The effects of benzodiazepine
inverse-agonist RY-10 on
learning in a new olfactory
apparatus
By Carol Dwan
Advisor: Mark Galizio
The GABA receptor
• GABA (gamma-aminobutyric acid) is the
most common inhibitory neurotransmitter
in the brain. When this molecule binds to
it’s receptor it makes the neuron less likely
to fire.
• Complex molecule with multiple receptor
sites
The GABA receptor
Benzodiazepines
• Are one class of molecules that bind to GABA
receptor and change it’s affinity for GABA.
benzodiazepine
Chloride
channel
Benzodiazepine drug actions
• Agonist: Increases the affinity of the receptor
for GABA: produces inhibitory effects in the
brain.
– Anxiolytic, sedative, anterograde amnesia
– Often used for sleeping pills, surgical anesthetics
• Antagonist: Blocks the benzodiazepine site
so that agonists can not bind.
• Inverse-agonist: Binds to the benzodiazepine
site, decreases receptor affinity for GABA:
causes the opposite effects of agonists
– procovulsant, anxiogenic and mnemonic enhancing.
Selective Mnemonic Enhancement
• There are several subtypes of GABA
receptors throughout the brain.
• The GABA a5 receptor is located primarily
in the hippocampus, a memory center in
the brain.
• RY-10 binds selectively to this receptor,
and so exerts its inverse-agonist effects
mainly in the memory center….with less
activity in motor or cognitive centers.
The Brain
Goal
• To test 6 rats on 4 doses (0,1,3,10 mg/kg)
of RY-10 in a RAP procedure in a new
olfactory apparatus.
Apparatus
Spices and spice cups
Pellet dispensers
Performance Component
1.
2.
3.
4.
5.
Door 1
Door 2
Door 3
Parsley(+)
Sage
Parsley(+)
Rosemary
Rosemary
Sage
Rosemary
Rosemary
Sage
Parsley(+)
Rosemary
Parsley(+)
Sage
Parsley(+)
Sage
Acquisition Component:
• Day 1: Garlic Clove Nutmeg(+)
• Day 2: Anise Caraway Cinnamon(+)
• Day 3: nutmeg cinnamon mustard (+)
Data Analysis
• I will perform a 2x4 ANOVA statistical
analysis looking for an interaction between
dose and component. If the drug does not
have a selective effect on learning there
will be a main effect of dose.
• Data will be analyzed graphically
Effect on learning and performance
(non selective)
7
6
5
4
performance
acquisition
3
2
1
0
saline
0
1
3
10
Both elements show improvement
Selective effect
7
6
5
4
performance
acquisition
3
2
1
0
saline
0
1
3
10
Possible benefits
• Recent testing of RY-10 did seem to show only
mnemonic enhancing effects (no motor side
effects) but did not properly control for
confounds. (follow up on Delorey’s study)
• This project is in collaboration with University of
Wisconsin chemist James Cook and Harvard
primate researcher James Rowlett. Compound
designed for selective binding, could have novel
behavioral effects.
• Apparatus ceiling effects prevented
The End
• Questions?