Transcript Kristen Ray - USD Biology

OCD


Neurochemical dysfunction (abnormalities in
serotonin (5-HT), dopamine (DA), and
glutamatergic transmitter systems)
Drug Therapy in OCD


Strategies targeting these systems
Role of serotonin (5-HT) neurotransmitter system
and glutamatergic system
SSRIs

Block action of 5HT transporter (5-HTT)
protein


Responsible for uptake of intrasynaptic 5-HT
released following an action potential
Prevent reuptake of 5-HT into the pre-synaptic
neuron

More serotonin left in synapse to bind with postsynaptic receptors

Serotonin receptors are activated by 5-HT


Receptors modulate the release of many
neurotransmitters, including glutamate, GABA,
dopamine, epinephrine/norepinephrine, and
acetylcholine, as well as many hormones.
Influence biological and neurological processes
such as aggression, anxiety, appetite, cognition,
learning, and memory
Targeting 5-HT receptor subtypes

Drugs that block the 5-HT2 family of receptors


Augment action of SSRIs or have therapeutic
efficacy by themselves
Blockade of 5-HT2A receptors and activation of
non-5HT2A receptors may have similar effects

Synergistic treatment with 5-HT2A antagonist/SSRI
combination

Risperidone


Potent 5-HT2A antagonist
blocks α2 adrenoreceptors



Presynaptic heteroreceptors on 5-HT neurons that
regulate release of 5-HT
Further enhance SSRI therapy through desensitization
of 5-HT1D terminal autoreceptor
5-HT2C receptor agonism

Psilocybin; mixed 5-HT2C/2A/1A receptor agonist
5-H1D/B receptor


Regulate release of 5-HT from presynaptic
terminal by reducing 5-HT neurotransmission
Activation of 5-HT1D/B receptor by an agonist
compound worsen OCD symptoms


Chronic deficits in 5-HT functioning
Agonist m-CPP

Silent polymorphism of G861C gene


5-HT1D/B receptors supersensitive, resulting in
chronic reductions in synaptic levels of 5-HT
5-HT1D/B antagonist compounds expected to
hasten onset of therapeutic action of SSRIs in
OCD

rapidly producing state of 5-HT1D/B receptor
insensitivity
Glutamatergic System

Glutamate
 most abundant excitatory neurotransmitter in the vertebrate nervous
system.
 Nerve impulses trigger release of glutamate from pre-synaptic cell
 Opposing post-synaptic cell, glutamate receptors
(NMDA receptors)
 Role in synaptic plasticity
 learning and memory in the brain

Glutamate transporters rapidly remove glutamate from extracellular space
 In brain injury or disease, work in reverse and excess glutamate
accumulates outside cells
 Causes calcium ions to enter cells via NMDA receptor channels
 Excitotoxicity- overstimulation of receptors leads to neuronal
damage and eventual cell death
“The Combined Effects of
Memantine and Fluoxetine
on an Animal Model of
Obsessive Compulsive
Disorder”

Effective class of drugs used to treat OCD

Fluoxetine

First in a generation of SSRIs for treatment of major
depressive disorder and anxiety disorders (OCD)



Good overall safety and tolerability
Better than most other antidepressants
Memantine



First used in treatment of Alzheimer’s dementia
low-affinity voltage-dependent antagonist at
glutamatergic NMDA receptors
Uncompetitive antagonist channel blocker
Aim of Study

Use mouse model of OCD

Examine whether a synergistic, as opposed to
additive relationship between NMDA antagonists
and SSRIs in treatment of OCD

Combining relatively low doses of both drugs

Low enough where do not decrease compulsive behavior when
administered alone
Isobologram


Graph of equally effective dose pairs
(isoboles) for a single effect level
Particular effect level is selected



50% of the maximum
Doses of drug A and drug B (each alone) that give
this effect are plotted as axial points in a Cartesian
plot
Straight line connecting A and B is the locus of
points (dose pairs) that will produce this effect in a
simply additive combination

Line of additivity allows a comparison with the actual
dose pair that produces this effect level experimentally
Isobologram

Third point plotted on graph


Combination points below the line of additivity


Synergism
Combination points along line of additivity


dose combinations of two drugs necessary to produce same
effect size
Simply Additive
Combination points above line of additivity

Subadditivity
Method




Male Swiss Webster mice
18-63 g depending on age
Kept at 68 to 72 °F in 12h/12h light-dark cycle
Ad libitum access to water and food pellets
Scratching Assay

Established as effective model


compulsive behavior in dogs with allergic
dermatitis
Intradermal injection in mice


Serotonin
Compound 48-80

Promotes histamine release and mast cell degranulation

Effect of fluoxetine on serotonin-induced scratching
compared to controls


Effect of memantine on serotonin-induced scratching
compared to controls


5,10,15,30 mg/kg
Effect of combination fluoxetine and memantine on
serotonin-induced scratching



5,10,15,30 mg/kg
5mg/kg fluoxetine
5mg/kg memantine
Effect of fluoxetine (10 mg/kg) and memantine (5
mg/kg) by compound 48-80 both alone and in
combination

Experimental mice


intraperitoneal injection of varying doses of
fluoxetine and/or memantine in saline (0.9% NaCl)
containing ascorbic acid (1mg/ml)
Control mice

Intraperitoneal injection of varying doses of saline
and ascorbic acid

0.1ml/10g of body weight

5 minutes later

Control and experimental mice subcutaneously
injected behind neck


0.1 ml of 0.4 mg/ml serotonin or 0.1 ml of compound
48-80 1 mg/ml in saline and ascorbic acid to induce
scratching
Each mouse then placed individually in
separate cage paired with control mouse in
separate cage given saline pretreatment


Cumulative number of scratches counted
continuously using manual counter
Cumulative scratches recorded every 5
minutes for 30 minutes

Other behaviors noted

motor activity, sedation, licking, and rearing
Statistical Analysis


Mean scratching scores for pretreated mice
compared to their saline controls
Cumulative scratches in mice injected with
drug were expressed as % of scratches
compared to saline controls
Results
Discussion

Combined doses of fluoxetine and memantine
required to produce 90% reduction in
scratching


much lower than doses of either drug alone
necessary to produce same effect
Synergistic relationship
Present study mechanisms most likely serotonergic and
glutamatergic
 Basis for synergism between fluoxetine and
memantine


SSRIs increase amount of serotonin in synapses and
NMDA antagonist block glutamate binding at NMDA
receptors
Both decreased serotonergic activity and increased
glutamatergic activity have been linked to the
expression of impulsive behaviors