Deschloroclozapine exhibits an exquisite agonistic effect at lower concentration compared to clozapine-N-oxide in hM3Dq expressing chemogenetically modified rats

Abstract

IntroductionWithin the realm of chemogenetics, a particular form of agonists targeting designer receptors exclusively activated by designer drugs (DREADDs) has emerged. Deschloroclozapine (DCZ), a recently introduced DREADDs agonist, demonstrates remarkable potency in activating targeted neurons at a lower dosage compared to clozapine-N-oxide (CNO).MethodsWe conducted a comparative analysis of the effects of subcutaneously administered CNO (1 mg/kg) and DCZ (0.1 mg/kg) in our transgenic rats expressing hM3Dq and mCherry exclusively in oxytocin (OXT) neurons.Results and DiscussionNotably, DCZ exhibited a swift and robust elevation of serum OXT, surpassing the effects of CNO, with a significant increase in the area under the curve (AUC) up to 3 hours post-administration. Comprehensive assessment of brain neuronal activity, using Fos as an indicator, revealed comparable effects between CNO and DCZ. Additionally, in a neuropathic pain model, both CNO and DCZ increased the mechanical nociceptive and thermal thresholds; however, the DCZ-treated group exhibited a significantly accelerated onset of the effects, aligning harmoniously with the observed alterations in serum OXT concentration following DCZ administration. These findings emphasize the remarkable efficacy of DCZ in rats, suggesting its equivalent or potentially superior performance to CNO at considerably lower dosages, thus positioning it as a promising contender among DREADDs agonists.

Chemogenetic Manipulation of Amygdala Kappa Opioid Receptor Neurons Modulates Amygdala Neuronal Activity and Neuropathic Pain Behaviors

“…Conversely, inhibition of Gi-DREADD (hM4Di) expressing CeA-KOR neurons resulted in hyperpolarization and decreased action potential firing (Figure 4(D3-D6)). Future studies can build on these findings to achieve temporal control over specific neuronal activation or inhibition with the administration of the normally pharmacologically inert ligand DCZ [58,59], allowing for a more detailed investigation of the dynamic role of CeA-KOR neurons in pain-related processing. The chemogenetic approach is both repeatable and reversible [60,61], facilitating the longitudinal study of CeA-KOR activation/inactivation on chronic pain-related behaviors.…”

Exploring memory-related network via dorsal hippocampus suppression

“…However, its pharmacokinetics indicate that the DCZ concentrations in the plasma and brain decrease significantly within two hours post- injection, and it is metabolized into C21 and DCZ-N-oxide. Some studies have reported equivalent or superior results with DCZ compared to other actuators (Ferrari et al, 2022; Nentwig et al, 2022; Shimizu et al, 2023). Therefore, DCZ could be a useful alternative worth considering in future research.…”