Midterm 2 Flashcards

(140 cards)

1
Q

what are the indolamines?

A

serotonin, melatonin

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2
Q

what enzyme converts DOPA to dopamine?

A

aromatic amino acid decarboxylase

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3
Q

what enzyme converts dopamine to norepinephrine?

A

dopamine beta-hydroxylase

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4
Q

tyrosine hydroxylase activity is regulated by:

A
  • high catecholamine levels (negative feedback)

- increased cell firing rate stimulates TH (increased synthesis of catecholamines)

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5
Q

what is a monoamine-specific transporter involved in vesicle packaging?

A

vesicular monoamine transporter (VMAT)

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6
Q

what drug blocks vesicular monoamine transporters?

A

Reserpine

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7
Q

what drugs induce synaptic vesicle release without cell firing?

A

amphetamine and methamphetamine (causes release of DA)

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8
Q

mesostriatal (nigrostriatal) pathway

A

from substantia nigra (A9) to striatum (caudate and putamen), facilitates voluntary movement

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9
Q

mesolimbocortical

A

from ventral tegmental area (A10) to limbic system and prefrontal cortex, reward pathway, implicated in schizophrenia

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10
Q

what are 3 brain regions where norepinephrine is produced?

A

locus coeruleus (pons) (A6), lateral tegmental area, dorsal medullary group

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11
Q

where does norepinephrine neurons project to?

A

forebrain, cerebellum, spinal cord, made in the vesicle

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12
Q

what are locus coeruleus (LC) connections to medial septum and medial preoptic areas involved in?

A

wake

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13
Q

what are LC connections to PFC involved in?

A

attention and working memory

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14
Q

what are the dopamine receptor subtypes?

A

ALL METABOTROPIC

  • D1-like (stimulate adenylyl cyclase and synthesis of cAMP): D1 and D5
  • D2-like (inhibit adenylyl cyclase and cAMP): D2, D3, D4
  • autoreceptor = D2 (activate a G protein that enhances potassium channel opening - GIRK)
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15
Q

DA transporter KO

A

extremely hyperactive, do not respond to psychostimulants

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16
Q

D1 receptor KO

A

deficits in several cognitive tasks

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17
Q

D2 receptor KO

A

impairment in spontaneous movement, coordination, and posture control

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18
Q

D1/D2 double KO

A

fatality during 2nd or 3rd week of life

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19
Q

NE adrenergic receptor

A
ALL METABOTROPIC
2 types:
-alpha 1: phosphoinsotide
-alpha 2: reduce synthesis of cAMP = Gi
-beta 1 and beta 2: stimulate adenylyl cyclase and enhance synthesis of cAMP, G2
-autoreceptor = alpha 2
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20
Q

agonists of alpha 2 receptors in PFC:

A

enhance working memory

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21
Q

agonists of alpha 1 receptors in PFC:

A

deleterious effect on cognitive functions, increased activation with stress to produce cognitive impairment

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22
Q

antagonists of beta-1 receptors (beta blockers)

A

generalized anxiety disorder

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23
Q

what are transporter-blocking drugs of catecholamines?

A
  • tricyclic antidepressants (inhibit uptake of NE and 5-HT)
  • antidepressant reboxetine and ADHD drug atomoxetine block NE transporters
  • cocaine blocks reuptake of all monoamines (DA, NE, 5-HT)
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24
Q

how are catecholamines inactivated?

A

-reuptake by transporters (repackaged into vesicles or broken down)

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25
what breaks down catecholamines for inactivation?
catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO)
26
what is the DA metabolite?
homovanillic acid (HVA)
27
what is the NE metabolite?
3-methoxy-4-hydroxyphenylglycol (MHPG) in brain and vanillymandelic acid (VMA) in PNS
28
MAO inhibitors
treat clinical depression
29
COMT inhibitors
enhance effectiveness of L-DOPA in treating Parkinson's disease by preventing breakdown of DOPA
30
what are some psychomotor stimulants and what are their effects?
cocaine, amphetamine/methamphetamine: -sensorimotor activation - increased alertness - heightened arousal - behavioural excitement
31
what are the different forms of cocaine?
- coca leaves (1% cocaine) - coca paste (60-80% cocaine) - cocaine hydrochloride (cocaine + HCl) (less potent, water soluble, oral/nasal/IV, not heat stable) - freebase/crack cocaine (cocaine + baking soda + water) (soluble in alcohol, can be heated/inhaled)
32
pharmacokinetics of cocaine:
- lipid soluble, easily crosses BBB and distributed, speed of action depends on ROA - ROA: oral, intranasal, inhalation, IV injection - absorption: stomach, mucous membranes, lungs - smoking = fastest initial onset of action
33
cocaine metabolism
half-life of 0.5 to 1.5 hours, metabolite: benzylecgonine (detectable in urine for days)
34
cocaine plus alcohol metabolism
metabolite: cocaethylene (cocaine-like activity, but longer half life and blocks calcium channels in heart)
35
pharmacodynamics of cocaine:
- monoamine reuptake inhibition (DA, NE-lowest affinity, 5-HT-highest affinity) - acts on reuptake transporter proteins - increased/prolonged post-synaptic effects
36
other cocaine uses:
- local anesthetics (lidocaine/xylocaine, procaine/novocain) - sympathomimetic (sympathetic nervous system activation) - inhibits voltage gated sodium channels in axon at high concentrations
37
what does the intensity of a cocaine "high" depend on?
- amount of DAT occupancy - rate of DAT occupancy (depends on ROA, smoking/IV = rapid) - baseline DA activity in mesolimbic pathway (amount of DA in synapse available for release)
38
dopamine receptors involved in cocaine effect:
D1: locmotor-stimulating effects, role in reinforcement (KO DOES NOT self-administer cocaine) D3: rewarding/reinforcing effects (antagonist blocks rewarding effects) D2: not involved in postsynaptic cocaine effect
39
incubation of cocaine craving
craving and relapse increase over time following withdrawal
40
brain activity of dependent users when presented with cocaine-related stimuli?
increased DA release in dorsal striatum
41
in the animal model of addiction, what are three traits used to predict transition from self-administration to compulsive use?
- increased locomotor activity (novel/inescapable environment) - preference of novel environment in free-choice environment over safe, known areas - impulsivity measured using 5-choice serial reaction-time visual attention task - DEMONSTRATES SENSATION-SEEKING AND IMPULSIVITY PERSONALITY TRAITS
42
effect of chronic cocaine exposure:
-reduced DA activity in striatum in response to drug challenge (baseline D2 receptor binding is reduced, methylphenidate had greater effect=less responsive to DA reuptake blocking, contributes to behavioural tolerance
43
what are some drugs with potential for stopping cocaine abuse:
- modafinil (used for narcolepsy and sleep apnea, effects DA/NE/Glu/GABA) - disulfiram/antabuse (treatment of alcohol abuse) - cocaine vaccines (antibodies bind cocaine or catalytic activity breaks down cocaine)
44
contingency management program
- views drug taking as an operant response to the reinforcing properties of the drug - reduce drug use by providing alternative reinforcers - community reinforcers enhance social relationships, job opportunities, etc.
45
amphetamine is a synthetic psychostimulant, what are 2 plant compounds from which it is synthesized?
- cathinone | - ephedrine
46
routes of administration for amphetamine:
oral, IV, SC injection
47
routes of administration for methamphetamine:
oral, snorted, IV, smoked
48
methamphetamine hydrochloride
crystalline form suitable for smoking
49
"speedball"
IV amphetamine or methamphetamine combined with heroine
50
what are the mechanisms of action of amphetamine/methamphetamine?
indirect agonists of catecholaminergic systems: 1) enter DA nerve terminals via uptake by DAT and cause vesicles to release DA 2) DA transported out of cell by reversal of DAT
51
therapeutic uses of amphetamines:
- narcolepsy - ADHD (helps readjust NE and DA levels, usually lower levels in PFC) - obesity
52
ADHD
- symptoms similar to damaged right PFC - pyramidal output neurons innervated by NE (alpha 2A) and DA (D1) - NE activation of alpha 2A increases signal/excitatory effect - DA activation of D1 decreases noise (inhibitory effect)
53
catatonic schizophrenia
alternating periods of immobility and excited agitation
54
paranoid schizophrenia
characteristic delusions of grandeur or persecution
55
disorganized schizophrenia
silly, immature emotions with disorganized behaviour
56
undifferentiated schizophrenia
cases not meeting the criteria of other subtypes of schizophrenia
57
altered connectivity in schizophrenia:
- increased DA synthesis and release - NMDA receptor hypofunction (GABAergic interneurons NMDA are functionally impaired, reduced GABA release onto pyramidal neurons, disinhibition = increased Glu release)
58
DA hypothesis of schizophrenia
excess DA function results in positive symptoms of schizophrenia (correlation between D2 receptor blockade and reduced symptoms)
59
DA imbalance in schizophrenia suggests symptoms are due to:
- reduced DA in mesocortical neurons (negative symptoms and impaired thinking) - excess DA in mesolimbic neurons (positive symptoms)
60
glutamate-DA interaction in schizophrenia:
inadequate glutamate causes: - increase in mesolimbic DA (normal: excite inhibitory GABA which functions to inhibit DA mesolimbic pathway) - decrease in PFC DA (normal: excite mesocortical DA neurons at NMDA receptors)
61
what are 3 classic antipsychotics/neuroleptics?
phenothizaines, butyrophenones, haloperidol | block D2 postsynaptic receptors and autoreceptors in basal ganglia, amygdala, NAcc, HPC, cerebral cortex
62
what are 4 DA pathways for drug action for treating schizophrenia?
1) mesolimbic (affects positive symptoms) 2) mesocortical (alleviates cognitive and negative symptoms) 3) nigrostriatal (produces motor side effects that resemble symptoms of PD) 4) tuberohypophyseal (regulates pituitary hormone secretion, produces neuroendocrine side effects)
63
atypical/2nd generation antipsychotics
reduce positive symptoms and produce fewer side effects e.g. DA stabilizers that are partial agonists and reduce DA effect
64
tardive dyskinesia
stereotyped involuntary movements, particularly of face/jaw, quick and uncontrolled movements of arms/legs, other motor effects, side effect of neuropsychotics/neuroleptics
65
broad-spectrum antipsychotics
(atypical/2nd generation antipsychotics): block D2 receptors and others, ex. clozapine has strong affinity for 5-HT, muscarinic, histaminergic, D4, weak affinity for D2
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akinesia
movement initiation problems
67
bradykinesia
slowing of movement
68
Parkinson's disease dementia (PDD)
frequently comorbid with Alzheimer's disease (AD) or Lewy body dementia (LBD), share symptoms but occur in different order
69
stages of Parkinson Disease:
1) degeneration in dorsal motor nucleus of the vagus and anterior olfactory structures (lose sense of smell) 2) raphe and locus coeruleus 3) substantia nigra, amygdala, nucleus basalis (motor symptoms begin) 4) degeneration of temporal lobe mesocortex 5) degeneration of the neocortex in temporal lobe, neocortex sensory association and premotor areas 6) degeneration of neocortex areas of primary sensory function and motor areas
70
what is the effect of increased excitation to subthalamic nucleus and internal globus pallidus in PD?
excitation of inhibitory neurons = inhibition of thalamus and motor structures in cortex = hard to initiate movements - less activation of D1 to caudate/putamen = less inhibition of globus pallidus int. seg., increased inhibition of thalamus - less inhibition of D2 to caudate/putamen = increased inhibition of globus pallidus ext. seg., decreased inhibition of subthalamic nucleus, increased activation of globus pallidus int. seg. increased inhibition of Va/VL part of thlamus - overall effect of decreasing activation of thalamus to cortex
71
protein aggregation in PD degneration
Lewy bodies (alpha-synuclein): formed by protein misfolding and proteosomal dysfunction, interrupt cell function and trigger apoptosis
72
MPTP (DA neurotoxin) (animal models of PD)
oxidation product MPP+ damages cells, formed by MAO-B in astrocytes and 5-HT neurons, transported by DA transporter into substantia nigra cells, MPP+ accumulates in mitochondria, blocks respiration, leads to cell death
73
rotenone (pesticide) (animal models of PD)
similar pathology to PD, acts by blocking complex I in respiratory chain to produce mitochondrial dysfunction
74
amantadine (symmetrel)
treatment for PD: NMDA receptor antagonist, monotherapy or decrease dyskinesias related to L-DOPA
75
serotonin synthesis
synthesized from tryptophan - tryptophan to 5-hydroxytryptophan by tryptophan hydroxylase - t-hydroxytryptophan to serotonin by aromatic L-amino acid decarboxylase
76
how to increase ratio of tryptophan in meals:
low protein, high carb meal. more likely to cross BBB, more 5-HT made
77
serotonin reuptake
5-HT transporter (SERT) - transports in either direction based on concentration gradient, blocked by SSRIs (prozac) and cocaine, MDMA (non-selective, also affects DA transporters)
78
breakdown of 5-HT by MAO produces:
5-hydroxyindol acetyladlehyde which is oxidized to 5-hydroxyindoleacetic acid (5-HIAA, measure of serotonin neuronal activity) or reduced to 5-hydroxytryptophol
79
serotonergic projections:
median raphe nuclei: limbic | dorsal median raphe: striatum, cerebral and cerebellar cortices, thalamus
80
2 morphologically distinct types of serotonergic axon terminals:
- fine axons with small varicosities (originate from dorsal raphe nuclei, sensitive to neurotoxic effects) - beaded axons with large spherical varicosities (originate from median raphe nuclei, resistant to neurotoxic effects)
81
negative feedback mechanism for serotonin:
serotonin released from dendrites or axon collaterals inhibits activity by somatodendritic autoreceptors
82
serotonin receptors:
5-HT 1: inhibitory 5-HT 2: excitatory 5-HT 3: ionotropic -modern: 7 families, mostly metabotropic
83
5-HT1 receptor family
coupled to second messengers via g-proteins (Gi/o), inhibit adenylyl cyclase/cAMP formation, increase opening of potassium channels, may lead to hyperpolarization and inhibition of firing
84
5-HT1P
gut
85
5-HT1S
spinal cord
86
agonists for 5-HT1A receptors
buspirone, ipsapirone, 8-OH-DPAT
87
antagonists for 5-HT1A receptors
WAY100635, WAY100135
88
mixed agonists/antagonists for 5-HT1A receptors
BMY7378, NAN-190
89
5-HT1B/1D receptors
high density receptor-binding regions: basal ganglia and raphe nuclei, agonists: triptans (sumatriptan/zolmitriptan)
90
5-HT2 receptor family
coupled to second messengers via g-proteins (Gq/11) - activation of phospholipase C, increase phosphoinositol hydrolysis, increase cytosolic calcium, inhibition of cAMP production - may also couple to G12/13 to mediate long term structural changes - 5-HT2A, 2B, 2C
91
5-HT2A receptors
- expressed in pyramidal cells and interneurons in the cortex - activation by LSD, psyocibin, and other psychedelics cause hallucinations and eventually psychosis - antagonists: clozapine, risperidone
92
5-HT2C
high density regions: limbic structures, basal ganglia, depolarization via opening of calcium channels
93
5-HT3 receptor family
ligand-gated ion channel - pentamer with 5 subunits surrounding a central channel (4 transmembrane segments and a large extracellular N-terminal region) - rapid depolarization due to opening of non-selective cation channels (sodium and calcium influx, potassium efflux)
94
5-HT4, 6, 7 receptors
all coupled preferentially to Gs | -promote cAMP formation by activation of various adenylyl cyclases, cAMP interacts with several targets
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pathways of 5-HT4
septo-hippocamp-habenulo-penduncular and striato-nigro-tectal pathway
96
5-HT6
cortex, limbic structures, striatum
97
5-HT7
thalamic, cortical and limbic regions
98
LSD effect on 5-HT neurons
blocks/inhibits firing, reduced 5-HT release from nerve terminals (partial agonist at receptor)
99
serotonin reuptake is inhibited by:
tricyclic antidepressants and SSRI
100
metabolis of serotonin is inhibited by:
monoamine oxidase inhibitors
101
anxiolytics target:
serotonin 1A
102
monoamine hypothesis of depression:
- reserpine induces depression as side effect (reduces levels of DA, NE, 5-HT) - MAOIs and TCAs increase NE and 5-HT and reverse reserpine-induced reduction in motor activitiy - depressed patients have low blood levels of tryptophan - decreased 5-HT turnover in depression (post-mortem)
103
tianeptine
selective serotonin reuptake enhance, an antidepressant, disproves the monoamine hypothesis
104
glucocorticoid hypothesis of depression
- depressed patients fail to respond to dexamethasone (synthetic glucocorticoid), no negative feedback in HPA axis - stress-related neuroendocrine abnormalities - prolonged/intense stress
105
neurotrophic hypothesis of depression
- low BDNF may cause loss of dendritic branches and decreased neurogenesis in HPC - stress, increased glucocorticoids decreases BDNF, causes atrophy and decreased cell survival - stress leads to methylation of BDNF genes, reducing expression (epigenetics)
106
what is the active agent in "magic mushrooms?" (psilocybin)
psilocin
107
what are the 5 dimensions of the altered states of consciousness (ASC) rating scale?
1) oceanic boundlessness 2) ego-disintegration anxiety 3) visionary restructuralization 4) reduced vigilance 5) auditory alterations
108
which serotonin subtypes play a role in producing hallucinations?
5-HT2A and 5-HT2C (phenethylamines bind to some receptors)
109
what are the mechanisms of action of indolamine and phenethylamine hallucinogens?
increased excitation of prefrontal cortical pyramidal neurons 1) activation of 5-HT2A receptors enhances Glu-excitation of pyramidal neurons in layer V of prefrontal cortex (glu release from thalamocortical afferents interferes with thalamic filtering of sensory info, resulting in overload at cortical level) 2) pyramidal cells in cortical layer V directly stimulated by activation of 5-HT2A receptors and secondarily stimulated by Glu released from other pyramidal cells in deep cortical layers that project to layer V (disrupts normal functioning of glutamatergic networks in PFC)
110
phencyclidine (PCP)
hallucinogen, termed dissociative anesthetics
111
ketamine
developed as safer alternative to PCP, less potent, shorter-acting, anesthetic for certain procedures
112
pharmacodynamics of PCP/ketamine
noncompetitive antagonists at NMDA receptors, binding site inside ion channel which produces cognitive deficits, may increase presynaptic Glu release in cortex
113
neurobiology of anxiety
PFC and anterior cingulate cortex exert inhibitory control over the primitive responses of subcortical regions. anxiety disorders are often considered to arise from an imbalance between emotion generating centres and higher cortical control
114
what is the neurotransmitter involved in anxiety?
- increased CRF (corticotropin-releasing factor) causes increased anxiety on behavioural tasks - increased norepinephrine from LC - decreased GABA A receptor barbiturate/benzodiazepine binding sites = increased anxiety - serotonin (varies depending on receptor subtype, acute vs. chronic treatment, brain region) - anxiety=increased firing of mesocortical DA neurons and increased DA turnover in PFC
115
obsessive-compulsive disorder neurobiology
involves a neural loop connecting basal ganglia with frontal lobe, thalamus, anterior cingulate. abnormal cell activity in basal ganglia and frontal lobes correlates with severity of symptoms, SSRIs effective because enhance 5-HT release which inhibits caudate (basal ganglia)
116
barbiturates
- anxiolytic - increase affinity of GABA A receptor for GABA - can open chloride channel without GABA
117
benzodiazepines
- anxiolytic | - enhance inhibitory GABA activity (increased chloride influx, requires GABA being present=safer than barbiturates)
118
buspirone (BuSpar)
- 2nd generation anxiolytic | - less effective in reducing physical symptoms than cognitive aspects of worry and poor concentration
119
tricyclic antidepressants, MAOIs, SSRIs
can reduce anxiety accompanying depression, SSRIs are first choice
120
glutamate is synthesized from glutamine by...
glutaminase (requires ATP)
121
what are the 3 vesicular glutamate transporters that move Glu into vesicles?
VGLUT1, VGLUT2, VGLUT3 (only found in glutamatergic neurons)
122
VLUGT2 KO mice
die immediately after birth
123
VGLUT1 KO mice
survive birth, but begin to die during the 3rd week of life
124
VGLUT3 KO mice
viable, completely death (inner hair cells of the cochlea require glutamate as a neurotransmitter)
125
which vesicle glutamate transporter is also involved in co-expression with other neurotransmitters?
VGLUT3 (VGLUT1 and 2 to a lesser extent)
126
what transporters remove glutamate from the synaptic cleft?
excitatory amino acid transporters (EAAT1-5) (take up both glutamate and aspartate)
127
EAAT2 KO mice
develop spontaneous epileptic seizures, shortened life span
128
role of glia in glutamate:
- astrocyte transporter takes up glutamate (EAAT1/EAAT2) - astrocytes convert glutamate into glutamine by glutamine synthetase - glutamine transported back into neurons for re-use
129
glutamate receptors
ionotropic (fast signalling) and metabotropic (2nd messengers; slower signalling)
130
Ionotropic Glutamate receptors
depolarize postsynaptic cell membranes, named after selective agonists 1) AMPA: sodium influx depolarizes 2) Kainate: sodium influx depolarizes 3) NMDA (sodium and calcium influx, calcium also activates second messenger)
131
NBQX
Glutamate antagonist that blocks AMPA and kainate receptors but not NMDA (produces sedation, reduced locomotor activity, and protection against seizures)
132
NMDA receptor
- opening of sodium/calcium channels requires glutamate and a co-agonist (glycine or d-serine) - at resting potential, magnesium ions bound to a site in the channel and blocks it, dissociates when membrane depolarizes
133
metabotropic glutamate receptors
mGluR1 to mGluR8 - G-protein coupled (some inhibit cAMP, some activate phosphoinositide second messenger system) - some on terminals act as presynaptic autoreceptors that inhibit Glu release
134
L-AP4
selective agonist at metabotropic glutamate receptors, suppresses synaptic transmission
135
which glutamate receptors are implicated in learning and memory?
AMPA and NMDA (ampakines enhance AMPA receptor action by reducing rate of desensitization, enhances cognitive function in animal models)
136
NMDA receptor antagonists lead to:
impaired spatial learning (hippocampus has high density of NMDA receptors)
137
which receptors play a key role in LTP (long term potentiation?)
NMDA receptors (for glutamate), persistent increase in synaptic strength produced by bursts of activity in presynaptic neuron)
138
how does LTP work in the glutamate system?
- single stimulation releases Glu which binds to AMPA and NMDA (NMDA still blocked by Mg) - tetanic stimulation leads to greater depolarization and opening of NMDA channels (Mg dissociates) - influx of calcium ions through NDMA activates several protein kinases (including calcium/calmodulin CaMKII) - phosphorylates existing AMPA receptors (enhances their sensitivity to Glu) - more AMPA receptors inserted into postsynaptic membrane
139
excitotoxicity in ischemia
massive release of glutamate in affected area, treatment with NMDA antagonists can reduce cell loss
140
glutamate theory in schizophrenia
abnoramlly high Glu release, agonists at mGluR2 inhibit Glu release in experimental animals