Psychopharmacology

1. Psychopharmacology PSYC550 Biological Bases of Behavior

2. Psychopharmacology • Psychopharmacology is the study of the effects of drugs on the nervous system and on behavior • The term drug has many meanings: • Medication to treat a disease • A chemical that is likely to be abused • An “exogenous” chemical that significantly alters the function of certain bodily cells when taken in relatively low doses (chemical is not required for normal cellular functioning)

3. Pharmacokinetics • Drug molecules interact with target sites to effect the nervous system • The drug must be absorbed into the bloodstream and then carried to the target site(s) • Pharmacokinetics is the study of drug absorption, distribution within body, and drug elimination • Absorption depends on the route of administration • Drug distribution depends on how soluble the drug molecule is in fat (to pass through membranes) and on the extent to which the drug binds to blood proteins (albumin) • Drug elimination is accomplished by excretion into urine and/or by inactivation by enzymes in the liver

4. Routes of Drug Administration • Routes of drug administration into the body • Intravenous (IV): into a vein (rapid absorption) • Intraperitoneal (IP): into the gut (used in lab animals) • Subcutaneous (SC): under the skin • Intramuscular (IM): into a muscle • Inhalation of the drug into the lungs • Topical: absorbed through the skin • Oral (PO): via the mouth • Intracerebral: into part of brain • Intracerebroventrical injection

5. Drug Effectiveness • Dose-response (DR) curve: Depicts the relation between drug dose and magnitude of drug effect • Drugs can have more than one effect • Drugs vary in effectiveness • Different sites of action • Different affinities for receptors • The effectiveness of a drug is considered relative to its safety (therapeutic index)

6. Tolerance and Sensitization • Repeated administration of a drug can alter its subsequent effectiveness • Tolerance: Repeated drug administration results in diminished drug effect (or requires increased dosage to maintain constant effect) • Withdrawal effects are often the opposite of the drug effect and often accompanies tolerance • Tolerance can reflect decreased drug-receptor binding or reduced postsynaptic action of the drug • Sensitization: Repeated drug administration results in heightened drug effectiveness

7. Synaptic Transmission • Transmitter substances are • Synthesized, stored, released, bound and terminated • Susceptible to drug manipulation • Definitions: • Agonist: a drug that facilitate the postsynaptic effects • Direct agonist: binds and actives a receptor • Antagonist: a drug that block or inhibit the postsynaptic effects • Direct agnonist: binds and blocks a receptor

8. Pre-/Post-synaptic Drug Actions • Presynaptic autoreceptors regulate the amount of NT released from the axon terminal • Drugs that activate presynaptic autoreceptors reduce the amount of NT released, an antagonistic action • Drugs that inactivate presynaptic autoreceptors increase the amount of NT released, an agonistic action

9. Neurotransmitters andNeuromodulators • Neurotransmitter binding to receptors produces either EPSPs or IPSPs • Glutamate produces EPSPs • GABA produces IPSPs • Neuromodulators alter the action of systems of neurons that transmit information using either glutamate or GABA

10. Acetylcholine • Acetylcholine (ACh) is the primary NT secreted by efferent CNS cells (causing muscular movement) • In the periphery: ACh neurons are found in: • Autonomic ganglia (e.g. the heart) • The neuromuscular junction (activation of muscle movement) • In brain: ACh neurons are found in: • Dorsolateral pons • Medial septum • Basal forebrain • ACh release in brain results in facilitatory effects

11. Drug-ACh Interactions • Choline is required for ACh synthesis • Hemicholinum inhibits the reuptake of choline • ACh release • Requires calcium ion entry • ACh release is blocked by botulinum toxin (botox) • ACh release is promoted by black widow spider venom • ACh is degraded by AChE • Neostygmine interferes with AChE activity

12. ACh Receptors • Nictotinic receptors arefound in skeletal muscle (ionotropic effect) • Agonists: ACh, nicotine • Antagonists: curare (arrow tips) • Muscarinic receptors are found in heart and smooth muscle (metabotropic effects) • Agonists: ACh, muscarine • Antagonists: Atropine (belladonna/pretty lady alkaloids)

13. Monoamine Neurotransmitters • The monoamine transmitters share a common structure and form a family of neurotransmitters • Catecholamines include dopamine (DA), norepinephrine (NE), and epinephrine (EPI) • Indolamines include serotonin (5-HT) • The cell bodies of monoamine neurons are located in the brainstem and give rise to axon terminals that are distributed widely throughout the brain

14. Catecholamine Synthesis

15. Dopamine • Dopamine is used by several neural systems • Nigrostriatal system projects from the substantia nigra to the caudate nucleus and putamen • Mesolimbic system projects from ventral tegmental area to the limbic system (including the nucleus accumbens, amygdala, and hippocampus) • Mesocortical system projects from the ventral tegmental area to the cortex • Dopamine receptors are metabotropic • D1 receptors are postsynaptic (excitatory), whereas D2 receptors are pre- and postsynaptic (inhibitory)

16. Drug-Dopamine Interactions • AMPT blocks tyrosine hydroxylase, preventing the conversion of tyrosine to l-DOPA • Reserpine prevents the storage of monoamine within vesicles • Cocaine blocks the reuptake of dopamine • Monoamine oxidase (MAO) within the axon terminal destroys excessive dopamine

17. Norepinephrine • Norepinephrine is synthesized from dopamine within vesicles • The locus coeruleus gives rise to NE fiber systems • NE is secreted from varicosities along axonal fibers • NE interacts with four receptor types in brain • Adrenergic receptors are metabotropic, mostly excitory • -adrenergic (subtypes 1 and 2(i)) • -adrenergic (subtypes 1 and 2)

18. Serotonin • Serotonin (5-HT) cells are mostly located in the gut (98%) with only 2% of serotonin cells in brain • Serotonin cell bodies are located in brainstem raphe nuclei and project to cortex • Serotonin systems: • D system originates in the dorsal raphe nucleus but does not form synapses (5-HT as a neuromodulator) • M system originates from the median raphe nucleus and these varicosities form synapses

19. Serotonin Synthesis 5-HT Precursor PCPA: inhibits TH 4.19

20. 5-HT: Release and Termination • Serotonin release: • No selective release blocker • Fenfluramine is a 5-HT releasing drug as well as block reuptake • Serotonin termination: • Reuptake is blocked by fluoxetine/Prozac (elevates 5HT) • MDMA/ecstasy is both serotonergic and noradrenergic agonist causing reuptake transporters to run reverse: hallucination and excitation

21. Serotonin Receptors • There are at least 9 types of 5-HT receptors • 5-HT1 : 1A, 1B, 1D, 1E, and 1F • 5-HT2 : 2A, 2B, and 2C (LSD is a direct agonist) • 5-HT3 • 5-HT3 receptors are ionotropic, the remainder are metabotropic • 5-HT1B and 5-HT1D are presynaptic autoreceptors

22. Glutamate • Glutamate (glutamic acid) is an excitatory neurotransmitter • Glutamate interacts with four receptor types • NMDA receptor: controls a CA++ channel • Activation by glutamine requires glycine binding and displacement of magnesium ions • AMPA receptor: controls sodium channels • Kainate receptor: controls sodium channels • Metabotropic glutamate receptor

23. GABA • GABA is synthesized from glutamic acid • GABA induces IPSPs • GABA acts via 2 receptors • GABAA: ionotropic receptor (controls a Cl- channel) • GABAA receptors contain 5 distinct binding sites • GABA site (direct agonist muscimol, direct antagonist bicuculline) • Benzodiazepine site (anxiety dissolving drugs, alcohol?) • Barbiturates (anesthetic for animals, alcohol?) • Steroid binding site • Picrotoxin binding site (indirect antagonist) • GABAB: metabotropic receptor (controls a K+ channel)

24. Peptides • Peptides consist of 2 or more amino acids (linked by peptide bonds) • Peptides are synthesized in the soma and transported to axon terminal in vesicles • Peptides are released from all parts of the terminal button and after release are enzymatically degraded (no reuptake) • Opiates (opium, morphine, heroin) receptor: endorgenouse peptides/opioids • for analgesia and reinforement • Antagonist: naloxone • Peptides can be co-released with other NTs • Peptide can serve as neuromodulator

25. Lipids • THC (marijuana) interacts with cannabinoid (CB) receptors in brain to produce analgesia and sedation • There are two endogenous ligands for the CB receptors, each is derived from lipid precursors • Anandamide • 2-arachidonyl glycerol (2-AG) • Anandamide interferes with 5-HT3 receptors to reduce vomiting and nausea

26. Soluble Gases • Soluble gases can diffuse widely to exert actions on distant cells • Nitric oxide (NO) is created within cells from the amino acid arginine, then diffuses out • NO exerts effects within intestinal muscles, dilates brain blood vessels, and contributes to the changes in blood vessels that produce penile erections • NO activates an enzyme that produces cyclic GMP (a second messenger) within adjoining cells

27. Adverse Effects of Drug Abuse • Alcohol abuse is associated with: • Automobile accidents • Fetal alcohol syndrome • Cirrhosis of the liver • Korsakoff’s syndrome • Cardiac disease • Risk of intracerebral hemorrhage

28. Substance Dependence • Substance Dependence: Three of the following criteria in 12 months: • Presence of withdrawal symptoms • Increasing doses/tolerance • Unsuccessful efforts to stop drug-taking • Considerable time spent in obtaining/taking drug • Drug interference with social/occupational functions

29. Positive Reinforcement and Drug-Taking • Drugs activate positive reinforcement mechanisms in brain • Most addictive drugs increase dopamine levels within the nucleus accumbens • Some induce release from presynaptic terminals • Other drugs block reuptake into presynaptic terminal • Some drugs may act via endogenous opioids • Immediacy of drug action: is crucial to drug reinforcement

30. Negative Reinforcement and Drug-Taking • Behaviors that terminate aversive effects are negatively reinforced: • “It feels so good when it stops hurting” • Withdrawal symptoms that accompany drug-taking are usually aversive • Starting drug-taking again will terminate the withdrawal state • Drug-taking has positively- and negatively-reinforced aspects

31. Mechanisms of Tolerance/Withdrawal • Pharmacological action of drug on receptors: • downregulation/upregulation • Classical Conditioning: • CS: Stimuli associated with drug-taking (e.g. Needles) • UCS: Drug • UCR: Drug effect and homeostatic response to drug • CS alone: elicits compensatory homeostatic effect

34. Drug Craving • Craving is an impulsion to reinstate drug-taking during abstinence • Reflects an activation of the mesolimbic dopamine system by drug cues (needles, mirrors, pipes, etc) • Unpleasant feelings of abstinence • Pleasant recall of positive drug state

35. Drug Craving and D3 Receptor • D3 receptors located within nuc. accumbens may mediate drug craving • D3 receptors are sensitized after cocaine use: • Cocaine-experienced monkeys will self-administer the D3 receptor agonist 7-OH-DPAT • Cocaine-naïve monkeys do not... • D3 receptor density is increased in nuc accumbens of cocaine-overdosed humans

36. Cocaine • Cocaine is a potent DA agonist • Binds and inactivates the DA transporter • Blocks reuptake to increase DA in synapse • Cocaine reinforcement is assessed using • Self-administration paradigm: animal presses lever that results in cocaine infusion via jugular catheter • Conditioned Place Preference paradigm: Does the animal prefer a compartment previously paired with the drug cue?

38. Cocaine Reinforcement: The Role of the Nucleus Accumbens • Positive Reinforcement and Cocaine: • Cocaine increases synaptic DA within the accumbens • Animals will self-inject DA agonists directly into the nuc. Accumbens (NAC) • Lesions of the NAC impairs self-administration of cocaine in rats • Negative Reinforcement and Cocaine: • Cocaine withdrawal results in reduced NAC dopamine

41. Alcohol • Alcohol effects depend on dose: • Low doses: reduces anxiety • Med-High doses: sedation and incoordination • Alcohol consumption produces: • Positive reinforcement: mild euphoria • Negative reinforcement: The aversive state of anxiety is reduced by alcohol consumption

43. Neural Bases of Alcohol Actions • Alcohol increases DA levels within NAC • Alcohol has effects at two receptor sites: • Inverse agonist at NMDA sites • Mediates increased DA release after alcohol • Mediates the sedative and anxiolytic effects of alcohol • Indirect agonist at GABAA sites • Mediates the anxiolytic effect of alcohol

44. Heritability of Alcohol Abuse • Twin studies: MZ twins show greater concordance for alcoholism than DZ twins • Cross-Fostering studies: examine rates of alcoholism in children adopted while young • Environment (one or more ALC adopted parents) • Heritage (one or more ALC biological parents) • Male steady drinking is strongly influenced by heritage • Male/female binge drinking is an interaction effect

45. Therapies for Drug Dependence • Cocaine use is reduced by: • Blockade of dopamine receptors • Issue: this also produces dysphoria and anhedonia • Blockade of D3 receptors • Use of “cocaine immunization” • Alcohol intake is reduced by: • 5-HT reuptake blockers • Opiate antagonists (naltrexone)

47. 10 The study of the movement of drugs through the body is called: • Pharmacokeratics • Pharmacodynamics • Pharmacokinetics • Pharmacotherapeutics

48. 10 This depicts the relationship between the drug dose and the magnitude of its effect: • Dose response curve • Half-life • Therapeutic Index • LD50