Source Paper
“Breakthrough” Dopamine Supersensitivity during Ongoing Antipsychotic Treatment Leads to Treatment Failure over Time
Anne-Noël Samaha, Philip Seeman, Jane Stewart, Heshmat Rajabi, Shitij Kapur
Journal of Neuroscience • 2007
Amphetamine-Induced Locomotion Suppression Assay
Objective: Assessment of antipsychotic efficacy in suppressing amphetamine-induced locomotor activity in rats over chronic treatment to evaluate treatment failure mechanisms
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Equipment2
Materials3
Software1
Not specified • Not specified
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Protocol Steps
Chronic antipsychotic treatment initiation
Rats were treated chronically with haloperidol or olanzapine at clinically relevant doses
Note: Treatment continued during behavioral testing to assess efficacy loss during ongoing use
View evidence from paper
“during ongoing treatment with clinically relevant doses, haloperidol and olanzapine progressively lose their efficacy”
Amphetamine-induced locomotion testing
Rats were administered amphetamine and locomotor activity was measured to assess antipsychotic suppression of drug-induced hyperactivity
Note: Testing performed during ongoing antipsychotic treatment to evaluate progressive loss of efficacy
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“suppressing amphetamine-induced locomotion”
Conditioned avoidance responding assessment
Rats were tested on conditioned avoidance responding task as a second model of antipsychotic-like effects
Note: Used as complementary behavioral model to amphetamine-induced locomotion
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“Using two models of antipsychotic-like effects in rats, we show that during ongoing treatment with clinically relevant doses, haloperidol and olanzapine progressively lose their efficacy in suppressing amphetamine-induced locomotion and conditioned avoidance responding”
Dose escalation testing
Antipsychotic dose was increased to determine if treatment failure could be temporarily reversed
Note: Treatment failure was at least temporarily reversible by additional dose increase
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“Treatment failure occurred despite high levels of dopamine D2 receptor occupancy by the antipsychotic and was at least temporarily reversible by an additional increase in antipsychotic dose”
Dopamine system analysis
Presynaptic and postsynaptic elements of dopamine system were studied to explore mechanisms of antipsychotic failure
Note: Measured basal dopamine, dopamine turnover, D2 receptor number, and D2 receptor affinity states
View evidence from paper
“To explore potential mechanisms, we studied presynaptic and postsynaptic elements of the dopamine system”
D2 receptor occupancy measurement
High levels of dopamine D2 receptor occupancy by antipsychotic were maintained and measured
Note: Treatment failure occurred despite high D2 receptor occupancy, indicating mechanism beyond simple receptor blockade
View evidence from paper
“Treatment failure occurred despite high levels of dopamine D2 receptor occupancy by the antipsychotic”
D2 receptor number quantification
D2 receptor number was measured and found to increase during antipsychotic treatment failure
Note: 20-40% increases in D2 receptor number observed with treatment failure
View evidence from paper
“20–40% increases in D2 receptor number”
D2 high-affinity state assessment
Proportion of D2 receptors in high-affinity state for dopamine (D2High) was measured
Note: 100-160% increases in proportion of D2High receptors observed with treatment failure
View evidence from paper
“100–160% increases in the proportion of D2 receptors in the high-affinity state for dopamine (D2High)”