Chapter 5 Outline

Chapter 5 Outline

Read Chapter 5, pages 159- 244. No reference needed.

Targeting Dopamine and Serotonin Receptors for Psychosis, Mood, and Beyond: So-Called “Antipsychotics”

Module 5 Weekly Note. Address each heading in the yellow outline note.

Targeting Mesolimbic/Mesostriatal Dopamine D2 Receptors Causes Antipsychotic Actions 161

Targeting Dopamine D2 Receptors in Mesolimbic/ Mesostriatal and Mesocortical Pathways Causes Secondary Negative Symptoms 162

Secondary Negative Symptoms Due to Targeting Mesolimbic Dopamine D2 Receptors 162

Secondary Negative Symptoms Due to Targeting Mesocortical Dopamine D2 Receptors 163

Targeting Tuberoinfundibular Dopamine D2 Receptors Causes Elevation of Prolactin 164

Targeting Nigrostriatal Dopamine D2 Receptors Causes Motor Side Effects 165

Drug-Induced Parkinsonism 166

Drug-Induced Acute Dystonia 169

Akathisia 169

Neuroleptic Malignant Syndrome 169

Tardive Dyskinesia 170

Drugs Targeting Dopamine D2 Receptors: So-Called First Generation or Conventional “Antipsychotics” 179

Drugs Targeting Serotonin 2A Receptors with or without Simultaneously Targeting Dopamine D2 Receptors 183

5HT2A Receptor Regulation of Dopamine Release in Three Downstream Pathways 184

Drugs Targeting Serotonin 1A Receptors and Dopamine D2 Receptors as Partial Agonists 189

D2 Partial Agonism 189

How Does D2 Partial Agonism Cause Fewer Motor Side Effects than D2 Antagonism? 192

5HT1A Partial Agonism 193

Links between Receptor Binding Properties of Drugs Used to Treat Psychosis and Other Therapeutic Actions and Side Effects 195

Mania 195

Antidepressant Actions in Bipolar and Unipolar Depression 195

Anxiolytic Actions 196

Agitation in Dementia 197

Sedative Hypnotic and Sedating Actions 197

Cardiometabolic Actions 198

Pharmacological Properties of Selected Individual First-Generation D2 Antagonists 201

Chlorpromazine 201

Fluphenazine 202

Haloperidol 202

Sulpiride 202

Amisulpride 203

An Overview of the Pharmacological Properties of Individual 5HT2A/ D2 Antagonists and D2/5HT1A Partial Agonists: The Pines (Peens), Many Dones and a Rone, Two Pips and a Rip 204

The Pines (Peens) 222

Many Dones and a Rone 234

Two Pips and a Rip 239

Selective 5HT2A Antagonist 240

The Others 240

Future Treatments for Schizophrenia 241

Roluperidone (MIN-101) 241

D3 Antagonists 241

Trace Amine Receptor Agonists and SEP- 363856 241

Cholinergic Agonists 242

A Few Other Ideas 242

Summary 242

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Weekly Notes – Chapter 2: Module 2

Transporters, Receptors, and Enzymes as Targets of Psychopharmacological Drug Action

Neurotransmitter Transporters as Targets of Drug Action.

Transporters control the transport of a neurotransmitter into and out of a neuron. They control the reuptake of neurotransmitters, which is the amount of time they spend in the synapse and thus affects communication between two neurons.

Classification and Structure – p. 29

Some of the neurotransmitter transporters have several transmembrane domains and are members of the SLC family. Their structure enables them to recognize specific chemical substances and transport them across the nerve cell membrane.

These transporters in general have 12 transmembrane regions. Plasma-membrane transporters include the SLC6 and SLC1 gene families.

Monoamine Transporters (SLC6 Gene Family)– p. 31

Major Monoamine Transporters

SERT = serotonin transporter NET = norepinephrine transporter DAT = dopamine transporter

Serotonin, norepinephrine, and dopamine transporters are members of the SLC6 family. Inhibitory drugs of these transporters may lead to higher levels of neurotransmitters in the synaptic cleft, which has significant therapeutic effects in psychiatric conditions.

Other Neurotransmitter Transporters (SLC6 and SLC1 Gene Families)– p. 34

GABA and Glutamate

GABA: There are several GABA transporters called GAT1–4.

Glutamate: Glutamate transporters are called EAAT1–5 and belong to the SLC1 family.

Other transporters control the levels of neurotransmitters such as GABA, glycine, and glutamate. Modifying these systems can also modify inhibitory or excitatory signaling and can have an impact on neurological and psychiatric symptoms.

Histamine and Neuropeptide Transporters– p. 35

Unlike monoamines, histamine and neuropeptides lack a presynaptic reuptake system. Their activity is regulated in other ways, such as being broken down by enzymes and diffused out of the cell.

Vesicular Transporters: Subtypes and Function.– p. 35

Neurotransmitters are taken into vesicles for release by vesicular transporters. They help to accumulate neurotransmitters within vesicles, ready for movement to the nerve cell for communication.

VMAT2 → serotonin, norepinephrine, dopamine, histamine

VAChT → acetylcholine

VIAAT → GABA

vGluT1–3 → glutamate

Vesicular Transporters as Drug Targets– p. 35

VMAT2 and other vesicular proteins can be influenced by psychotropic medications and stimulant drugs. Altered vesicular storage can significantly affect neurotransmitter release.

G-Protein-Linked Receptors– p. 36

These receptors have 7 membrane-spanning regions and convert binding of neurotransmitters into intracellular signals. The effects can be seen in the immediate receptor, but can also be seen in second messengers, proteins, and gene expression.

Structure and Function

The activity of receptors is not binary, but lies on a continuum from full activation to decreased activation. Agonists activate receptors; antagonists are molecules that don't activate receptors; partial agonists activate receptors, albeit not as strongly as full agonists; and inverse agonists decrease constitutive activity.

G-Protein-Linked Receptors as Targets of Psychotropic Drugs– p. 36

Several receptor types interact with psychotropic medications, including dopamine, serotonin, histamine, GABA, adrenergic, and melatonin receptors. The clinical effects of drugs vary depending on whether they stimulate, block, or stabilize receptor activity.

The Agonist Spectrum

Full agonist → Partial agonist → Antagonist → Inverse agonist

Full agonist: Creates maximum receptor activation and signal transduction.

Antagonist: Blocks agonist activity but does not independently activate the receptor. True antagonists are described as "silent".

Partial Agonist: Produces more activity than an antagonist; however, it has less activity than a full agonist. Partial agonists can function as stabilizers. When neurotransmitter activity is low, it increases activity; when full-agonist activity is high, it reduces activity to an intermediate level.

Light/rheostat analogy: Full agonist = brightest light Partial agonist = dimmed light but still shining No agonist = light off

Inverse Agonist: Reduces receptor activity below baseline constitutive activity. Inverse agonists are above simple antagonists and are neither neutral nor silent. It produces a conformational transformation in the G-protein-linked receptor that stabilizes the inactive form.

Full agonist: ↑↑↑ activity Partial agonist: ↑ activity Antagonist: baseline Inverse agonist: ↓ below baseline

Enzymes as Sites of Psychopharmacological Drug Action -p. 45

Enzymes are yet another pharmaceutical target. The effects of drugs can alter the synthesis and degradation mechanisms of neurotransmitters or alter how they are used in the cell, which can change the function of the neurons.

Enzymes convert a substrate into a product.

Substrate → binds active site → enzyme modifies substrate → product

Irreversible Inhibitor: Binds permanently to the enzyme and cannot be displaced by the substrate. Enzyme activity returns only after the cell synthesizes new enzyme molecules. Sometimes it is called a "suicide inhibitor." It is called this because it permanently inhibits the enzyme and therefore kills it.

Reversible Inhibitor: Can be displaced by the enzyme's substrate because it is able to compete with it. Whether the inhibitor or substrate predominates depends on factors such as relative affinity and concentration.

Important enzymes targeted by psychotropic drugs include:

MAO – monoamine oxidase

Acetylcholinesterase

GSK – glycogen synthase kinase

Lithium may inhibit GSK-3, potentially contributing to neuroprotective effects, long-term plasticity, and its antimanic/mood-stabilizing actions

Cytochrome P450 Drug-Metabolizing Enzymes As Targets Of Psychotropic Drugs-p. 49

CYP450 enzymes are mainly responsible for how medicines are metabolized in the body. Enzyme activity can vary, affecting drug concentration, efficacy, and the risk of adverse effects in treating psychological disorders, making metabolism a critical factor.

Pharmacokinetics vs. Pharmacodynamics

The CYP450 system is found primarily in the liver and gut and is important for drug metabolism.

Pharmacokinetics = what the body does to the drug: A – Absorption D – Distribution M – Metabolism E – Excretion

Pharmacodynamics = what the drug does to the body, including its mechanism of action, therapeutic effects, and adverse effects.

Important CYP450 enzymes listed. CYP1A2, CYP2B6, CYP2D6, CYP2C9, CYP2C19, CYP3A4

Poor/intermediate metabolizer: ↓ metabolism → potentially ↑ drug concentrations and adverse effects. Ultra-rapid metabolizer: ↑ metabolism → potentially ↓ drug concentrations and reduced effectiveness.

Pharmacogenomic testing and therapeutic drug monitoring can sometimes help guide treatment, particularly in treatment-resistant patients.

Summary -p. 50

Transporters regulate neurotransmitter movement, receptors convert the chemical signal into a cellular response, and enzymes regulate biochemical processes. Drugs that affect the brain's chemistry, or signaling systems, are called psychotropic drugs, and they are used to achieve therapeutic effects.

Source: Stahl's Essential Psychopharmacology, Chapter 2, pp. 29–50.