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.
Background: For 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). Aim: To 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 (BD1008) sigma receptor antagonists on cocaine consumption. Methods: Male 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. Results: The 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. Conclusion: BEST model (with TIPR analysis) is more sensitive than the current models in differentiating the drug effects on cocaine consumption.