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OCD

OCD. 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.

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OCD

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  1. OCD OCD

  2. 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

  3. 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 post-synaptic receptors

  4. 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

  5. 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

  6. Risperidone • Potent 5-HT2A antagonist • blocks α2 adrenoreceptors • Presynapticheteroreceptors 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

  7. 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

  8. 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

  9. 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

  10. “The Combined Effects of Memantine and Fluoxetine on an Animal Model of Obsessive Compulsive Disorder”

  11. 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

  12. 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

  13. 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

  14. Isobologram • Third point plotted on graph • dose combinations of two drugs necessary to produce same effect size • Combination points below the line of additivity • Synergism • Combination points along line of additivity • Simply Additive • Combination points above line of additivity • Subadditivity

  15. 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

  16. 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

  17. Effect of fluoxetine on serotonin-induced scratching compared to controls • 5,10,15,30 mg/kg • 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 • 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

  18. 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

  19. 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

  20. 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

  21. 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

  22. Results

  23. 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

  24. 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

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