A novel baseline-effect shift tracking model for more sensitive detection of differences in the effects of closely related dopamine transporter inhibitor/ sigma receptor antagonist drug combinations on psychostimulant use.

Paul, R.; Gandhi, R. M.; Job, M. O.

doi:10.1101/2024.08.27.609852

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bioRxiv · 10.1101/2024.08.27.609852

A novel baseline-effect shift tracking model for more sensitive detection of differences in the effects of closely related dopamine transporter inhibitor/ sigma receptor antagonist drug combinations on psychostimulant use.

Paul, R.·Gandhi, R. M.·Job, M. O.

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Abstract

BackgroundFor the purpose of improving the ability to distinguish the activity of closely related drugs on psychostimulant use to enable more specific drug effect characterization, we have developed a new model termed the baseline-effect shift tracking (BEST) model. BEST compares/contrasts the baseline-drug activity relationship(s). AimTo compare the current model to our BEST model to determine which was more effective in distinguishing the effects of combinations of a dopamine transporter inhibitor (methylphenidate, MPD) and selective sigma1 (BD1063) and non-selective sigma (BD1008) receptor antagonists on cocaine consumption. MethodsMale Sprague Dawley rats were trained to self-administer cocaine (n = 9, 0.32 mg/kg/infusion) or sucrose pellets (n = 6, 20 mg pellets/delivery). We determined the effects for cocaine/sucrose of combinations of MPD (1 mg/kg i.p) and 1) BD1063 (0, 3.2, 10 mg/kg i.p), and 2) BD1008 (0, 3.2, 10 mg/kg i.p) on a) consumption at zero price (Q0), and b) essential value (eValue, demand elasticity) estimated using behavioral economic analysis of within-session demand curves, and c) the total intake under the price response curve (TIPR). We compared the models using ANOVA/ regression analysis. ResultsThe current model did not detect any differences in the effects of these drug combinations on cocaine/ sucrose taking behavior. For cocaine, but not for sucrose, the BEST model detected differences in the effects of these drug combinations on TIPR in subjects with higher baseline activity. ConclusionBEST model (with TIPR analysis) is more sensitive than the current models in differentiating drug effects on cocaine consumption.

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Paul, R., Gandhi, R. M., Job, M. O.. 2024-08-28. A novel baseline-effect shift tracking model for more sensitive detection of differences in the effects of closely related dopamine transporter inhibitor/ sigma receptor antagonist drug combinations on psychostimulant use.. https://doi.org/10.1101/2024.08.27.609852

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