Post on 04-Jan-2016
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
Door 1 Door 2 Door 3
1. Parsley(+) Sage Rosemary
2. Sage Rosemary Parsley(+)
3. Parsley(+) Rosemary Sage
4. Rosemary Sage Parsley(+)
5. Rosemary 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)
0
1
2
3
4
5
6
7
saline 0 1 3 10
performance
acquisition
Both elements show improvement
Selective effect
0
1
2
3
4
5
6
7
saline 0 1 3 10
performance
acquisition
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?