Source Paper
“Breakthrough” Dopamine Supersensitivity during Ongoing Antipsychotic Treatment Leads to Treatment Failure over Time
Anne-Noël Samaha, Philip Seeman, Jane Stewart, Heshmat Rajabi,
Source Paper
Anne-Noël Samaha, Philip Seeman, Jane Stewart, Heshmat Rajabi,
Journal of Neuroscience • 2007
Antipsychotics often lose efficacy in patients despite chronic continuous treatment. Why this occurs is not known. It is known, however, that withdrawal from chronic antipsychotic treatment induces behavioral dopaminergic supersensitivity in animals. How this emerging supersensitivity might interact with ongoing treatment has never been assessed. Therefore, we asked whether dopamine supersensitivity could overcome the behavioral and neurochemical effects of antipsychotics while they are still in use. 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. Treatment failure occurred despite high levels of dopamine D 2 receptor occupancy by the antipsychotic and was at least temporarily reversible by an additional increase in antipsychotic dose. To explore potential mechanisms, we studied presynaptic and postsynaptic elements of the dopamine system and observed that antipsychotic failure was accompanied by opposing changes across the synapse: tolerance to the ability of haloperidol to increase basal dopamine and dopamine turnover on one side, and 20–40% increases in D 2 receptor number and 100–160% increases in the proportion of D 2 receptors in the high-affinity state for dopamine (D 2 High ) on the other. Thus, the loss of antipsychotic efficacy is linked to an increase in D 2 receptor number and sensitivity. These results are the first to demonstrate that “breakthrough” supersensitivity during ongoing antipsychotic treatment undermines treatment efficacy. These findings provide a model and a mechanism for antipsychotic treatment failure and suggest new directions for the development of more effective antipsychotics.
Objective: Assessment of antipsychotic efficacy in suppressing amphetamine-induced locomotor activity in rats over chronic treatment to evaluate treatment failure mechanisms
This is a Amphetamine-Induced Locomotion Suppression Assay protocol using rat as the model organism. The procedure involves 8 procedural steps, 2 equipment items, 3 materials. Extracted from a 2007 paper published in Journal of Neuroscience.
Model and subjects
rat • Not specified • unknown • Not specified • Not specified
Study window
Estimated timing pending
Core workflow
Chronic antipsychotic treatment initiation • Amphetamine-induced locomotion testing • Conditioned avoidance responding assessment
Primary readouts
Key equipment and reagents
Verified items
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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
“during ongoing treatment with clinically relevant doses, haloperidol and olanzapine progressively lose their efficacy”
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
“suppressing amphetamine-induced locomotion”
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
“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”
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
“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”
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
“To explore potential mechanisms, we studied presynaptic and postsynaptic elements of the dopamine system”
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
“Treatment failure occurred despite high levels of dopamine D2 receptor occupancy by the antipsychotic”
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
“20–40% increases in D2 receptor number”
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
“100–160% increases in the proportion of D2 receptors in the high-affinity state for dopamine (D2High)”
This section explains what the experiment is doing, which readouts matter, what the data artifacts usually look like, and how the analysis should flow from raw capture to reported result.
Assessment of antipsychotic efficacy in suppressing amphetamine-induced locomotor activity in rats over chronic treatment to evaluate treatment failure mechanisms
Objective
Assessment of antipsychotic efficacy in suppressing amphetamine-induced locomotor activity in rats over chronic treatment to evaluate treatment failure mechanisms
Subjects
From paperrat • Not specified • unknown • Not specified • Not specified
Cohort notes
From paperNot specified in provided text
Chronic antipsychotic treatment initiation (Ongoing throughout experiment)
Amphetamine-induced locomotion testing (Not specified)
Conditioned avoidance responding assessment (Not specified)
Dose escalation testing (Not specified)
Amphetamine-induced locomotor activity suppression
From paperNot specified in provided text
Artifact type
Longitudinal gait metrics and per-animal performance tables
Comparison focus
Compare recovery trajectory across post-injury timepoints and treatment conditions
Conditioned avoidance responding
From paperNot specified in provided text
Artifact type
Longitudinal gait metrics and per-animal performance tables
Comparison focus
Compare recovery trajectory across post-injury timepoints and treatment conditions
Dopamine D2 receptor occupancy levels
From paperNot specified in provided text
Artifact type
Longitudinal gait metrics and per-animal performance tables
Comparison focus
Compare recovery trajectory across post-injury timepoints and treatment conditions
Basal dopamine levels
From paperNot specified in provided text
Artifact type
Longitudinal gait metrics and per-animal performance tables
Comparison focus
Compare recovery trajectory across post-injury timepoints and treatment conditions
Amphetamine-induced locomotor activity suppression
From paperRaw artifact
Per-run gait capture with paw placement, timing, and stride features for each animal
Processed artifact
Cleaned gait metrics table and recovery trend summary across timepoints
Final reported form
Group comparisons of gait indices, stride metrics, or recovery curves
Conditioned avoidance responding
From paperRaw artifact
Per-run gait capture with paw placement, timing, and stride features for each animal
Processed artifact
Cleaned gait metrics table and recovery trend summary across timepoints
Final reported form
Group comparisons of gait indices, stride metrics, or recovery curves
Dopamine D2 receptor occupancy levels
From paperRaw artifact
Per-run gait capture with paw placement, timing, and stride features for each animal
Processed artifact
Cleaned gait metrics table and recovery trend summary across timepoints
Final reported form
Group comparisons of gait indices, stride metrics, or recovery curves
Basal dopamine levels
From paperRaw artifact
Per-run gait capture with paw placement, timing, and stride features for each animal
Processed artifact
Cleaned gait metrics table and recovery trend summary across timepoints
Final reported form
Group comparisons of gait indices, stride metrics, or recovery curves
Acquisition
Collect raw experimental outputs with enough metadata to preserve sample identity, condition, and timing.
Preprocessing / cleaning
Not specified in provided text
Scoring or quantification
Quantify the primary readouts for this experiment: Amphetamine-induced locomotor activity suppression; Conditioned avoidance responding; Dopamine D2 receptor occupancy levels; Basal dopamine levels.
Statistical comparison
Statistical method not yet structured for this page.
Reporting output
Report representative outputs alongside summary comparisons for Amphetamine-induced locomotor activity suppression, Conditioned avoidance responding, Dopamine D2 receptor occupancy levels, Basal dopamine levels.
Source links and direct wording from the methods section for validation and deeper review.
Citation
Anne-Noël Samaha et al. (2007). “Breakthrough” Dopamine Supersensitivity during Ongoing Antipsychotic Treatment Leads to Treatment Failure over Time. Journal of Neuroscience
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