87:13, with each cortical neuron innervating mum. Similar to receptor antagonist drugs, 255 other neurons, forming on average more partial agonists can compete with a full ago than 1100 synapses per neuron. This remark nist for binding to the receptor. Increasing able connectivity reveals the complexity of concentrations of a partial agonist will inhibit microcircuits within even a small volume of the full agonist response to a level equivalent cerebral cortex. to its efficacy, whereas a competitive antago Most neuron‐to‐neuron communication nist will completely eliminate the response in the CNS involves chemical neurotrans of the full agonist. mission at up to a quadrillion of synapses. The amino acid and biogenic amine neuro transmitters must be synthesized in the 110 presynaptic terminal, taken up, and stored 100 in synaptic vesicles, and then released by 90 Drug A exocytosis, when an action potential invades 80 Drug B 70 the terminal to trigger calcium influx. Once 60 Drug C released into the synaptic cleft, transmitters 50 can diffuse to postsynaptic sites where they 40 are able to bind their receptors and trigger 30

% Maximum effect 20 signal transduction to alter the physiology of 10 the postsynaptic neuron. Just as exocytotic 0 release of neurotransmitters is the on‐switch –10 –9 –8 –7 –6 –5 –4 for cell‐to‐cell communication in the CNS, Log [drug] M the off‐switch is typically a transport pump Figure 1.3 Theoretical logarithmic concentration‐ that mediates the reuptake of the transmitter response relationships for three agonists with similar into the presynaptic terminal or uptake into potency but different efficacies. Drug A is an agonist glia surrounding the synapse. A schematic of that produces a maximum response while Drugs B and C are partial agonists only capable of evoking a a presynaptic terminal depicted in Figure 1.4 partial response. Drug A is therefore more illustrates the molecular sites that regulate efficacious than Drug B, which in turn is more neurotransmission. Once synthesized or efficacious than Drug C. provided by reuptake, the neurotransmitter

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the extracellular concentration of transmitters PRESYNAPTIC Action and therefore a mechanism for termination TERMINAL potential of their respective synaptic actions. The mono amine transporters (dopamine, norepi nephrine, and 5‐hydroxytryptamine) are the pharmacological targets for antidepressants Vesicle and psychostimulants. Presynaptic terminals also express neuro pH transmitter autoreceptors that function as local circuit negative feedback inhibitor Autoreceptor mechanisms to inhibit further exocytotic release of the transmitter when its synaptic concentration is elevated. Figure 1.5 illustrates the comparison of Transporter presynaptic terminals for the biogenic amine neurons: dopamine, norepinephrine, and 5‐hydroxytryptamine (serotonin). The Figure 1.4 Presynaptic terminal of monoaminergic neuron, depicting sites of vesicular release, reuptake biosynthesis of each biogenic amine trans transport, and vesicular transport and storage. mitter is indicated with uptake and storage in Monoamine transmitters are synthesized in the synaptic vesicles. The vesicular uptake of all cytoplasm or vesicle. Transport from the cytoplasm three biogenic amines depicted is mediated to the vesicular compartment is mediated by the by a common transporter, vesicular mono reserpine sensitive vesicular membrane transporter (VMAT2). Release into the synapse occurs by amine transporter 2 (VMAT2). VMAT2 is exocytosis triggered by an action of potential the vesicular monoamine transporter that invasion of the terminal. Neurotransmitters are transports dopamine, norepinephrine, and rapidly transported from the synaptic cleft back into 5‐hydroxytryptamine into neuronal synaptic the cytoplasm of neuron by a process termed vesicles. VMAT2 is an H+‐ATPase antiporter, reuptake, which involves a selective, high‐affinity, Na+‐dependent plasma membrane transporter. which uses the vesicular electrochemical gradient to drive the transport of biogenic amines into the vesicle (Lohr et al. 2017). is transported into the synaptic vesicle for In contrast to VMAT2 being expressed in subsequent exocytosis. The pH gradient all three biogenic amine neurons, each across the vesicular membrane is established neurotransmitter neuron expresses a distinct by the vacuolar H+‐ATPase, which uses ATP plasma membrane transporter. These trans hydrolysis to generate the energy required to porters are members of the SLC6 symporter move H+ ions into the vesicle (Lohr et al. family that actively translocate amino acids 2017). This movement of H+ ions creates the or amine neurotransmitters into cells against vesicular proton gradient and establishes an their concentration gradient using, as a driv acidic environment inside the vesicle (pH ing force, the energetically favorable coupled of ~5.5). Specific reuptake transporters are movement of ions down their transmem localized on the plasma membrane where brane electrochemical gradients. The dopa they recognize transmitters and transport mine transporter (DAT), the norepinephrine them from the synaptic cleft into the transporter (NET), and the serotonin trans cytoplasm of the terminal (Torres et al. 2003). porter (SERT) are all uniquely expressed in These transporters have evolved to recognize their respective neurotransmitter neurons specific transmitters such as dopamine, and couple the active transport of biogenic serotonin, norepinephrine, glutamate, and amines with the movement of one Cl− and gamma‐aminobutyric acid (GABA). In all two Na+ ions along their concentration gra cases, these presynaptic transporters regulate dient. The ionic concentration gradient is

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DOPAMINE NEURON NOREPINEPHRINE NEURON 5-HYDROXYTRYPTAMINE NEURON

Tyrosine Tyrosine Tyrosine

L-DOPA L-DOPA 5-Hydroxytryptamine Fluoxetine Modafinil Nisoxetine paroxetine DA Vanoxerine DA Reboxetine 5-HT sertraline

DA DA 5-HT DA NE Adrenergic autoreceptors 5-HT autoreceptors DAT NET autoreceptors SERT

DA receptors Adrenergic receptors 5-HT receptors

Figure 1.5 Schematic comparison of dopamine, norepinephrine, and 5‐hydroxytryptamine (serotonin) synapses. Each neuron expresses a monoamine transporter selective for its neurotransmitter. These transporters function as reuptake pumps that terminate the synaptic actions of the transmitters and promote uptake and eventual storage of the transmitter in vesicles. Selective drug inhibitors of each monoamine transporter are shown. Abbreviations: DA, dopamine; DAT, dopamine transporter; NE, norepinephrine; NET, norepinephrine transporter; 5‐HT, 5‐hydroxytryptamine; SERT, serotonin transporter. 12/14/2018 8:23:22 AM 8 General Principles of Psychopharmacology

created by the plasma membrane Na+/K+ being used as an antihypertensive. Some ATPase and serves as the driving force for patients treated with reserpine developed transmitter uptake. Examples of drugs that depressive symptoms severe enough in act as selective inhibitors for all three bio some cases to produce suicide ideation. genic transporters are listed. The three mon Animals given reserpine also developed oamine transporters, DAT, NET, and SERT, depression‐like symptoms consisting of represent important pharmacological targets marked sedation. Reserpine was shown to for many behavioral disorders including deplete the CNS of DA, NE, and 5‐HT by depressive, compulsive and appetite‐related virtue of its ability to block the vesicular behavioral problems. The three neurotrans uptake of these monoamines. Blocking the mitter terminals also express unique presyn vesicular uptake of monoamines leads to a aptic autoreceptors that regulate exocytotic depletion of the transmitters due to degrada release. tion by the mitochondrial enzyme MAO. Therefore, vesicular storage of monoamines is not only a prerequisite for exocytosis but Biogenic Amine also a means of preventing degradation of the transmitters in the cytosolic compartment. Neurotransmitters One other observation in the 1950s was and Affective Disorders that imipramine, developed initially as an antipsychotic drug candidate, elevated mood The role of biogenic amines in affective dis in a subpopulation of schizophrenic patients orders has a long history, beginning in with comorbid depressive illness. Preclinical the 1950s. The biogenic amine theory research revealed that imipramine, and other for affective disorders emerged as pharma tricyclic antidepressants, were able to block cologists and psychiatrists began to explore monoamine transport into presynaptic ter the biologic basis for mental disorders. minals. This action would therefore produce Initially, insights were gained from better an elevation of synaptic levels of biogenic understanding of the cellular actions of drugs amines. All these observations with iproni and correlation of this knowledge of drug azid, reserpine, and imipramine were there action with the therapeutic and behavioral fore consistent with the original formulation responses to the same drugs in the clinic. In of the biogenic amine hypothesis for affective its original formulation, the biogenic amine disorders. theory for affective disorders stated that Although today we continue to recognize depression was due to a deficiency of bio the role of biogenic amines in depression, genic amines in the brain, while mania was several discrepancies in the original due to an excess of these transmitters. In the hypothesis are appreciated. As an example, 1950s, iproniazid was used in the treatment some clinically effective antidepressants do of tuberculosis, and it was observed that in not block the presynaptic transport of some patients with depressive symptoms, monoamines and are not MAO inhibitors. their mood improved over the course of However, importantly for a hypothesis that a chronic regimen with iproniazid. attempts to correlate synaptic levels of Concurrently, preclinical research showed monoamines with mood, while synaptic that iproniazid was an inhibitor of the levels of monoamines are elevated within a enzyme monoamine oxidase (MAO). MAO time domain of a few hours after antidepres catalyzes the degradation of dopamine (DA), sant administration, the symptoms of depres norepinephrine (NE), and serotonin (5‐HT), sion do not resolve until several weeks of and inhibition of MAO was found to elevate chronic therapy with antidepressant drugs. the levels of these transmitters in animal Contemporary hypotheses to explain the brains. Also, in the 1950s, reserpine was mechanism of action of antidepressant drugs

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therefore seek an appropriate temporal synaptic levels of biogenic amines, contem correlation between neurochemical drug porary views of the mechanism of action of action and the mitigation of the symptoms antidepressants are focused on the regula of depression. Rather than a focus on the tion of receptor signaling.

References

Lohr, K.M., Masoud, S.T., Salahpour, A., and neocortical microcircuitry. Cell 163: Miller, G.W. (2017). Membrane transporters 456–492. as mediators of synaptic dopamine Torres, G.E., Gainetdinov, R.R., and Caron, dynamics: implications for disease. European M.G. (2003). Plasma membrane monoamine Journal of Neuroscience 45 (1): 20–33. transporters: structure, regulation and Makram, H., Muller, E., Ramaswamy, S. et al. function. Nature Reviews Neuroscience 4 (1): (2015). Reconstruction and stimulation of 13–25.

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