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Effects of benztropine analogs on delay discounting in rats

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Abstract

Rationale

Methylphenidate and d-amphetamine, medications used for treatment of attention deficit hyperactivity disorder (ADHD), are used recreationally and self-administered by laboratory animals. Benztropine (BZT) analogs, like those medications, increase synaptic dopamine levels but are less effective in maintaining self-administration, suggesting clinical utility with less abuse liability.

Objectives

The current study was designed to evaluate potential therapeutic effects of BZT analogs related to ADHD.

Methods

Rats responded under a delay-discounting procedure in which responses on one lever produced immediate delivery of a single food pellet and alternative responses produced four food pellets either immediately or with various temporal delays, with those delays arranged in ascending or random orders in different groups of rats. Selection of the smaller more immediate reinforcer has been suggested as an aspect of “impulsivity,” a trait with suggested involvement in ADHD. Other rats were studied under fixed-interval (FI) 300-s schedules to assess drug effects on behavior under temporal control.

Results

d-Amphetamine, methylphenidate, and the BZT analog AHN 1-055, but not AHN 2-005 or JHW 007, increased selection of the large, delayed reinforcer with either arrangement of delays. All drugs changed the temporal distribution of responses within the FI from one with responses concentrated at the end to a more uniform distribution. Changes in the temporal distribution of FI responding occurred with drugs that did not affect discounting suggesting that discounting does not arise directly from the same temporal control processes controlling FI responding.

Conclusions

AHN 1-055 may be of clinical utility in the treatment of ADHD.

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Acknowledgments

We want to thank Bettye Campbell for her expert technical assistance in conducting these experiments. The benztropines: AHN 1-055, AHN 2-005, and JHW 007, were synthesized in the Medicinal Chemistry Section, National Institute on Drug Abuse (NIDA)-Intramural Research Program (IRP), by J. Cao, funded by ZIA DA000389.

Funding

The current studies were supported by funding from the NIDA-IRP to Dr. Jonathan L. Katz (ZIA DA000103).

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Authors and Affiliations

  1. Department of Psychology, Louisiana State University, Baton Rouge, LA, 70803, USA

    Paul L. Soto

  2. Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, USA

    Takato Hiranita

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  1. Paul L. Soto
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Correspondence to Paul L. Soto.

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Appendix. β coefficients, p values, and resulting odds ratios for logistic regression predictors

Appendix. β coefficients, p values, and resulting odds ratios for logistic regression predictors

The logistic regression model used to analyze the individual trial outcomes from the delay discounting procedure was ln(odds) = β0 + β1 ln(Delay Ratio) + β2 log(Dose Ratio) + β3 log(Delay Ratio) : ln(Dose Ratio), where delay ratio was calculated as the delay to the large reinforcer (0, 16, or 40 s) divided by the delay to the small reinforcer (0 s) with 0.1 (the feeder operation time) added to the numerator and denominator of the ratio, dose ratio was calculated as the dose, in milligram per kilogram, of the drug divided by vehicle (0) with 0.1 added to the numerator and denominator of the ratio to avoid division by zero, and log(Dose Ratio):ln(Delay Ratio) represents the interaction of the two predictor variables. Trials in which the large reinforcer was selected were coded as 1 and trials in which the small reinforcer was selected were coded as 0. The model results are presented in Table 1 below.

Table 1 Beta coefficients of the logistic regression predictors with standard error of the coefficient (SE) in parentheses, p value for the coefficient, and resulting odds ratios with 95% confidence limits (CLs) in parentheses for predictors from logistic model fits to individual trial outcomes in the delay discounting procedure from vehicle and drug administration sessions. Chi-square (χ2) values and resulting p values for each model fit are noted in parentheses following each section title
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Soto, P.L., Hiranita, T. Effects of benztropine analogs on delay discounting in rats. Psychopharmacology 237, 3783–3794 (2020). https://doi.org/10.1007/s00213-020-05655-0

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