General Flashcards
(95 cards)
1
Q
What are examples of negative symptoms in schiz?
A
- Anhedonia
- Emotion flattening
- Avolition
- Social withdrawal
2
Q
What are examples of positive symptoms in schiz?
A
- Delusions
- hallucinations
- thought disorder
- disorganized/abnormal behavior
3
Q
What are examples of cognitive dysfunction in schizophrenia?
A
- memory impairment
- attention deficits
- executive function problems
- working memory deficits
4
Q
Primary neurotransmitter system targeted by TASP?
A
The glutamatergic system, particularly through GlyT1 inhibition to enhance NMDA R function.
5
Q
Role of glycine in NMDA R function?
A
- Co agonist at NMDA receptors, facilitating their activation.
6
Q
What is the rationale for using GlyT1 inhibitors over direct glycine agonists in treating schiz?
A
GlyT1 inhibitors increase glycine levels only in regions with active glutamate release,
- reducing the risk of overstimulation and excitotoxicity, and adverse side effects.
7
Q
What cognitive test was used in the study to assess the effects of TASP0315003 on cognitive deficits?
A
Object recognition test.
8
Q
What does the social recognition test measure in animal models of schizophrenia?
A
Ability to remember and recognize a previously encountered conspecific.
9
Q
What was the effect of TASP0315003 on MK-801-induced cognitive deficits in the study?
A
TASP significantly improved social memory in MK-801-treated rats, but did not restore it to normal levels.
10
Q
What are the observed side effects of TASP0315003 in the study?
A
TASP DID NOT cause motor dysfunction, sedation, catalepsy, and also did show potential antidepressant effects.
11
Q
the significance of motor dysfunction in antipsychotic treatments?
A
- Motor dysfunction i.e. extrapyramidal symptoms are common side effects in traditional antipsychotics.
- less likely with TASP.
12
Q
How did TASP0315003 affect social interaction in PCP-treated mice?
A
TASP significantly reversed social deficits
- without affecting baseline social behaviour
- no sign of tolerance with repeated treatment.
13
Q
What was the antidepressant effect observed in the forced swimming test with TASP0315003?
A
TASP significantly reduced immobility time, suggesting an antidepressant effect.
14
Q
How does the PCP model of schizophrenia differ from the MK-801 model?
A
- PCP model used to induce negative symptoms like social withdrawal
- MK-801 model primarily used to study cognitive deficits.
15
Q
A limitation of the animal models used in the TASP0315003 study?
A
- Models may have limited predictive validity for human schizophrenia,
particularly for negative + cognitive symptoms
16
Q
Which neurotransmitter system is involved in both the positive and negative symptoms of schizophrenia?
A
- Dopaminergic system primarily linked with positive symptoms
- glutamate system ( NMDA R hypofunction) associated with negative + cognitive symptoms
17
Q
What findings suggest that TASP0315003 could be a promising treatment for schizophrenia?
A
- TASP improves cognitive deficits, enhances social memory, reduces social withdrawal in animal models,
- shows antidepressant effect, without causing significant motor side effects.
18
Q
What cognitive domain did TASP0315003 most significantly improve in the study?
A
Social memory.
19
Q
How did the study confirm the mechanism of action of TASP0315003 on GlyT1?
A
By measuring increased glycine conc. in CSF of rats after administration of TASP.
20
Q
Which animal tests were used to assess motor side effects in the study?
A
- Rotarod performance test
- Spontaneous locomotor activity test
21
Q
The implications of TASP0315003 showing no significant effect on rotarod performance?
A
Suggests TASP does not impair motor coordination, common side effect of many antipsychotics.
22
Q
What effect did TASP0315003 have on spontaneous locomotor activity in rats and mice?
A
TASP did NOT significantly affect spontaneous locomotor activity
- indicating no sedative or stimulant effects.
23
Q
What is the significance of TASP0315003 not inducing catalepsy in rats?
A
Indicates TASP is less likely to cause extrapyramidal symptoms
- (common antipsychotic symptoms)
24
Q
How does TASP0315003 compare to traditional antipsychotics in terms of side effects?
A
- TASP has fewer CNS side effects, i.e. motor dysfunction + sedation
25
Which receptor is indirectly modulated by TASP0315003 to improve schizophrenia symptoms?
NMDA R - through increased glycine availability.
26
What did the study use as a measure of cognitive improvement in social recognition?
Reduction in invesigation duration ratio (RID) during social recognition test.
27
Why are GlyT1 inhibitors considered a novel approach in the treatment of schizophrenia?
- They target cognitive dysfunction + negative symptoms, poorly managed by current antipsychotics.
28
Why was the forced swimming test included in the study?
To test potential antidepressant effects of TASP
29
What did the study reveal about the effects of TASP0315003 on memory?
- improved both object recognition + social recognition memory in animal models.
30
Which symptom of schizophrenia is most directly addressed by TASP0315003 according to the study?
Cognitive dysfunction, particularly memory impairments.
31
What pharmacokinetic property of TASP0315003 supports its use in treating central nervous system disorders?
Ability to cross the blood-brain barrier effectively.
- with a brain-to-plasma (B/P) ratio of 0.523
32
How does TASP0315003 affect neurotransmitter systems other than the glutamatergic system?
- Minimal effects on others, making it a targeted treatment with potentially fewer side effects.
33
What were the rotarod and locomotor activity tests used to assess?
Rotarod: Motor function
Locomotor: spontaneous activity
-> to determine if TASP caused any motor dysfunction or sedation.
34
What methodological steps were taken in social recognition test?
- Both time-dependent memory test + control condition with unfamiliar rat presented during second test.
- To ensure TASP effects were due to enhanced social memory, not just increased general exploration.
35
Role of MK-801 in the study?
- NMDA receptor antagonist
- induces cognitive deficits + social recognition impairments in rats
- mimicks NMDA R hypofunction seen in schiz
- allows for evaluation of TASP reversing these effects
36
Statistical tests in novel object + social recognition tests:
- one way + two way ANOVA to assess differences in exploratory preferences + social memory ratios across groups.
- Post-hoc tests ; Dunnett's + Student's t-test applied to compare specific treatment groups to controls
37
How did the combination of TASP0315003 and risperidone enhance social memory?
- Combo of TASP + risperidone potentiated effects of social memory, more than what each drug achieved alone
- Implies combining GlyT1 inhibitors with exisiting antipsychotics could enhance therapeutic outcomes -> particularly negative + cognitive symptoms
38
What are the differing effects of TASP on GlyT1 and GlyT2?
- TASP inhibits GlyT1 with high potency , much weaker inhibition of GlyT2
- Allows for targeted enhancement of NMDA R function without affecting GlyT2, minimzing off-target effects, + side effects related to non-specific glycine transport inhibition.
39
What mechanisms allows TASP to cross blood-brain barrier?
- Small molecular size + lipophilicity
- this facilitates passive diffusion into the CNS
40
How was [³H]strychnine used in the study?
- Radiolabeled ligand in binding assay
- To bind to strychnine-sensitive GlyRs in rat brainstem + spinal cord membranes.
- Found that TASP didnt significantly bind to GlyRs > does not intefer with their inhibitory functions + avoiding side effects e.g. sedation.
41
What was the role of [³H]MDL105,519 in the study?
- Radiolabeled ligand to bind to strychnine-insensitive glycine sites on NMDA Rs.
- Binding assay to determine if TASP had any direct effect on this co-agonist sites
- TASP didnt significantly affect these sites, indicating mechanism of action is through GlyT1 inhibition, not direct modulation of NMDARs.
42
How does TASP exert its effects on NMDAR function without directly binding to receptor's glycine sites?
- Inhibits GlyT1, increasing synaptic glycine levels.
- this enhances NMDAR function, by better saturated glycine co-agonist sites
- Improving cognitive functions related to NMDAR activity.
43
Key findings from binding assays?
- TASP did not significantly bind to GlyRs > avoiding potential inhibitory side effects
- Did not directly affect NMDAR glycine sites, suggesting mechanism of action is primarily through GlyT1 inhibition.
- Can enhance NMDAR in a controlled manner, without significant off-target effects.
44
What are strychnine-sensitive glycine receptors?
- Inhibitory ionotropic receptors
- Mediate glycine, leading to neuronal inhibition
- Used to see if TASP binds to these, would indicate off-target effect.
- Can be blocked by strychnine
45
What are strychnine-insensitive glycine sites?
- Specific co-agonist binding sites on NMDA Rs
- That require co-agonists glycine (or d-serine) to activate receptor alongside glutamate.
- Directly involved in NMDAR activation
- Not blocked by strychnine
46
Purpose of using strychnine-sensitive GlyRs?
- To assess off-target effects
- If TASP had binding affinity to GlyRS, could block them, mimicking strychnine + leading to unwanted side effects, neuronal excitability, muscle spasms, etc.
- TASP did not bind to GlyRs.
- Drug is unlikely to cause dangerous excitatory effects.
47
What is Pre Pulse Inhibition?
- Biomarker/ Measure of sensorimotor gating, where weak pre-stimulus inhibits reaction of subsequent stronger stimulus
- Often impaired in schiz > sensory overload + bad concentration
- Brain unable to filter unnecessary info
48
What is DAAO
- Enzyme that degrades D-serine, reducing the activation of NMDAR > potentially exacerbating schiz symptoms
- Inhibiting DAAO is a strategy for enhancing NMDA R function.
49
What is serine racemase + implication in schiz?
- Enzyme converting L-serine to D-serine
- Decreased serine racemase activity can reduce D-serine levels, contributing to NMDAR hypofunction > possibly linked to schiz pathophysiology
50
Limitations of the study:
- Failure to replicate efficacy of GlyT1 inhibitors in clinical settings, despite promising preclinical results.
(bitoperbin/Org25935)
- Exact neural mechanisms not fully understood; need more detailed mechanistic studies
- Some very weak activity at 5-HT1A receptor and the serotonin transporter > does introduce a confounding factor, can't completely rule out off-target effects.
51
What was the primary method used to measure cognitive enhancement in the study?
Behavioural tests
52
Effect of TASP on MK-801-induced cognitive deficits in the object recognition test?
Significantly improved effects
(but not completely reversed)
53
What mice did the study primarily use in behavioural tests?
ICR mice
54
Social recognition findings of TASP on MK-801 & PCP?
- Significantly improved social deficits induced by MK-801
- Significantly reversed social deficits induced by PCP
55
Object recognition findings of TASP on MK-801?
Significantly improved cognitive deficits induced by MK-801, did not completely reverse them.
56
Which specific brain region was assessed to determine the effects of TASP0315003 on glycine levels?
Cerebrospinal fluid (CSF)
57
What was the observed effect of TASP on MK-801-induced hyperlocomotion?
It significantly reduced hyperlocomotion
( only MK-801 treated - did not affect locomotor activity in natural rodents)
58
Which enzyme involved in D-serine metabolism is indirectly targeted by TASP mechanism of action?
DAAO
59
What was the Open Field box used for:
- Measure exploratory behaviour + potential anxiolytic effects.
- Object recognition test
60
What was the half-life of TASP observed in the rodent model?
4-6 hours.
61
Which enzyme's activity is indirectly increased by the action of TASP?
Serine racemase
62
How did researchers ensure that observed effects of TASP were not due to changes in locomotor activity?
Comparing locomotor activity with and without drug administration.
63
What specific role did prefrontal cortex play in effects observed with TASP administration?
- Primary site of increased glycine levels.
63
What is the preference index + what was TASP effect on it?
- How much more time rodents spent exploring novel object
- TASP showed higher preference index; better recognition memory
64
What was the significance of the delay between training and test phases in novel object recognition test?
To measure long-term memory retention
65
What is acute administration of TASP?
Single dose or short term dose , given once or over a short period.
66
What is sub-chronic administration of TASP?
Administration over a longer period (weeks), but long enough to be considered chronic.
67
What was the result of acute administration of TASP?
- Significant improvements in tests, suggesting rapid onset of action on enhancing NMDA R function
68
How long was TASP administered sub-chronically?
Daily over a 8 day period
68
Purpose of sub-chronic administration of TASP0315003?
- Assess sustainability of drug's effects
- Monitor potential tolerance development + long-term side effects
69
How did the improvements after sub-chronic administration compare to acute administration?
- Slightly improved from acute, indicating benefits are maintained/enhanced with repeat dosing
70
Relationship between NMDA receptor hypofunction and the dopaminergic system in schizophrenia?
NMDA R hypofunction results in decreased dopamine release in PFC
71
How did study assess the selectivity of TASP for GlyT1 compared to other potential off-target receptors?
Radioligand binding assays
72
Which brain region is primarily implicated in regulation of executive functions often disrupted in schiz?
PFC
73
What was a key finding regarding TASP’s effect on locomotor activity when administered sub-chronically?
No significant effect
74
Dopamine hypothesis suggests positive symptoms are primarily due to:
Enhanced dopamine release in mesolimbic pathway
75
key difference in the cognitive outcomes observed between MK-801 and PCP models?
PCP induced more pronounced social withdrawal than MK-801
76
What specific cognitive domain is primarily affected by MK-801 in rodent models?
Working memory
77
What specific aspect of cognition was most improved by TASP in the rodent models?
Object recognition memory
78
What role do 5-HT2A receptors play in the treatment of schiz?
They increase dopamine release in PFC when antagonized.
79
Which gene is associated with the regulation of NMDA receptor expression and is implicated in schiz?
DISC-1
Neuregulin
Dysbindin
80
How does NMDA receptor hypofunction in schizophrenia contribute to positive symptoms?
By disinhibiting the mesolimbic dopamine pathway
81
Which brain region is primarily involved in the regulation of emotions and is implicated in the pathology of schizophrenia?
Amygdala
82
What is the primary function of the NMDA receptor in synaptic transmission?
Mediates calcium influx, promoting synaptic plasticity
83
Hypothesized impact of prenatal exposure to infection on the development of schizophrenia, particularly concerning the immune response?
- Exaggerated microglial response, leading to neuroinflammation, synaptic pruning + risk of psychosis
84
What do GABAergic interneurons do?
- Maintain balance between excitation + inhibition
- Modulate excitatory neuron activity through inhibitory neurotransmission.
- INHIBITORY CONTROL !!
85
What happens when there is dysfunction of GABAergic interneurons in PFC?
- Leads to cortical disinhibition, where inhibitory control is weakened
- Leading to hyperactivity in cortical circuits.
86
How is NMDA R hypofunction linked to GABAergic interneurons?
NMDA R hypofunction reduces the excitation of GABAergic interneurons, leading to diminished inhibitory control.
87
Effect of GABAergic interneuron dysfunction on mesolimbic dopamine pathway?
contributes to disinhibition of mesolimbic pathway, increasing dopamine release IN PFC+ positive symptoms
88
NMDA R hypofunction hypothesis?
Impaired NMDAR activity reduces excitatory drive on GABAergic interneurons, leading to cortical disinhibiton + positive symptoms.
89
What is long-term potentiation (LTP)?
- Process that strengthens synaptic connections
- Crucial for learning + memory
90
Why are NMDA receptors crucial for LTP?
NMDAR mediate calcium influx, essential for initiating + maintaining LTP
91
What is the impact of NMDA receptor hypofunction on LTP?
Impairs LTP, leading to learning + memory deficits.
92
In which test did TASP demonstrate no evidence of tolerance with repeated administration?
Social interaction test with PCP-treated mice
93
Which parameter was used to assess the effect of TASP on memory in the novel object recognition test?
Preference index
