question

What is a drug? How can it get into the nervous system? Where do drugs exert their actions?

answer

=>A drug is a exogenous chemical. that is not an essential nutrient, that significantly alters the function of cells when taken in low doses. =>Drugs exert their actions in molecules on or within cells.

question

Effects of drug

answer

Changes in physiological processes and behavior

question

Psychoactive Drug

answer

- drugs that alter mood, thought, or behavior - most used to manage psychopathology - some used recreationally

question

What is pharmacokinetics?

answer

Processes by which drugs are Absorbed, Distributed, Metabolized, and Excreted.

question

Lipid solubility

answer

Most important factor determining entry of drug through Blood-Brain Barrier

question

What are the possible routes of administration of a drug?

answer

=>Absorbed (Oral, sublingual, suppository, topical, skin patch)=>Injected (Subcutaneous, intra-muscular, intraperitoneal, intravenous), =>Inhaled =>Spinal/intracranial (intrathecal, intracerebroventricular, intraparenchymal)

question

What happens when a drug is broken down in your body?

answer

Normal levels of enzyme convert drugs into metabolites which maybe therapeutic, harmful, or inactive .

question

What determines half life?

answer

rate of enzymatic breakdown and excretion determines half-life - however, some drugs broken down into biologically active molecules, extending effective lifespan - individual differences in metabolism

question

Why do different people have different responses to a drug?

answer

Drug response is dependent on the genotype, physiology, lifestyle and environment of an individual; All of which varies from person to person.

question

Difference between Pharmacokinetics and Pharmacodynamics

answer

Pharmacokinetics: The effect of body on drugs Pharmacodynamics: The effect of drugs on the body

question

How do affinity and efficacy contribute to the actions of a drug?

answer

=>Affinity describes the degree of attraction of a drug for its target. =>Efficacy refers to the ability of the drug to exert its physiological action

question

Dose-response function

answer

Plot of effectiveness across doses

question

Therapeutic index

answer

Drugs usually have more than one effect - comparison of doses that exert benefical effects vs doses that exert toxic effects (Margin of safety) ... LD50 (Lethal dose) vs ED50 (Effective dose)

question

Compare agonist and antagonist drugs

answer

Agonists mimic or increase neurotransmitter actions where as Antagonists block or decrease neutrotransmitter actions

question

Describe competitive, noncompetitive, and irreversible antagonists/agonists.

answer

=> Competitive antagonist or agonist attachs to the same binding site as endogenous neurotransmitter. => Non-competitive Antagonist or agonist binds to a noncompetitive site => Irreversible antagonist modifies receptor rendering it permanently inactive. => Inverse agonists bind to the same receptors as a known agonist but produces action opposite to that agonist

question

What is meant by the therapeutic index (LD50/ED50) or margin of safety?

answer

Drugs usually have more than one effect - Comparsion of doses that exert benefical effects vs. doses that exert toxic effects.

question

Distinguish drug sensitization from drug tolerance.

answer

=>drug sensitization means an increase in effectiveness of a drug with repeated/ chronic exposure. =>Drug tolerance means a decrease in effectiveness of a drug with repeated/chronic exposure.

question

Cross sensitization/ cross tolerance

answer

Increase/ decrease in effectiveness of a novel drug after repeated or chronic exposure to a different drug. sensitization and tolerance are action-specific, and may be dissociable

question

Withdrawal symptoms

answer

Rebound actions after repeated/chronic drug administration, observed upon cessation of drug taking

question

Why do withdrawal symptoms occur?

answer

Due to drug-induced tolerance -Alterations in receptor number or affinity -Alterations in receptor-coupling to effectors (ion channels and/or second messengers)

question

Why do we consider some drugs to be neuromodulators? Provide some examples of neuromodulatory actions.

answer

*Neuromodulators* *perform* *broader* *actions* *on* *functional* *circuits* it is proposed that glutamate, GABA, and glycine are pure neurotransmitters, whereas others may technically be considered neuromodulators - presynaptic facilitation/presynaptic inhibition: actions on presynaptic heteroreceptors at axoaxonic synapses to increase or decrease release of neurotransmitter - synaptic actions: actions on synaptic receptors to modulate actions of glutamate/GABA/glycine - metabotropic receptors - extrasynaptic actions: actions on receptors outside of synapse to modulate actions of glutamate/GABA/glycine - spillover, varicosities that do not form synapses

question

What are the 7 features of a classical neurotransmitter/neuromodulator ?

answer

1. synthesized by presynaptic neuron (contains appropriate biosynthetic enzymes) 2. released by presynaptic neuron when stimulated 3. can be chemically or pharmacologically identified 4. binds to specific receptors on postsynaptic membrane 5. should reproduce at postsynaptic cell effects that are observed upon stimulation of presynaptic neuron 6. blocking release, or blocking binding to postsynaptic receptors prevents presynaptic activity (action potentials) from affecting postsynaptic neuron 7. active mechanisms to terminate actions of chemical (neuronal or glial uptake, enzymatic degradation)

question

Describe 7 mechanisms of agonist action and 7 mechanisms of antagonist action. Give some examples.

answer

*Agonist* 1. Drug is a precursor 2. Drug stimulates NT release 4. Drug blocks autoreceptors 5. Drug activates postsynaptic receptor 6. Drug blocks reuptake 7. Drug inactivates metabolizing enzyme *Antagonist* 1. Drug inactivates biosynthetic enzyme 2. Drug inhibits NT release 3. drug prevents storage 4. drug activates autoreceptors 5. Drug blocks postsynaptic receptors

question

Name 3 catecholamines

answer

Dopamine , Norepinephrine, epinephrine,

question

Name 2 indoleamines.

answer

Melatonin, Serotonin

question

Name 3 amino acid neurotransmitters.

answer

Glutamate, GABA, Glycine

question

Describe the synthesis, packaging, inactivation, and reuptake of acetylcholine.

answer

synthesized by choline acetyltransferase (ChAT) from choline and acetyl-CoA - packaged into vesicles by VAChT - inactivated by hydrolysis of ACh to choline by acetylcholinesterase (AChE) and butyrylcholinesterase - choline is reuptaken by high affinity choline transporter (ChT), and then converted back to ACh

question

Where is acetylcholine found in your nervous system?

answer

- found in preganglionic fibers of sympathetic ns and all fibers of parasympathetic ns - found in all motor neurons, released at all neuromuscular junctions - brainstem: pedunculopontine nucleus and dorsolateral tegmental nuclei, - projections to brainstem, deep cerebellar nuclei, LC, raphe, inferior olive - basal forebrain: basal nucleus of Meynert and medial septal nucleus - projections to neocortex and hippocampus - internal transmission in striatum

question

What types of receptors does acetylcholine bind?

answer

- binds to ionotropic nicotinic receptors (2 molecules) - Na+ channel - neuromuscular junctions and CNS axoaxonic synapses (facilitation) - binds to metabotropic muscarinic receptors - predominant form of ACh receptor in CNS

question

What are the normal functions of acetylcholine in your nervous system?

answer

- implicated in motor function (NMJs), REM sleep (pons), learning and memory (basal forebrain activating cortical arousal), addictive effects of nicotine - deficits in Alzheimer's disease - deficits in Myasthenia Gravis

question

What disease processes involve abnormalities in acetylcholine neurotransmission?

answer

- deficits in Alzheimer's disease - deficits in Myasthenia Gravis

question

What drugs interact with acetylcholine neurotransmission, and how?

answer

*Agonist* -drug activates postsynaptic receptors nicotine, muscarine -drug inactivates metabolizing enzyme Aricept (donepezil) neostigmine *Antagonists* -Drug blocks postsynaptic receptors *curare*

question

Describe the synthesis, packaging, inactivation, and reuptake of dopamine.

answer

- synthesized by enzymatic modification of tyrosine (Amino acids) (tyr or Y) - at least 3 release mechanisms - Ca2+-dependent exocytosis - spontaneous or drug-induced reversal of DAT and NET - Ca2+-independent dendritic release - inactivated primarily by reuptake through DAT or NET - also inactivated by MAO-A, MAO-B, COMT

question

Where is dopamine found in your nervous system?

answer

- synthesized mostly in nigrostriatal and mesocorticolimbic neurons (A9 and A10) and tubero-infundibular neurons

question

What types of receptors does dopamine bind?

answer

binds to metabotropic receptors - D1 class = D1, D5, positive association with adenylate cyclase - exclusively postsynaptic, mediate excitatory actions - D2 class = D2, D3, D4, negative association with adenylate cyclase - pre- and postsynaptic - D2 autoreceptors on dendrites and soma hyperpolarize membrane - D2, D3, D4 on postsynaptic membrane mediate inhibitory actions

question

What are the normal functions of dopamine in your nervous system?

answer

implicated in movement, attention, learning, motivation - implicated in inhibition of lactation

question

What disease processes involve abnormalities in dopamine neurotransmission?

answer

deficits/abnormalities in Parkinson's disease, schizophrenia, drug addiction

question

What drugs interact with dopamine neurotransmission, and how?

answer

*Agonist* -drug is a precursor l-DOPA -drug activates postsynaptic receptors bromocriptine (mimics cocaine), apomorphine (Prefers to bind to presynaptic (antagonist) but in high doses, it goes on the postsynaptic and becomes and agonist) -drug blocks/reverses reuptake cocaine, Ritalin (Slower) amphetamine (faster, big rush) -drug inactivates metabolizing enzyme deprenyl *Antagonist* -drug prevents storage reserpine -drug activates autoreceptors apomorphine -drug blocks postsynaptic receptors neuroleptics (Not fun drugs, feels senseless and awful)

question

Describe the synthesis, packaging, inactivation, and reuptake of norepinephrine.

answer

- synthesized by enzymatic modification of tyrosine (tyr or Y) - at least 3 release mechanisms - Ca2+-dependent exocytosis - spontaneous or drug-induced reversal of DAT and NET - Ca2+-independent dendritic release - inactivated primarily by reuptake through DAT or NET - also inactivated by MAO-A, MAO-B, COMT

question

Where is norepinephrine found in your nervous system?

answer

- synthesized in postganglionic fibers of sympathetic nervous system and released at targets of sympathetic innervation - synthesized in cells that project from locus coeruleus and lateral tegmental field, and released through varicosities - these do not from traditional synapses

question

What types of receptors does norepinephrine bind?

answer

- binds to metabotropic receptors - ?1, ?2, ?1, ?2 adrenoceptors found in CNS and PNS - ?3 adrenoceptors found in PNS (especially adipose - enhances lipolysis) - all 5 types sensitive to EPI as well as norEPI - ?1 produce EPSP; ?2 are autoreceptors produce IPSP - ?1, ?2 adrenoceptors increase excitability of postsynaptic membranes

question

What are the normal functions of norepinephrine in your nervous system?

answer

regulation of mood, arousal, sexual behavior, autonomic nervous system tone, "fight-or-flight" responses, energy metabolism, vigilance, vasoconstriction

question

What drugs interact with norepinephrine neurotransmission, and how?

answer

*Agonist* drug activates postsynaptic receptors adrenaline, ephedrine drug blocks reuptake trycyclics, NSRIs Ritalin drug inactivates metabolizing enzyme clorgyline *Antagonist* drug blocks postsynaptic receptors ?-blockers

question

What disease processes involve abnormalities in norepinephrine neurotransmission?

answer

- deficiency/disregulation in ADHD (Not enough arousal to sustain goal-directed behavior), depression, schizophrenia, hypotension - deficiency suspected in Alzheimer's disease because release from varicosities has anti-inflammatory role in CNS

question

Where is epinephrine found in your nervous system?

answer

- synthesized by chromaffin cells in adrenal medulla and released in response to sympathetic innervation - minor neurotransmitter in brain - implicated in energy metabolism, "fight-or-flight" responses

question

Describe the synthesis, packaging, inactivation, and reuptake of serotonin

answer

- synthesized by enzymatic modification of tryptophan (trp or W) - at least 3 release mechanisms - Ca2+-dependent exocytosis - spontaneous or drug-induced reversal of SERT - Ca2+-independent dendritic release - inactivated primarily by reuptake through SERT - deaminated preferentially by MAO-B

question

Where is serotonin found in your nervous system?

answer

- synthesized in 9 raphe nuclei and released from varicosities, not axon terminals - some varicosities (D system from dorsal raphe) do not appear to form synapses, and release is diffuse (neuromodulation) - some varicosities (M system from median raphe) form conventional synapses

question

What types of receptors does serotonin bind?

answer

- binds to at least 14 different kinds of receptors - 5HT1A, 5HT1B, 5HT1D, 5HT1E, 5HT1F all metabotropic - 5HT2A, 5HT2B, 5HT2C all metabotropic - 5HT3 is ionotropic, Cl- channel - 5HT1B, 5HT1D are presynaptic autoreceptors

question

How does glutamate neurotransmission contribute to learning?

answer

- implicated in sensory processing, plasticity, and virtually every brain function

question

What are the normal functions of serotonin in your nervous system?

answer

- implicated in regulation of mood, feeding, sleep, arousal, pain, sensory processing

question

What disease processes involve abnormalities in serotonin neurotransmission?

answer

disregulation implicated in major depression, bipolar disorder, OCD

question

What drugs interact with serotonin neurotransmission, and how?

answer

*Agonist* drug activates postsynaptic receptors LSD (messes with sensory processing), buspirone (Anxiolytic drug) drug blocks reuptake SSRIs (first considered for depression), NSRIs *Antagonist* drug blocks postsynaptic receptors clozapine

question

Where is Melatonin found in your nervous system?

answer

- released from pineal gland - elevated in evenings, induces sleepiness

question

Name the endogenous neurotransmitter system that marijuana (i.e., THC) emulates?

answer

*Unconventional* *Neurotransmitters* - *Lipids* - *Endocannabinoids* *(eCB)* Anandamide

question

At what receptors do barbiturates, alcohol, and benzodiazepines act?

answer

*GABAa* receptor -Barbiturates and Alcohol -Benzodiazepines

question

What disease processes involve abnormalities in glutamate neurotransmission?

answer

- disregulation implicated in schizophrenia, epilepsy

question

Describe the synthesis, packaging, inactivation, and reuptake of glycine.

answer

- derived from glucose metabolism through serine intermediate - recycled through glial uptake and metabolism to glutamine - predominant inhibitory neurotransmitter in brainstem, spinal cord, and retina - binds to ionotropic glycine receptor; ionotropic (Cl- channel), postsynaptic - co-factor in NMDA receptor activation

question

What drugs interact with GABA neurotransmission, and how?

answer

Agonist -drug activates postsynaptic receptors diazepam, EtOH pentobarbital Antagonists- drug blocks postsynaptic receptors bicuculine

question

What are the normal functions of glutamate in your nervous system?

answer

Implicated in sensory processing, plasticity, and virtually every brain function activation of NMDA receptor-associated ion channels is dependent upon contiguous presynaptic and postsynaptic activity - at resting potential, NMDA ion channels are blocked by Mg2+ - if the postsynaptic membrane is sufficiently depolarized, Mg2+ is expelled Therefore, NMDA receptors function as "coincidence detectors" for presynaptic neurotransmitter release, and postsynaptic depolarization

question

How are psychoactive drugs classified? Give a general overview of each.

answer

-Sedative Hypnotics and Anxiolytics -Antipsychotics -Antidepressants -Narcotic Analgesics -Stimulants -Hallucinogens

question

Hallucinogens

answer

Alters sensory processing and cognition Mescaline, LSD, psilocybin

question

Stimulants

answer

Increase motor behavior, arousal and elevate mood Cocaine, amphetamine, methamphetamine and methylphenidate

question

Narcotic Analgesics

answer

- derived from opium poppy or artificially synthesized - opium, heroin, morphine, codeine, fentanyl, etc. - agonists at endogenous ?, ?, and ? opioid receptors - imitate endogenous enkephalin, endorphin, and dynorphin

question

Antidepressants

answer

- MAOIs (e.g. selegiline) - tricyclic antidepressants (amitriptyline) - second generation antidepressants - SSRIs (e.g. fluoxetine) - NSRIs (e.g. duloxetine) - ketamine

question

Antipsychotics

answer

- classical neuroleptics - haloperidol, chlorpromazine - atypical neuroleptics - clozapine, risperidone - all these drugs are antagonists at D2, D3, D4 receptors

question

Sedative Hypnotics and Anxiolytics

answer

- minor tranquilizers, anxiolytics, sleeping pills - alcohol, barbiturates, benzodiazepines - all these drugs produce tolerance and cross-tolerance through actions on GABA-A receptors

question

What disease processes involve abnormalities in GABA neurotransmission?

answer

Disregulation implicated in epilepsy

question

What types of receptors does glutamate bind?

answer

- 4 major subtypes of glutamate receptors, w/ at least 8 types of mGluRs - AMPA receptor; ionotropic (most abundant; Na+ channel) - NMDA receptor; ionotropic (Ca2+ channel) - kainate receptor; ionotropic (Na+ channel) - mGluR1- mGluR8; metabotropic - multiple binding sites on NMDA receptor - glutamate - glycine, co-binding required - Zn2+, binding decreases activity - polyamine (promote growth and development), binding increases activity - Mg2+- blocks Ca2+ conductance - PCP - blocks Ca2+ conductance

question

Describe the synthesis, packaging, inactivation, and reuptake of opioid and non-opioid peptides.

answer

- *Opioid* *Peptides* (endorphin, enkephalin, dynorphin, N/OFQ) - *Non-opioid* *Peptides* (peptide YY, substance P, CCK, and many others) - short chains of amino acids cleaved from macroproteins by peptidases - manufactured in soma, transported slowly to axon terminal - stored in large (~100nm) dense core vesicles, release from HFS or burst-firing APs - cannot respond quickly to increased demand - inactivated by diffusion or enzymatic metabolism; some products retain biological activity (e.g. angiotensin I converted to more and more active angiotensin II and III)

question

What drugs interact with glycine neurotransmission, and how?

answer

Antagonist: drug blocks postsynaptic receptors strychnine, tetanus toxin

question

Where is opioid and non-opioid peptides found in your nervous system?

answer

*Opioid* *Peptides* - fairly ubiquitous distribution, descending projections from periaqueductal grey, opioid actions in forebrain (social), midbrain (motivation), brainstem (life functions)

question

What are the normal functions of GABA in your nervous system?

answer

implicated in virtually every brain function

question

What drugs interact with *opioid* and non-opioid peptides neurotransmission, and how?

answer

*Agonist* - drug activates postsynaptic receptors *heroin*, *morphine*, *oxycodone* *Antagonist*-drug blocks postsynaptic receptors *naloxone*, *naltrexone*

question

Where is glutamate found in your nervous system?

answer

- ubiquitous, predominant excitatory neurotransmitter in CNS and PNS

question

What types of receptors does GABA bind?

answer

- 2 subtypes of GABA receptors - GABAA receptor; ionotropic (Cl- channel), postsynaptic - GABAB receptor; metabotropic (G-protein-coupled to K+ channel), presynaptic autoreceptor and postsynaptic receptor - multiple binding sites on GABAA receptor - GABA - barbiturate - benzodiazepine - steroid - picrotoxin

question

What are the normal functions of opioid and non-opioid peptides in your nervous system?

answer

*Opioid* implicated in analgesia, socialization, feeding, behavioural reinforcement, defense responses, anxiety responses, gastric motility *Non-opioid* -regulation of feeding, gastric motility, circadian rhythms, anxiety/stress responses -pain signaling - mood disorders, stress, nausea

question

Describe the synthesis, packaging, inactivation, and reuptake of glutamate

answer

- glutamic acid, most abundant excitatory neurotransmitter in CNS - synthesized from glucose metabolism (?-ketoglutarate) and amino acid precursors (glutamine) in axon terminals - recycled through glial uptake and metabolism to glutamine

question

Where is GABA found in your nervous system?

answer

- ubiquitous, predominant inhibitory neurotransmitter in CNS and PNS

question

What types of receptors does glycine bind?

answer

binds to ionotropic glycine receptor; ionotropic (Cl- channel), postsynaptic

question

Describe the synthesis, packaging, inactivation, and reuptake of GABA

answer

- gamma aminobutyric acid, most abundant inhibitory neurotransmitter in CNS - synthesized from glucose metabolism (?-ketoglutarate) through a glutamic acid intermediate by glutamic acid decarboxylase (GAD) - recycled through glial uptake and metabolism to glutamine

question

What types of receptors does opioid and non-opioid peptides bind?

answer

Opioid Peptides - binding to metabotropic receptors - enkephalins = ?, ?, ? - endorphins = ?, ?, ? - dynorphins = ?, ?, ? - N/OFQ = NOP - all 4 receptor types exhibit negative association with adenylate cyclase Non-Opioids Peptides - NPY, PYY, CCK - regulation of feeding, gastric motility, circadian rhythms, anxiety/stress responses - binds to Y1-Y5 GPCRs - substance P - principal mechanism of pain signaling - mood disorders, stress, nausea - binds to neurokinin 1 (NK1) receptor - others - neurotensin, galanin, somatostatin, VIP, TRH, CRH, AGRP, bombesin, ghrelin, orexin, oxytocin, vasopressin, various neurokinins, relaxin, etc.

question

Where is glycine found in your nervous system?

answer

predominant inhibitory neurotransmitter in brainstem, spinal cord, and retina

question

What is Drug Addiction?

answer

Historical perspective: Use of plant alkaloids as recreational drugs probably predates written history

question

Current perspective on Drug Addiction

answer

Addiction is a chronic, often relapsing brain disease that causes compulsive drug seeking and use, despite harmful consequences to the addicted individual and to those around him or her. Although the initial decision to take drugs is voluntary for most people, the brain changes that occur over time challenge an addicted person's self-control and hamper his or her ability to resist intense impulses to take drugs.

question

The Moral Model

answer

Failure of moral character or lack of self-control

question

The Disease Model

answer

-an addict is a person who requires medical treatment

question

The Dependence Model

answer

-drug-taking behavior serves to avoid unpleasant withdrawal symptoms -Negative reinforcement.

question

The Positive Reinforcement Model

answer

Drugs activate a neural system that reinforces behavior. -Mesocorticolimbic dopamine system -Speed of onset.

question

Incentive Sensitization Theory

answer

The more you crave it, the more you don't like it Addicts increase doses to try to attain former hedonic effects.

question

Intrinsic Variables

answer

(From within) -Genes -Experience -Emotional disorders -Psychaitric disorders -Age

question

Extrinsic Variables

answer

(From outside) -Availability and cost -Socioeconomic status -Educational opportunities

question

What influences subjective responses to drug abuse?

answer

Neurobiological factors.

question

Age of First Use

answer

Vulnerability for drug addiction appears to be highest during adolescence

PSB3340 Chapter 4: Neurochemistry – Flashcards

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