2. Academic Validation
  3. Comparison of three DREADD agonists acting on Gq-DREADDs in the ventral tegmental area to alter locomotor activity in tyrosine hydroxylase:Cre male and female rats

Comparison of three DREADD agonists acting on Gq-DREADDs in the ventral tegmental area to alter locomotor activity in tyrosine hydroxylase:Cre male and female rats

  • Behav Brain Res. 2023 Sep 16;114674. doi: 10.1016/j.bbr.2023.114674.
Hannah L Robinson 1,  Katherine L Nicholson 1,  Keith L Shelton 1,  Peter J Hamilton 2,  Matthew L Banks 3
Affiliations

Affiliations

  • 1 Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
  • 2 Department of Anatomy and Neurobiology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
  • 3 Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA. Electronic address: mbanks7@vcu.edu.
PMID: 37722510 DOI: 10.1016/j.bbr.2023.114674
Abstract

Rationale: Despite the increasingly pervasive use of chemogenetic tools in preclinical neuroscience research, the in vivo pharmacology of DREADD agonists remains poorly understood. The pharmacological effects of any ligand acting at receptors, engineered or endogenous, are influenced by numerous factors including potency, time course, and receptor selectivity. Thus, rigorous comparison of the potency and time course of available DREADD ligands may provide an empirical foundation for ligand selection.

Objectives: Compare the behavioral pharmacology of three different DREADD ligands clozapine-N-oxide (CNO), compound 21 (C21), and deschloroclozapine (DCZ) in a locomotor activity assay in tyrosine hydroxylase:cre recombinase (TH:Cre) male and female rats.

Methods: Locomotor activity in nine adult TH:Cre Sprague-Dawley rats (5 female, 4 male) was monitored for two hours following administration of d-amphetamine (vehicle, 0.1-3.2mg/kg, IP), DCZ (vehicle, 0.32-320µg/kg, IP), CNO (vehicle, 0.32-10mg/kg), and C21 (vehicle, 0.1-3.2mg/kg, IP). Behavioral sessions were conducted twice per week prior to and starting three weeks after bilateral intra-VTA hM3Dq DREADD virus injection.

Results: d-Amphetamine significantly increased locomotor activity pre- and post-DREADD virus injection. DCZ, CNO, and C21 did not alter locomotor activity pre-DREADD virus injection. There was no significant effect of DCZ, CNO, and C21 on locomotor activity post-DREADD virus injection; however, large individual differences in both behavioral response and receptor expression were observed.

Conclusions: Large individual variability was observed in both DREADD agonist behavioral effects and receptor expression. These results suggest further basic research would facilitate the utility of these chemogenetic tools for behavioral neuroscience research.

Keywords

DREADD; TH:Cre rats; clozapine N-oxide; compound 21; deschloroclozapine; locomotor activity.

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