Abstract
Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) represent a technical revolution in integrative neuroscience. However, the first used ligands exhibited dose-dependent selectivity for their molecular target, leading to potential unspecific effects. Compound 21 (C21) was recently proposed as an alternative, but in vivo characterization of its properties is not sufficient yet. Here, we evaluated its potency to selectively modulate the activity of nigral dopaminergic (DA) neurons through the canonical DREADD receptor hM4Di using TH-Cre rats. In males, 1 mg.kg-1 of C21 strongly increased nigral neurons activity in control animals, indicative of a significant off-target effect. Reducing the dose to 0.5 mg.kg-1 circumvented this unspecific effect, while activated the inhibitory DREADDs and selectively reduced nigral neurons firing. In females, 0.5 mg.kg-1 of C21 induced a transient and residual off-target effect that may mitigated the inhibitory DREADDs-mediated effect. This study raises up the necessity to test selectivity and efficacy of chosen ligands for each new experimental condition.
Highlights
Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are chemogenetic tools that represent one of the major breakthroughs of the last ten years in integrative neuroscience [1,2]
We thereby infused into the substantia nigra pars compacta (SNc) of male and female tyrosine hydroxylase (TH)-Cre rats, a floxed virus encoding for the inhibitory DREADDs hM4Di coupled to mCherry (♂-hM4Di and ♀-hM4Di)
Decreasing the dose of Compound 21 (C21) to 0.5 mg.kg-1 allowed to completely circumvent this unspecific effect on SNc neuronal activity (Mixed-effects analysis highlights a main effect of treatment: F(1, 13) = 16.08, p < 0.01; of the time: F(8, 98) = 6.38, Fig 2. hM4Di-mCherry and mCherry expression in mesencephalic DA neurons of TH-Cre rats. (A) On the left, schema of the three levels of mesencephalon used for quantified viral expression with three areas: lateral SNc, medial SNc and Ventral Tegmental Area (VTA)
Summary
Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are chemogenetic tools that represent one of the major breakthroughs of the last ten years in integrative neuroscience [1,2]. Combining the precision of genetics with pharmacology, DREADDs provide a remote, prolonged and reversible control of neuronal or extra-neuronal subpopulations via conditional expression and allow the study of complex phenomena in awake animals. As such, they were elegantly used to induce tonic modulation, affording an alternative to optogenetics which is more adapted for phasic modulation [3], and to study the implication of different neural system in various behaviors such as feeding, memory, pain or motivation (reviewed in [4]).
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