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Neuropharmacology > Exam 2 > Flashcards

Exam 2 Flashcards

1
Q

Name the ionotropic glutamate receptors

A

NMDA, AMPA, and Kainate

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2
Q

Name the 3 groups of metabotropic glutamate receptors

A

Group 1 coupled to Gq and PLC

Group 2 and Group 3 coupled to Gi/o and inhibition of adenylyl cyclase. they are autoreceptors

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3
Q

NMDA receptors are permeable to what cations?

A

Na+, K+, Ca++

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4
Q

NMDA receptors are activated by —– and co activated by ——–

A

glutamate & NMDA, glycine

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5
Q

Antagonists of NMDA receptors include:

A

PCP, Ketamine, dextromethorphan (cough) memantine (alzeheimers), riluzole (ALS), ifenprodil

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6
Q

NMDA receptors are blocked by —— which means it requires —– to unblock

A

Mg++, depolarization

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7
Q

—– are positive allosteric modulators for NMDA receptors

A

polyamines

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8
Q

AMPA/Kainate receptors are permeable to what cations?

A

Na+, and K+

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9
Q

AMPA/Kainate receptors have what effect on neurons?

A

excitatory, depolarizing effect

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10
Q

AMPA agonists by affinity

A

AMPA > glutamate > kainate

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11
Q

Kainate agonists by affinity

A

Kainate > glutamate > AMPA. also domoate

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12
Q

Name some AMPA/Kainate antagonists

A

antiepileptics

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13
Q

LTP is known to ultimately lead to insertion of more —- channels in post synaptic membranes

A

AMPA

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14
Q

Presynaptic mGluRs act as —— autoreceptors (mGluR–/—) by reducing ——-

A

inhibitory, II/III, ca++ influx

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15
Q

Postsynaptic mGluRs (mGluR—-) modulate a variety of ligand and voltage gated ion channels

A

I

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16
Q

Describe Group 1 of metabotropic glutamate receptors

A

excitatory, Gq coupled , activates PLC which activates ion channels increase NMDA, mostly postsynaptic

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17
Q

Describe Group II of glutamate receptors

A

inhibitory, Gi/Go coupled, reduces cAMP, decreases transmitter release, decrease NMDA, mostly presynaptic and on glia cells

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18
Q

Describe Group III of glutamate receptors

A

inhibitory, Gi/Go coupled, reduces cAMP, decrease neurotransmitter release, decrease NMDA, mostly presynaptic

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19
Q

Name and categorize some glutamate transporters

A

Vesicular transporters: VGluT1-3 high affinity for glutamate

Membrane transportersL GLAST (glia), GLT-1(glia), EAAC1, sEAAT5

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20
Q

GABA receptors are targeted to treat

A

Fear, anxiety, epilepsy

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21
Q

Antiepileptics inhibits

A

GABA-T

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22
Q

—– and —– are ligand gated ion channels as GABA receptors

A

GABA A and GABA C

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23
Q

—-is a G protein coupled receptor for GABA

A

GABA B

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24
Q

GABA A and GABA C are —- and —- selective

A

Cl-, HCO3-

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25
Q

GABA A and GABA C are —– and have —– effect on neurons due to —— entering the cell

A

inhibitory, hyper polarizing, Cl-

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26
Q

Positive allosteric modulators do what?

A

increase the effect of a given neurotransmitter

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27
Q

Describe GABA A pharmacology by name agonists, antagonists, positive allosteric modulators, and negative allosteric modulators

A

Agonists: GABA, muscimol

Positive allosteric modulators: benzodiazepines, non-benzos that bind to benzo site, barbiturates , anesthetics, ethanol

Negative allosteric modulators: flumezanil

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28
Q

Describe how alpha subunits of GABA have specific benzodiazepine mediated effects

A

Alpha 1: sedative, antero amnesia, anticonvulsant effects

Alpha 2: anxiolytic and muscle relaxant effects

Alpha 3: anxiolytic and muscle relaxant effects

Alpha 5: cognitive effects

goals for anxiety drug is to bind to alpha 2 or 3 subtypes but not alpha 1

goal for sedative is to bind to alpha 1

alpha 5 binding is not desirable

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29
Q

Name high affinity and low affinity GABA transporters

A

High affinity: GAT-1 GAT-2 GAT-3

Low affinity: BGT-1

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30
Q

Describe the synaptic function of GABA B receptors

A

-inhibit presynaptic ca++ channels and adenylyl cyclase resulting in decreased transmitter release
-also found post-synaptically but are outside the synapse and only activated with high frequency stimulation (with high synaptic GABA levels)

metabotropic

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31
Q

Describe the pharmacology of glycine receptors

A

-channels are cl-/hco3- selective
-inhibitory, hyperpolarizing effect on neurons
-agonists: glycine, beta or L alanine, taurine, L-serine, proline
-positive allosteric modulators: anesthetics, neurosteroids, ethanol
-negative allosteric modulator: pregnenolone
antagonists: strychnine

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32
Q

Describe the nature of epilepsy

A

excitation spreads throughout a network of interconnected neurons but is normally prevented by inhibitory mechanisms

epileptogenesis can arise is excitatory transmission is facilitated or inhibitory transmission is reduced

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33
Q

Seizures are associated with

A

episodic high-frequency discharge of impulses by a group of neurons in the brain

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34
Q

What determines the symptoms that are produced by seizures?

A

the site of primary discharge and extent of its spread

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35
Q

Describe epileptogenesis

A

probably results from abnormally exaggerated and prolonged action of excitatory transmitter. Activation of NMDA receptors mimics PDS and initiates seizure activity which implicated glutamate involvement. Excitotoxic damage to inhibitory neurons is belied to be responsible.

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36
Q

Describe the mechanism of action of anti epileptic drugs

A

Increase GABA transmission

blocking reuptake of GABA from the synapse

reduced GABA metabolism via inhibition of GABA transaminase

allosteric modulation of GABA receptor

antiepileptics return na+ channels to the inactive state, preventing repetitive firing of axons

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37
Q

Name the 3 major dopaminergic projections in the CNS

A

mesostriatal, ventral tegmental area, arcuate nucleus

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38
Q

Nucleus accumbens dopamine is increased by..

A

heroin, nicotine, alcohol intake

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39
Q

Output neurons from the nucleus accumbens are…

A

GABAergic

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40
Q

Rewarding inputs ….. the activity of output neurons from the nucleus accumbens

A

inhibit

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41
Q

opioid receptors or dopamine receptors on nucleus accumbens neurons are

A

inhibitory

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42
Q

Stimulants increase — input from —- onto —- neurons

A

dopamine, VTA, NAc

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43
Q

Opioids—- NAc neurons directly but also inhibit —– which —- VTA DA neurons

A

inhibit, GABAergic VTA interneurons, dis-inhibits

44
Q

Nicotine —- opioidergic and DA VTA neurons

A

activates

45
Q

Cannabinoids —- glutamatergic input into the NAc

A

inhibit

46
Q

what is pharmacodynamic tolerance?

A

compensatory change of receptor number or sensitivity

47
Q

what is pharmacokinetic tolerance?

A

increased metabolism due to enzyme induction

48
Q

what is behavioral tolerance?

A

adjustment of behavior to compensate for adverse effects (ex broad based gait to walking near wall in alcohol dependent individuals)

49
Q

what is cross tolerance?

A

physiologic tolerance to others of same drug class or similar action

50
Q

Describe treatments for addiction for stimulants, opiates, ethanol, and nicotine

A

CBT is most successful

Stimulants: DA modulating drugs are largely ineffective

Opiates: methadone (long acting opiate agonist) can be slowly tapered off, clonidine is effective against withdrawal symptoms, naltrexone is used for rapid detoxification, buprenorphine is a partial mu agonist that can block effects of other opiates

Ethanol: rapid removal of ethanol can produces withdrawal symptoms so slow removal of GABAergic stimulation using a benzo is effective

Nicotine: bupropion is a nicotinic antagonist, varenicline is a nicotinic partial agonist

51
Q

Describe positive, negative, cognitive symptoms of schizophrenia

A

Positive: hallucinations, delusions

Negative: flattened affect, apathy, avolition, anhedonia

Cognitive: thought disorder, loose association, incoherence, sensorimotor gating deficits

52
Q

Describe the pathophysiology of schizophrenia

A

thought to involve DA and glutamate signaling pathways (due to psychotic effects produced by NMDA antagonists)

53
Q

the clinical potency of an antipsychotic drug is strongly correlated with…

A

its ability to bind to D2 receptors

54
Q

What is a 2nd generation antipsychotic?

A

5HT 2A antagonism is more potent than D2 receptor antagonism

beneficial effects on both positive and negative symptoms

low or absent likelihood of extrapyramidal motor system effects

55
Q

What are extra-pyramidal side effects?

A

results from activities of drugs on the extra-pyramidal system (regions outside of the pyramidal system that participate in movement)

56
Q

Name some extra-pyramidal side effects

A

Tardive dyskinesia: involuntary, irregular muscle movements, usually of the face and tongue

Akathisia: severe restlessness of limbs

Dystonia: muscular spasms, frequently of the tongue or jaw

Oculogyric crisis: spasms of the eye muscles

Parkinsonism: rigidity, bradykinesia/akinesia, resting temor, postural instability

57
Q

Basal ganglia function is

A

stratal (extrapyramidal) circuits involved in preparation and initiation of movement, production of motor patterns skills habits

58
Q

Parkinsons disease is a result of a loss of

A

dopamine neurons in the substantia nigra

59
Q

describe the treatment of Parkinson’s

A

strategy is to increase dopaminergic signaling in basal ganglia

L-dopa most common therapeutic however L-dopa is converted to dopamine outside the brain thus is is often given with carbidopa which cannot cross the BBB.

There are also dopamine agonists, muscarinic antagonists, MAOB inhibitors which block breakdown of dopamine, NMDA antagonists, deep brain stimulation, and stem cell transplants

60
Q

name some complications of chronic L-dopa therapy

A

L-Dopa has a short hand life, motor fluctuations, non-motor complications, neuropsychiatric complications

61
Q

serotonin is synthesized from —– by ———-

A

tryptophan, tryptophan hydroxylase

62
Q

5-HT neurons are confined to —- nuclei

A

raphe nuclei

63
Q

Describe the types raphe nuclei and what they innervate

A

caudal raphe: innervates medulla and spinal cord

dorsal raphe: innervates cortex, thalamus, striatum, and midbrain

median raphe: innervates hippocampus, septum, and limbic structures

64
Q

Serotonin participates in what biological functions?

A

sleep, arousal, attention, sensory processing, emotion, appetite and mood

65
Q

5HT3 is the only —- channel while all others are —–

A

ion, G protein coupled

66
Q

MDMA has psychostimulant properties and mood enhancing and psychedelic properties through increasing release of

A

DA, NE 5-HT

67
Q

Name the different antidepressant classes

A

Serotonin-selective reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, psychostimulants

68
Q

describe the pharmacology of SSRIs

A

all act by blocking SERT, have variable half lives, often combined with other drugs (like Wellbutrin), has adverse effects including GI irritation, sexual dysfunction, CNS activation (agitation, insomnia), and weight gain

69
Q

describe the pharmacology of tricyclic antidepressants

A

block both SERT and NET, significant side effects, fatal in overdose

70
Q

describe the pharmacology of SNRIs

A

venlafaxine is like TCA without the side effects, duloxetine target population of depression and pain

71
Q

Describe the pharmacology of bupropion

A

Norepinephrine and dopamine reuptake inhibitor, and nicotinic receptor antagonist, few significant drug interactions, not associated with weight gain, used to treat sexual dysfunction from SSRIs, side effects include insomnia, dry mouth, tremor, seizures

72
Q

Describe different cholinesterase inhibitors

A

reversible: (physostigmine, neostigmine) used for glaucoma, myasthenia gravis, bladder dysfunction

irreversible: organophosphates , pesticides, nerve gases

centrally acting: tacrine, donepezil (used for alzeheimers)

73
Q

describe toxin acting at cholinergic synapses

A

botulinum toxin and tetanus toxin prevent release of ACh vesicles

alpha-latrotoxin stimulates ACh vesicle release

74
Q

Name and describe the 3 sites of cholinergic neurotransmission (CNS)

A

Basal forebrain: nucleus basilus innervates sensory and limbic cortices so it’s involved in arousal, emotion, cortical responses to sensory input and also innervates learning/memory regions of cortex and hippocampus

Brainstem: pedunculopontine nucleus and laterodorsal tegmental nucleus which innervates the ventral segmental area, thalamus, cortex, and to some extent basal ganglia. Also other areas of the brainstem involved in reward, sensory perception, movement

Striatum: cholinergic interneurons participate in circuitry underlying motor learning and motor control

75
Q

What is Myasthenia Gravis? How is it treated?

A

autoimmune disorder where immune system attacks nicotinic receptors at NMJ

Typically treated with cholinesterase inhibitors or drugs that suppress the immune system

76
Q

Describe muscarinic acetylcholine receptors

A

GPCRs, 5 subtypes were M1, M3, M5 couple to Gq and M2 and M4 couple to Gi/o. They are located in the cortex, hippocampus, striatum, thalamus, basal forebrain, substantial nigra.

Agonists include carbachol, arecoline, oxotremorine, pilocarpine

Antagonists include atropine, scopolamine

77
Q

Describe M2 receptors

A

Ones found in the heart are activated by acetylcholine from vagus nerve leading to opening of GIRKs which slows down heart rate

78
Q

Describe effects of anticholinergic drugs

A

many impact function of the parasympathetic nervous system

treats overactive bladder, bronchodiators, pupillary dilation, cholinesterase inhibitor overdose

drugs that have anticholinergic properties: antihistamines, tricyclic antidepressants, antipsychotics

side effects include: dry mouth, blurred vision, decreased perspiration, elevated heart rate, urinary retention, constipation, dizziness, confusion, delirium

79
Q

Describe some aspects of Alzheimers

A

earliest symptoms are memory impairment, with progression ability to learn new information is severely compromised, patients can become depressed irritable aggressive and eventually delusions and hallucinations, ultimately leads to loss of independence

80
Q

Briefly describe the pathophysiology of Alzheimers

A

discovered based on duplications of region that codes for amyloid precursor protein (APP) and APP is increased in these families

81
Q

Describe APP. What does it do? how is it metabolized?

A

APP participates in regulating synaptic transmission, axonal transport, gene expression, and neuronal growth

It is metabolized in the beta pathway where APP is cleaved by beta secretase and gamma secretase to form ABeta peptides and the alpha pathway which results in the prevention of production of Abeta

82
Q

Describe ABeta aggregates. What are their normal functions? How does aggregates effect the body?

A

has normal functions related to neuronal growth and repair

ABeta 42 forms aggregates of small oligomers that form plaques which is toxic to neurons. Small oligomers of ABeta 42 block LTP and disrupt learning and memory. Microglia attempt to clear ABeta aggregates but in the process can release inflammatory cytokines which can lead to neuronal death.

83
Q

Describe alzheimers pathophysiology of Tau. What does it normally do? How can it become bothersome?

A

Tau is a microtubule associated protein. It is normally phosphorylated by kinases leading to its release from the microtubule so that axonal transport can proceed. Hyperphosphorylation of these kinases can lead to the production of neurofibrillary tangles. ABeta can stimulate aggregation of tau. Presence of NFTs is highly correlated to degree of neuronal loss and cognitive impairment.

84
Q

Describe pathophysiology of ApoE. What does it normally do? How can it become bothersome?

A

Apolipoprotein E is a protein that normally plays a role in cholesterol transport, uptake and redistribution. Increased levels of ApoE4 is a risk factor for AD as it can increase ABeta production and bind to and phosphorlate tau. Increased levels of ApoE2 is protective possibly due to clearance of ABeta aggregates.

85
Q

Describe treatments of AD

A

Currently AchE inhibitors which can be effective for symptoms but not for disease modification. Most strategies focus on ABeta.

86
Q

Broadly describe cannabinoid receptors

A

GPCRs. CB1 are expressed in the brain while CB2 receptors are expressed in immune cells.

87
Q

Describe CB1 receptor ligands

A

3 types: endogenously produced, plant derived, and synthetic

endogenous ligands (endocannabinoids) synthesized from membrane phospholipids . They are not stored in cells, they are synthesized and immediately released, and act as retrograde messengers

88
Q

How does cannabinoids play a role in feeding and emesis?

A

CB1 receptors are expressed in the hypothalamus and they stimulate food intake. CB1 antagonists under investigation as anti obesity drugs. Cannabinoid agonists suppress nausea and vomiting.

89
Q

How do endocannabinoids play a role in pain management?

A

number of studies demonstrate analgesic effects of selective CB1 receptor agonists. Data also suggests role of CB2 receptor in inhibition of pain perception (anti-nociception) and of chronic pain. Inhibitors of endocannabinoid degradation and selective CB2 receptor agonists may constitute strategy for treating chronic pain.

90
Q

Describe purinergic signaling

A

signaling molecules are nucleotide/nucleoside derivatives of AGUTC.

91
Q

How is purinergic signaling ubiquitous?

A

neuron to neuron signaling, neuron to glia signaling, glia to glia signaling, purinergic signaling following excessive ATP release from neurons due to overstimulation or cell damage can promote the presence of reactive astrocytes and activated microglia. These glia cells can then start proinflammatory cascades and may contribute to diseases processed such as alzheimers and chronic pain.

92
Q

Describe nitric oxide signaling

A

Nitric oxide diffuses out of cells and activates guanylate cyclase in neighboring neurons. NO can also react with oxygen radicals leading to peroxynitrite formation and may contribute to neuronal damage in ischemia-reperfusion situations such as stroke

93
Q

Norepinephrine is produced by neurons in the —- and ——

A

pons and medulla

94
Q

The —— in the —– contains over 50% of NE neurons in the brain and provides innervation to the —–

A

locus ceruleus, pons, cortex

95
Q

NE signaling contributes to the —– cycle, —-, and —-

A

sleep-wake cycle, attention, anxiety

96
Q

NE modulating drugs are used in the treatment of ——-

A

ADHD (examples include Strattera)

97
Q

NE acting on beta receptors in the —– increases memory for —-

A

amygdala, negative emotion

98
Q

——– is the rate limiting enzyme for NE. Additionally it is inhibited by —–. ——- is a required cofactor for the rate limiting enzyme

A

tyrosine hydroxylase, catecholamines (negative feedback), tetrahydrobiopterin

99
Q

catecholamines are degraded by —– or ——. ——- is mostly in noradrenergic neurons and metabolizes —-, —-, —, and —-. —— is mostly in serotonergic and histaminergic neurons and metabolizes —-. —- inhibitors inhibit the breakdown of —– and are used as antidepressants

A

MAO or catechol-o-methyltransferase (COMT), MAOa, 5HT, NE, EPI, DA, MAOb, DA, MAOIs, catecholamines

100
Q

—— pumps NE, DA, 5HT into vesicles. It is inhibited by —- and —–.

A

Vesicular monoamine transporter (VMAT), respirine, tetrabenazine

101
Q

Catecholamine regulation occurs by

A

diffusion away from synapses, metabolic transformation (MAO and COMT), and reuptake into nerve terminals by catecholamine transporters

102
Q

describe the pharmacology of cocaine

A

inhibits reuptake of NE, EPI, and DA by blocking NET/DAT

103
Q

describe the pharmacology of methylphenidate (Ritalin)

A

blocks NET/DAT, probably does not lead to increased NET/DA release

104
Q

describe amphetamine pharmacology

A

inhibits reuptake of NE/DA via competition (less NE/DA is taken up), depletes NE/DA from vesicles via disruption of proton gradient, stimulates efflux of NE/DA through phosphorylation of NET/DAT, weak MAO inhibitor

105
Q

Describe g protein coupling with adrenergic receptors and its effects

A

Alpha 1 - Gq- increased PLC, increased calcium

Alpha 2- GoGI - decreased calcium channels, decreased adenyl cyclase, increased potassium channel

Beta 1,2,3 - Gs - increased AC, increased ca channels

Neuropharmacology (2 decks)

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