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?