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
Conditioned Avoidance Responding Task
Objective: Evaluate the effects of antipsychotic treatment on conditioned avoidance responding behavior in rats to assess whether dopamine supersensitivity develops during ongoing antipsychotic treatment and undermines treatment efficacy
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Protocol Steps
Conditioned Avoidance Responding Task Setup
Establish conditioned avoidance responding model in rats as one of two models used to assess antipsychotic-like effects
Note: This is one of two behavioral models used in the study; the other being amphetamine-induced locomotion
View evidence from paper
“Using two models of antipsychotic-like effects in rats, we show that during ongoing treatment with clinically relevant doses”
Baseline Conditioned Avoidance Responding Assessment
Measure baseline conditioned avoidance responding behavior before antipsychotic treatment initiation
Note: Baseline measurements establish control values for comparison during treatment
View evidence from paper
“conditioned avoidance responding”
Initiate Antipsychotic Treatment
Begin chronic continuous treatment with haloperidol or olanzapine at clinically relevant doses
Note: Treatment is continuous and chronic; doses are clinically relevant
View evidence from paper
“during ongoing treatment with clinically relevant doses, haloperidol and olanzapine progressively lose their efficacy”
Monitor Conditioned Avoidance Responding During Treatment
Assess conditioned avoidance responding behavior at multiple timepoints during ongoing antipsychotic treatment to detect progressive loss of efficacy
Note: Progressive loss of efficacy is observed despite high dopamine D2 receptor occupancy
View evidence from paper
“progressively lose their efficacy in suppressing amphetamine-induced locomotion and conditioned avoidance responding. Treatment failure occurred despite high levels of dopamine D2 receptor occupancy”
Dose Escalation Test
Increase antipsychotic dose to determine if treatment failure is reversible
Note: Treatment failure was at least temporarily reversible by additional dose increase
View evidence from paper
“was at least temporarily reversible by an additional increase in antipsychotic dose”
Assess Dopamine System Changes
Examine presynaptic and postsynaptic elements of the dopamine system to identify mechanisms underlying treatment failure
Note: Measurements include basal dopamine, dopamine turnover, D2 receptor number, and D2 receptor affinity state
View evidence from paper
“we studied presynaptic and postsynaptic elements of the dopamine system and observed that antipsychotic failure was accompanied by opposing changes”