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) Both elements show improvement

Selective effect

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?