Exam 2 Flashcards
(105 cards)
1
Q
Name the ionotropic glutamate receptors
A
NMDA, AMPA, and Kainate
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
3
Q
NMDA receptors are permeable to what cations?
A
Na+, K+, Ca++
4
Q
NMDA receptors are activated by —– and co activated by ——–
A
glutamate & NMDA, glycine
5
Q
Antagonists of NMDA receptors include:
A
PCP, Ketamine, dextromethorphan (cough) memantine (alzeheimers), riluzole (ALS), ifenprodil
6
Q
NMDA receptors are blocked by —— which means it requires —– to unblock
A
Mg++, depolarization
7
Q
—– are positive allosteric modulators for NMDA receptors
A
polyamines
8
Q
AMPA/Kainate receptors are permeable to what cations?
A
Na+, and K+
9
Q
AMPA/Kainate receptors have what effect on neurons?
A
excitatory, depolarizing effect
10
Q
AMPA agonists by affinity
A
AMPA > glutamate > kainate
11
Q
Kainate agonists by affinity
A
Kainate > glutamate > AMPA. also domoate
12
Q
Name some AMPA/Kainate antagonists
A
antiepileptics
13
Q
LTP is known to ultimately lead to insertion of more —- channels in post synaptic membranes
A
AMPA
14
Q
Presynaptic mGluRs act as —— autoreceptors (mGluR–/—) by reducing ——-
A
inhibitory, II/III, ca++ influx
15
Q
Postsynaptic mGluRs (mGluR—-) modulate a variety of ligand and voltage gated ion channels
A
I
16
Q
Describe Group 1 of metabotropic glutamate receptors
A
excitatory, Gq coupled , activates PLC which activates ion channels increase NMDA, mostly postsynaptic
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
18
Q
Describe Group III of glutamate receptors
A
inhibitory, Gi/Go coupled, reduces cAMP, decrease neurotransmitter release, decrease NMDA, mostly presynaptic
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
20
Q
GABA receptors are targeted to treat
A
Fear, anxiety, epilepsy
21
Q
Antiepileptics inhibits
A
GABA-T
22
Q
—– and —– are ligand gated ion channels as GABA receptors
A
GABA A and GABA C
23
Q
—-is a G protein coupled receptor for GABA
A
GABA B
24
Q
GABA A and GABA C are —- and —- selective
A
Cl-, HCO3-
25
GABA A and GABA C are ----- and have ----- effect on neurons due to ------ entering the cell
inhibitory, hyper polarizing, Cl-
26
Positive allosteric modulators do what?
increase the effect of a given neurotransmitter
27
Describe GABA A pharmacology by name agonists, antagonists, positive allosteric modulators, and negative allosteric modulators
Agonists: GABA, muscimol
Positive allosteric modulators: benzodiazepines, non-benzos that bind to benzo site, barbiturates , anesthetics, ethanol
Negative allosteric modulators: flumezanil
28
Describe how alpha subunits of GABA have specific benzodiazepine mediated effects
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
29
Name high affinity and low affinity GABA transporters
High affinity: GAT-1 GAT-2 GAT-3
Low affinity: BGT-1
30
Describe the synaptic function of GABA B receptors
-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
31
Describe the pharmacology of glycine receptors
-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
32
Describe the nature of epilepsy
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
33
Seizures are associated with
episodic high-frequency discharge of impulses by a group of neurons in the brain
34
What determines the symptoms that are produced by seizures?
the site of primary discharge and extent of its spread
35
Describe epileptogenesis
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.
36
Describe the mechanism of action of anti epileptic drugs
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
37
Name the 3 major dopaminergic projections in the CNS
mesostriatal, ventral tegmental area, arcuate nucleus
38
Nucleus accumbens dopamine is increased by..
heroin, nicotine, alcohol intake
39
Output neurons from the nucleus accumbens are...
GABAergic
40
Rewarding inputs ..... the activity of output neurons from the nucleus accumbens
inhibit
41
opioid receptors or dopamine receptors on nucleus accumbens neurons are
inhibitory
42
Stimulants increase --- input from ---- onto ---- neurons
dopamine, VTA, NAc
43
Opioids---- NAc neurons directly but also inhibit ----- which ---- VTA DA neurons
inhibit, GABAergic VTA interneurons, dis-inhibits
44
Nicotine ---- opioidergic and DA VTA neurons
activates
45
Cannabinoids ---- glutamatergic input into the NAc
inhibit
46
what is pharmacodynamic tolerance?
compensatory change of receptor number or sensitivity
47
what is pharmacokinetic tolerance?
increased metabolism due to enzyme induction
48
what is behavioral tolerance?
adjustment of behavior to compensate for adverse effects (ex broad based gait to walking near wall in alcohol dependent individuals)
49
what is cross tolerance?
physiologic tolerance to others of same drug class or similar action
50
Describe treatments for addiction for stimulants, opiates, ethanol, and nicotine
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
Describe positive, negative, cognitive symptoms of schizophrenia
Positive: hallucinations, delusions
Negative: flattened affect, apathy, avolition, anhedonia
Cognitive: thought disorder, loose association, incoherence, sensorimotor gating deficits
52
Describe the pathophysiology of schizophrenia
thought to involve DA and glutamate signaling pathways (due to psychotic effects produced by NMDA antagonists)
53
the clinical potency of an antipsychotic drug is strongly correlated with...
its ability to bind to D2 receptors
54
What is a 2nd generation antipsychotic?
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
What are extra-pyramidal side effects?
results from activities of drugs on the extra-pyramidal system (regions outside of the pyramidal system that participate in movement)
56
Name some extra-pyramidal side effects
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
Basal ganglia function is
stratal (extrapyramidal) circuits involved in preparation and initiation of movement, production of motor patterns skills habits
58
Parkinsons disease is a result of a loss of
dopamine neurons in the substantia nigra
59
describe the treatment of Parkinson's
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
name some complications of chronic L-dopa therapy
L-Dopa has a short hand life, motor fluctuations, non-motor complications, neuropsychiatric complications
61
serotonin is synthesized from ----- by ----------
tryptophan, tryptophan hydroxylase
62
5-HT neurons are confined to ---- nuclei
raphe nuclei
63
Describe the types raphe nuclei and what they innervate
caudal raphe: innervates medulla and spinal cord
dorsal raphe: innervates cortex, thalamus, striatum, and midbrain
median raphe: innervates hippocampus, septum, and limbic structures
64
Serotonin participates in what biological functions?
sleep, arousal, attention, sensory processing, emotion, appetite and mood
65
5HT3 is the only ---- channel while all others are -----
ion, G protein coupled
66
MDMA has psychostimulant properties and mood enhancing and psychedelic properties through increasing release of
DA, NE 5-HT
67
Name the different antidepressant classes
Serotonin-selective reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, psychostimulants
68
describe the pharmacology of SSRIs
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
describe the pharmacology of tricyclic antidepressants
block both SERT and NET, significant side effects, fatal in overdose
70
describe the pharmacology of SNRIs
venlafaxine is like TCA without the side effects, duloxetine target population of depression and pain
71
Describe the pharmacology of bupropion
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
Describe different cholinesterase inhibitors
reversible: (physostigmine, neostigmine) used for glaucoma, myasthenia gravis, bladder dysfunction
irreversible: organophosphates , pesticides, nerve gases
centrally acting: tacrine, donepezil (used for alzeheimers)
73
describe toxin acting at cholinergic synapses
botulinum toxin and tetanus toxin prevent release of ACh vesicles
alpha-latrotoxin stimulates ACh vesicle release
74
Name and describe the 3 sites of cholinergic neurotransmission (CNS)
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
What is Myasthenia Gravis? How is it treated?
autoimmune disorder where immune system attacks nicotinic receptors at NMJ
Typically treated with cholinesterase inhibitors or drugs that suppress the immune system
76
Describe muscarinic acetylcholine receptors
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
Describe M2 receptors
Ones found in the heart are activated by acetylcholine from vagus nerve leading to opening of GIRKs which slows down heart rate
78
Describe effects of anticholinergic drugs
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
Describe some aspects of Alzheimers
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
Briefly describe the pathophysiology of Alzheimers
discovered based on duplications of region that codes for amyloid precursor protein (APP) and APP is increased in these families
81
Describe APP. What does it do? how is it metabolized?
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
Describe ABeta aggregates. What are their normal functions? How does aggregates effect the body?
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
Describe alzheimers pathophysiology of Tau. What does it normally do? How can it become bothersome?
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
Describe pathophysiology of ApoE. What does it normally do? How can it become bothersome?
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
Describe treatments of AD
Currently AchE inhibitors which can be effective for symptoms but not for disease modification. Most strategies focus on ABeta.
86
Broadly describe cannabinoid receptors
GPCRs. CB1 are expressed in the brain while CB2 receptors are expressed in immune cells.
87
Describe CB1 receptor ligands
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
How does cannabinoids play a role in feeding and emesis?
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
How do endocannabinoids play a role in pain management?
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
Describe purinergic signaling
signaling molecules are nucleotide/nucleoside derivatives of AGUTC.
91
How is purinergic signaling ubiquitous?
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
Describe nitric oxide signaling
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
Norepinephrine is produced by neurons in the ---- and ------
pons and medulla
94
The ------ in the ----- contains over 50% of NE neurons in the brain and provides innervation to the -----
locus ceruleus, pons, cortex
95
NE signaling contributes to the ----- cycle, ----, and ----
sleep-wake cycle, attention, anxiety
96
NE modulating drugs are used in the treatment of -------
ADHD (examples include Strattera)
97
NE acting on beta receptors in the ----- increases memory for ----
amygdala, negative emotion
98
-------- is the rate limiting enzyme for NE. Additionally it is inhibited by -----. ------- is a required cofactor for the rate limiting enzyme
tyrosine hydroxylase, catecholamines (negative feedback), tetrahydrobiopterin
99
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
MAO or catechol-o-methyltransferase (COMT), MAOa, 5HT, NE, EPI, DA, MAOb, DA, MAOIs, catecholamines
100
------ pumps NE, DA, 5HT into vesicles. It is inhibited by ---- and -----.
Vesicular monoamine transporter (VMAT), respirine, tetrabenazine
101
Catecholamine regulation occurs by
diffusion away from synapses, metabolic transformation (MAO and COMT), and reuptake into nerve terminals by catecholamine transporters
102
describe the pharmacology of cocaine
inhibits reuptake of NE, EPI, and DA by blocking NET/DAT
103
describe the pharmacology of methylphenidate (Ritalin)
blocks NET/DAT, probably does not lead to increased NET/DA release
104
describe amphetamine pharmacology
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
Describe g protein coupling with adrenergic receptors and its effects
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
