Abstract
Rationale
Designer receptors exclusively activated by designer drugs (DREADDs) are a tool for “remote control” of defined neuronal populations during behavior. These receptors are inert unless bound by an experimenter-administered designer drug, commonly clozapine-n-oxide (CNO). However, questions have emerged about the suitability of CNO as a systemically administered DREADD agonist.
Objectives
Second-generation agonists such as JHU37160 (J60) have been developed, which may have more favorable properties than CNO. Here we sought to directly compare effects of CNO (0, 1, 5, & 10 mg/kg, i.p.) and J60 (0, 0.03, 0.3, & 3 mg/kg, i.p.) on operant food pursuit.
Methods
Male and female TH:Cre + rats and their wildtype (WT) littermates received cre-dependent hM4Di-mCherry vector injections into ventral tegmental area (VTA), causing inhibitory DREADD expression in VTA dopamine neurons of TH:Cre + rats. All rats were trained to stably lever press for palatable food on a fixed ratio 10 schedule, and doses of both agonists were tested on separate days in counterbalanced order.
Results
All three CNO doses reduced operant rewards earned in rats with DREADDs, and no CNO dose had behavioral effects in WT controls. The highest J60 dose tested significantly reduced responding in DREADD rats, but this dose also increased responding in WTs, indicating non-specific effects. The magnitude of CNO and J60 effects in TH:Cre + rats were correlated and were present in both sexes.
Conclusions
Findings demonstrate the usefulness of directly comparing DREADD agonists when optimizing behavioral chemogenetics, and highlight the importance of proper controls, regardless of the DREADD agonist employed.
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Data availability
Data will be made available upon reasonable request.
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Acknowledgements
We thank NIDA Drug Supply Program for supplying CNO, and NIMH Drug Supply Program for supplying JHU37160.
Funding
Funding was provided by NIH grants P50 DA044118, T32 MH119049, R01 DA055849, and U01 DA053826.
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Lawson, K.A., Ruiz, C.M. & Mahler, S.V. A head-to-head comparison of two DREADD agonists for suppressing operant behavior in rats via VTA dopamine neuron inhibition. Psychopharmacology 240, 2101–2110 (2023). https://doi.org/10.1007/s00213-023-06429-0
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DOI: https://doi.org/10.1007/s00213-023-06429-0