Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

SCHIZOPHRENIA > Methods > Flashcards

Methods Flashcards

1
Q

What is the primary function of TASP0315003?

A

A potent, orally active, selective inhibitor of GlyT1,

Which increases glycine levels and enhances NMDA receptor function.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

How does TASP affect glycine intake in vitro?

A

TASP effectively inhibits glycine uptake in C6 glioma cells and rat frontal cortical synaptosomes,

specifically targeting GlyT1.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Does TASP affect GlyT2?

A

TASP has weak inhibitory activity on GlyT2, indicating high specificity for GlyT1.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What is the significance of TASP0315003’s specificity for GlyT1?

A

High specificity for GlyT1 minimizes off-target effects and reduces the likelihood of adverse side effects.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What did the in vivo studies of TASP0315003 reveal about its effect on glycine levels?

A

Oral administration of TASP increases glycine levels in CSF of rats,

Confirming its’ ability to cross blood brain barrier + block GlyT1 In Vivo.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

How did TASP0315003 perform in the novel object recognition test?

A

TASP improved recognition memory in rats with MK-801-induced cognitive deficits, by increasing exploratory behaviour towards novel objects.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What effect did TASP0315003 have in the social recognition test?

A

TASP improved social memory retention in rats, indicated by reduced ratio of investigation duration (RID), without altering initial social interaction between the rats.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

How did TASP0315003 affect social interaction in PCP-treated mice?

A

TASP reversed social interaction deficits caused by PCP, which models negative symptoms of schizophrenia.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

What were the findings from the forced swim test?

A

TASP reduced immobility time in the test, suggesting it may possess antidepressant properties.

( in a similar way to fluvoxamine)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Did TASP0315003 affect locomotor activity or motor coordination in the study?

A

TASP did not impair locomotor activity or motor coordination, –> it does not cause sedative or motor side effects.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What was observed regarding catalepsy in the study?

A

Unlike risperidone, TASP did not induce catalepsy. So it does not cause motor side effects associated with antipsychotics that target dopamine receptors.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

What did pharmacokinetic analysis reveal about TASP0315003?

A

TASP and its maleate salt form had similar plasma levels,
peaking around 4 hours post administration,
and able to penetrate the blood-brain barrier.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What are the overall conclusions about TASP0315003 from the study?

A
  • promising therapeutic agent for schiz
  • particularly for negative and cognitive symptoms
  • due to it’s ability to enhance NMDA receptor function, by increasing glycine availability without significant off-target effects or CNS side effects.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What type of behavioral deficits did the MK-801-induced model simulate, and how did TASP0315003 address these deficits?

A
  • MK-801 stimulates cognitive deficits by inducing NMDA receptor hypofunction.
    –> leading to impaired recognition memory + social memory.
  • TASP reversed and improved both object recognition + social memory.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

How did TASP0315003’s effect compare with other drugs like clozapine and risperidone in the study?

A

TASP improved social memory + cognitive deficits WITHOUT causing motor side effects like catalepsy, which are associated with Risperidone.
Also without affecting locomotor activity, unlike clozapine.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What does the rotarod performance test assess, and what were the results for TASP0315003?

A

Assesses motor coordination and balance.
TASP did not impair rotarod performance, indicating it does not affect coordination.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Why is the lack of sedative effects from TASP0315003 significant?

A

Suggests TASP a more tolerable treatment option for schiz, fewer side effects than other antipsychotics.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

What was the time course of plasma levels for TASP0315003, and why is this relevant?

A

Time course showed TASP peaked at 4hrs post administration.
Helps determine dosing schedule for maintaining effective glycine levels in brain.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

What neurotransmitter system is impliated in the research?

A

Glutamatergic neurotransmitter system.

20
Q

What is TASP + it’s primary function?

A

A selective inhibitor of GlyT1
Responsible for inhibiting glycine reuptake from synaptic cleft back into presynaptic neuron or surrounding glial cells.
Increasing extracellular glycine levels.

21
Q

What role does glycine play in function of NMDA receptors?

A
  • Co-agonist at receptor.
  • Crucial for synaptic plasticity, learning, memory.
  • Increasing glycine levels = enhances NMDA R function.
22
Q

TASP selectivity for GlyT1 over GlyT2 does what?

A

Minimizes adverse effects like motor dysfunction,
As GlyT2 is involved in glycine transport in spinal cord and brainstem.
Selectivity focuses its action on increasing synaptic glycine levels relevant to NMDA receptor modulation.

23
Q

What evidence to support NMDA R hypofunction involvement in schiz?

A

NMDA R antagonists i.e. Ket + PCP can induce symptoms like schiz negative + cognitive symptoms + cause abnormal behaviour in rodents similar to seen in schiz.

24
Q

Rationale behind using glycine modulatory sites on NMDA R for treatment?

A

Indirectly enhances NMDA R function, and avoids several undesireable effects from direct stimulation of NMDA R using agonists.

25
Q

Mixed results in previous studies on GlyT1 inhibitors in schiz?

A

Some showed GlyT1 improved negative + cognitive symptoms, others failed to replicate results.
Further research needed to clarify efficacy of GlyT1 inhibitors.

26
Q

What hypotheses was tested?

A

TASP would show efficacy in animal models reflecting cognitive dysfunctions + negative symptoms of schiz, i.e. social withdrawal, WITHOUT causing significant CNS side effects like sedation or motor dysfunction.

27
Q

What animal models were used?

A

Wistar rats & ICR mice.

28
Q

Purpose of using [³H]glycine?

A
  • radioactive form of glycine (tritiated) used to track + measure glycine uptake in cells.
  • Allows for evaluation of TASP inhibitory activity on GlyT1 in C6 glioma cells + rat frontal cortical synaptosomes.
29
Q

What are non-specific [³H]glycine uptake?

A
  • Glycine uptake that occurs independently of specific transport mechanism being studied
  • Background noise of experiment.
  • Measure it to isolate the activity of specific transporter, GlyT1.
30
Q

Purpose of binding assays?

A

To determine specificity + strength of TASP interaction with glycine receptors and serotonin receptors.

31
Q

What ligands were used in the binding assays?

A
  • [³H]strychnine for strychnine-sensitive glycine receptors,
  • [³H]MDL105,519 for NMDA receptor glycine sites,
  • [³H]8-OH-DPAT for the 5-HT1A receptor,
  • [³H]paroxetine for the serotonin transporter.
32
Q

What were the in vivo behavioral effects of TASP?

A

Reduction of hypolocomotion:
- counteracted effects of PCP-induced hyperactivity, by increasing glycine levels + activating NMDA receptors.

Improvement in Prepulse inhibition (PPI):
- Improved sensorimotor gating deficits by enhancing NMDA R function.

33
Q

How was glycine concentration measured in the CSF of rats?

A
  • Chemical derivatization + high-performance liquid chromatography (HPLC) with electrochemical detection, after administering TASP maleate.
  • Rats anaethetized with isoflurane.
  • CSF collected 4 hrs after dosing.
34
Q

Why were ALX5407 and ALX1393 used in the study?

A
  • Compounds served as controls to clarify specificity of TASP
  • ALX5407 inhibit GlyT1
  • ALX1393 inhibit GlyT2
  • Help differentiate specific from non-specific uptake during 3HGlycine uptake assays.
35
Q

What are binding assays?

A
  • Determine how well ligand binds to its target protein, assess specificity, strength of interaction + number of available receptors or active sites.
  • To understand affinity of a compound for its target.
  • Crucial for drug efficacy.
36
Q

How do TASP + NFDS compare in their effects on cognitive + social tests?

A
  • Both inhibit GlyT1 + improve social memory and curioisty
  • Different effects on anxiety-related behaviour, TASP showing a trend toward reducing anxiety, but not statistically significant.
37
Q

Purpose and findings of the Elevated Plus Maze test:

A
  • Assesses anxiety-related behaviour, by measuring rats willingness to explore more open + elevated areas.
  • TASP showed trend toward reducing anxiety -> by more time spent exploring open arms of maze.
38
Q

What might account for differences in anxiolytic effects between TASP + NFDS?

A
  • How each compound interacts with different receptor symptoms beyond GlyT1 inhibiton.
  • Modulation of glutamatergic transmission may indirectly influence mGluR2 activity.
39
Q

What is mGluR2?

A
  • Subtype of metabotropic glutamate receptor
  • G-protein coupled receptor
  • Associated with anxiety, stress response + cognitive function
40
Q

Effects of TASP when in conjunction with mGluR2 agonists/antagonists?

A
  • TASP with mGluR2 agonists: may be an additive effect on reducing anxiety + enhancing cognition
  • with mGluR2 antagonists: anxiolytic effects are diminished

-> indicates mGluR2 activity is contributing factor to these effects.

41
Q

How might NMDA R modulation by TASP, influence mGluR2 signalling?

A
  • Inhibiting GlyT1 increases glycine levels -> enhances NMDA R function
  • May indirectly influence mGluR2 signaling
42
Q

How long did the sub-chronic treatment of PCP last in the study before conducting the social interaction test?

A

12 days

43
Q

Which other GlyT1 inhibitor is mentioned in the study as having similar effects to TASP?

A

NFPS

44
Q

TASP had no significant activity at most receptors except which three?

A
  • 5-HT1A receptor
  • Serotonin transporter
  • Melanocortin-1 receptor
45
Q
A

SCHIZOPHRENIA (5 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions