3 1 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 Veterinary Psychopharmacology, Second Edition. Sharon L. Crowell-Davis, Thomas F. Murray, and Leticia Mattos de Souza Dantas. © 2019 John Wiley & Sons, Inc. Published 2019 by John Wiley & Sons, Inc. 0004197911.INDD 3 12/14/2018 8:23:20 AM 4 General Principles of Psychopharmacology 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. 0004197911.INDD 4 12/14/2018 8:23:21 AM Srcua Faue o h eta Nros Syste CNSS) annd Neurotransmision 5 100% 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.