Chapter 4

1. Chapter 4 Psychopharmacology

2. Psychopharmacology • The study of the effects of dugs on the nervous system and on behavior • Q: What is a drug? • A: “An exogenous chemical not necessary for normal cellular functioning that significantly alters the functions of certain cells of the body when taken in relatively low doses” • Drug effect – the changes a drug produces in an animal’s physiological processes and behavior • Sites of action – the locations at which molecules of drug interact with molecules located on or in cells of the body, thus affecting some biochemical processes of these cells

3. Principles of Psychopharmacology • Pharmacokinetics – the process by which drugs are absorbed, distributed within the body, metabolized, and excreted • Routes of administration • Intravenous (IV) injection – directly into a vein; fastest route • Intraperitoneal (IP) injection – into the peritoneal cavity – the space that surrounds the stomach, intestines, liver, and other abdominal organs • Intramuscluar (IM) injection – into a muscle • Subcutaneous (SC) injection – into the space beneath the skin • Oral administration – admin into the mouth, so that it is swallowed; most common with humans • Sublingual admin – placing substance beneath tongue • Intrarectal admin – into the rectum • Inhalation – admin of a vaporous substance into lungs • Topical admin – directly onto skin or mucous membrane • Intracerebroventricular (ICV) admin – into one of the cerebral ventricles; to allow for widespread distribution in the brain

4. Principles of Psychopharmacology • Distribution of drugs within the body • Several factors determine the rate at which a drug in the bloodstream reaches sites of action within the brain: • Lipid solubility: BBB blocks only water-soluble molecules; thus, lipid-soluble molecules can pass into brain and distribute themselves • Depot binding – binding of a drug with various tissues of the body or with proteins in the blood; causes drugs to not reach their site of action • e.g. Albumin – a protein found in the blood that transports free fatty acids and can bind with some lipid-soluble drugs • Can delay or prolong the effects of a drug • Inactivation and Excretion • Drugs do not remain in body indefinitely • Most deactivated by enzymes • Excreted by kidneys

5. Drug effectiveness • The best way to measure the effectiveness of a drug is to plot a dose-response curve • Do this by giving subjects various doses of a drug and plotting effects • Increasingly stronger doses of a drug causes increasingly larger effects, until a maximum effect is reached

6. Drug effectiveness • One measure of a drug’s margin of safety is its therapeutic index • The ratio b/t the dose that produces the desired effect in 50% of the animals (ED 50) and the dose that produces toxic effects in 50% of the animals (LD 50) • The lower the therapeutic dose is, the more care must be taken when prescribing the drug • Why do drugs vary in effectiveness? • Different drugs may have different sites of action • Affinity – the readiness with which 2 molecules join together; drugs in CNS produce effects by binding to receptors, transport molecules or enzymes • The higher the affinity, the lower the concentration needed to produce effects

7. Effects of repeated administration • In some cases, when a drug is administered repeatedly its effects will diminish, i.e. develop tolerance • e.g. heroin, once taken regularly enough, individual will suffer withdrawal symptoms (opposite to those produced by a drug) when they stop taking it; caused by same mech as tolerance • Tolerance is the body’s attempt to compensate for the effects of a drug • In other cases, a drug will become more and more effective, sensitization • Less common than tolerance • Some drug effects show tolerance while others may show sensitization • e.g. cocaine; repeated admin may causes more movement disorders, while euphoric effects may show tolerance

8. Placebo effects • An innocuous substance that has no specific physiological effect • Often used for control groups in clinical drug studies

9. Sites of drug action • Most drugs affecting behavior do so by affecting synaptic transmission: • Antagonist – a drug that opposes or inhibits the effects of a particular NT on the postsynaptic cell • Agonist – a drug that facilitates the effects of a particular NT on the postsynaptic cell

10. Sites of drug action • Effects on production of NT • precursors can increase rate of NT synthesis and release; agonist (Step 1) • NT synthesis is controlled by enzymes; some drugs can inactive these enzymes, thus preventing NT production; antagonist (Step 2 in diagram) • Effects of storage and release of NT • transporter molecules that fill synaptic vesicles with molecules of NT can be blocked by a drug; thus, preventing NT to fill vesicles; antagonist (Step 3) • Some drugs prevent release of NT from terminal button by deactivating proteins that help fuse vesicles to membrane; antagonist (Step 5) • some drugs can trigger release of NT; agonist (Step 4)

11. Sites of drug action • Effects on receptors • Some drugs can bind to postsynaptic receptors like NT • Direct agonist – a drug that mimics the effects of a NT by binding with and acting on a receptor (Step 6) • Receptor blocker – a drug that binds with a receptor but does not activate it; prevents the natural ligand from binding with the receptor (Step 7) • Some receptors have multiple binding sites; NT can bind to main sites, while other ligands can bind to alternative sites • these alternative sites can be blocked by a drug, termed noncompetitive binding • drug attached to alt site could prevent ion channels from opening; indirect antagonist • drug attaches to alt site and facilitates opening of ion channel; indirect agonist • some presynaptic membranes have autoreceptors that regulate amount of NT released; stimulation of autoreceptors causes less NT to be released • drugs that activate autoreceptors act as antagonists  less NT released (Step 8) • drugs that block autoreceptors act as agonists  more NT released (Step 9)

12. Sites of drug action • Effects on reuptake or destruction of NT • drugs can attach to transporter molecules responsible for reuptake and block it; thus NT in synapse for longer duration; agonist (Step 10) • drugs can bind with enzyme that destroys NT, preventing enzyme from working; agonist (Step 11)

13. Neurotransmitters and Neuromodulators • In the brain, most synaptic communication is accomplished by 2 NT: • One with excitatory effects: glutamate • One with inhibitory effects: GABA • Most of the activity of local circuits of neurons involves balances b/t the excitatory and inhibitory effects of these chemicals • Most other NT have modulating effects, i.e. they tend to activate or inhibit entire circuits of neurons that are involved in particular brain functions

14. Acetylcholine • Primary NT secreted by efferent axons of the CNS • All muscular movement is accomplished by the release of ACh, also found in ganglia of ANS and at target organs of the parasymp branch of the ANS • Involved mostly in 3 systems in brain: • Dorsolateral pons, basal forebrain, & medial septum • Composed of choline and acetate • Synthesis: • Acetyl-CoA and choline are combined by choline acetyltransferase (ChAT) • 2 drugs affect the release of ACh: • Botulinum toxin – ACh antagonist; prevents release by terminal buttons; found in improperly canned food • Black widow spider venom – stimulates release of ACh • Deactivated by acetylcholinesterase (AChE), which is present in the presynaptic membrane, and produces choline and acetate • Two types of ACh receptors: • Nicotinic – ionotropic ACh receptor that is stimulated by nicotine and blocked by curare • Muscarinic – metabotropic ACh receptor that is stimulated by muscarine and blocked by atropine; slower action, longer lasting

15. Monoamines • Catecholamines: • Dopamine • Norepinephrine • Epinephrine • Indolamines • Serotonin

16. Dopamine (DA) • Produces both excitatory and inhibitory postsynaptic potentials, depending on postsynaptic receptor • Implicated in movement, attention, learning, and reinforcing effects of drugs • Synthesis of catecholamines: • Tyrosine (obtained via diet) converted to L-DOPA by tyrosine hydroxylase • L-DOPA converted to DA by DOPA decarboxylase • DA converted to Norepinephrine (NE) by DA β-hydroxylase

17. Dopaminergic systems • Nigrostriatal system – originates in the substantia nigra and terminates in the neostriatum (caudate and putamen); control of movement • Mesolimbic system – originates in ventral tegmental area (VTA) and terminates in the nucleus accumbens, amygdala, & hippocampus; reward pathway • Mesocortical system – originates in VTA and terminates in prefrontal cortex; formation of STM, planning, strategies

18. Dopamine • Parkinson’s disease – a neurological disease caused by degeneration of DA neurons in nigrostriatal system; movement disorder with symptoms of tremors, rigid limbs, poor balance, difficulty initiating movements; individuals with Parkinson’s are given L-DOPA as Tx • Several types of DA subreceptors: D1 and D2 most common • Other drugs effecting DA • AMPT • Reserpine • Apomorphine • Monoamine oxidase (MAO) – enzyme that destroys catecholamines

19. Norepinephrine (NE) & Epinephrine • Aka Noradrenaline & adrenaline • NE found in neurons in ANS • Epinephrine produced by adrenal glands • NE synthesis is finished in the vesicles of the terminal button • DA fills the vesicles, and is then converted to NE via DA β-hydroxylase • Fusaric acid blocks activity of this enzyme and prevents production of NE without affecting DA • Excess NE is destroyed by MAO, type A • Cell bodies of most important NE system are in locus coeruleus • Most noradrenergic cells release NE via axonal varicosities (beadlike swellings of the axonal branches) instead of terminal button • Several types of subreceptors: • β1 & β2 receptors, and α1 & α2 receptors: sensitive to both NE and epinephrine, all metabotropic with GPCRs • In general, behavioral effects are excitatory

20. Serotonin (5-HT) • Complex behavioral effects: regulation of mood, control of eating, sleep, and arousal, regulation of pain • Precursor is tryptophan, which is obtained through diet; converted to 5-HTP by the enzyme tryptophan hydroxylase; which is converted to 5-HT by the enzyme 5-HTP decarboxylase • Most 5-HT neurons found in raphe nuclei of the pons, medulla and midbrain and project to cerebral cortex; also innervate basal ganglia, dentate gyrus and hippocampal formation • 5-HT release from varicosities rather than terminal buttons; 2 types • D system – originates in dorsal raphe nucleus; thin axonal fibers that do not form synapses with other neurons (i.e. 5-HT serves as modulator here) • M system – originates in median raphe nucleus; thick axonal fibers, form conventional synapses • 2 systems have different behavioral effects • At least 9 different subreceptors • Drugs that inhibit reuptake of 5-HT (SSRIs) most widely used clinically for mental disorders (e.g. fluoxetine, or Prozac) • LSD and MDMA affects 5-HT systems

21. Amino Acids • At least 8 amino acids have been suggested to serve additionally as NT • Glutamate • GABA • Glycine • Peptides

22. Glutamate • Principle excitatory NT in the CNS • Produced in abundance, no way to disrupt synthesis without disrupting other cellular activities • 4 types of receptors: • NMDA – ionotropic, controls calcium channel that is normally blocked, and allows influx of calcium so it can serve as a 2nd messenger; involved in forming new memories • AMPA – ionotropic, controls sodium channel, stimulated by AMPA • Kainate – ionotropic, controls sodium channel, stimulated by kainic acid • Metabotropic glutamate receptor – sensitive to glutamate • PCP – a drug that binds with the PCP binding site of the NMDA receptor and serves as an indirect antagonist; hallucinogenic drug

23. GABA • Primary inhibitory NT in CNS • Produced from glutamic acid by the enzyme glutamic acid decarboxylase (GAD) • 2 subreceptors: • GABAA – have at least 5 different binding sites: • primary for GABA, of which muscimol acts a agonist and bicuculline acts as antagonist • 2nd binding site binds with drugs in benzodiazepines (e.g. Valium; anxiolytic – anxiety-reducing) • 3rd binding site binds with barbituates • GABAB

24. Glycine • Inhibitory NT in SC and lower portions of brain • Receptor is ionotropic, controls chloride channel, and thus produces inhibitory postsynaptic potentials • Strychnine – glycine antagonist

25. Peptides • Neurons in the CNS release a large variety of peptides from all parts of the terminal button, not just active zone, allowing molecules to travel to other cells • Best known family of peptides is the endogenous opioid family (opioid refers to natural ligands, opiate to drugs) • e.g. enkephalin • 3 types of opiate receptors: • μ (mu) • δ (delta) • κ (kappa) • Several neural systems activated: analgesic, fleeing and hiding behaviors, reinforcement • Naloxone – opiate receptor antagonist

26. Lipids • various substances derived from lipids can serve as NT • Cannabinoids – endogenous ligand for receptors that bind with THC, the active ingredient in marijuana • 2 types of cannabinoid receptors: CB1 and CB2, both metabotropic • THC produces analgesia, sedation, stimulates appetite, reduces nausea (used with cancer treatments), aids in glaucoma; reduces concentration and memory, alters visual and auditory perceptions, etc. • Anandamide – natural ligand that binds to cannabinoid receptor

27. Nucleosides • compound that consists of a sugar molecule bound with a purine or pyrimidine base • Adenosine – serves as neuromodulator in brain, released when cells are short of fuel or oxygen • Agonists have general inhibitory effects on behavior • Caffeine is antagonist, thus producing excitatory effects

28. Soluble gases • Neurons use at least 2 simple, soluble gases, nitric oxide (NO) and carbon monoxide (CO), to communicate with each other • NO used as a messenger in many parts of the body, e.g. control muscle walls of intestines, dilates blood vessels in brain, etc.