Based on the previous literature, we systematically assorted the dose of donepezil from 0

Based on the previous literature, we systematically assorted the dose of donepezil from 0.02C0.2 to 2.0 mg/kg in C57BL/6J mice and found that while the higher dose (2.0 mg/kg) recapitulated the previously-reported depressant-like properties in rodents, the lower doses (0.02 and 0.2 mg/kg) produced the antidepressant-like responses reported in additional studies. of additional studies in both humans and rodents display antidepressant effects. Our study was one of the 1st to systematically vary dose to include very low concentrations while measuring behavioral effects, potentially explaining the apparent disparate findings in the field. The possibility of antidepressant tasks for AChEIs in rodents may provide hope for fresh major depression treatments. Importantly, MDD is definitely a psychosocial stress-linked disorder, and in rodents, stress is a major experimental manipulation for studying major depression mechanisms, so an important long term direction will be to determine the degree to which these depression-related effects are stress-sensitive. In sum, getting a greater understanding of the potentially restorative mood-related effects of low dose AChEIs, both in rodent models and in human being subjects, should be a prioritized topic in ongoing translational study. presynaptic launch of norepinephrine, which might be expected to potentiate the depression-like effects of physostigmine. But perhaps the agonist activity of guanfacine on postsynaptic 2A receptors facilitates noradrenergic signaling. The depression-related effects of physostigmine in mice, reported with this paragraph, have been corroborated by another group at a low dose (0.03 mg/kg) (Van Enkhuizen et al., 2015). Additional studies in rats further implicate physostigmine in promoting depression-like behavior. Administration of physostigmine to rats that were exposed to inescapable footshooks, delivered intermittently over a 60 min period the day before the FST, amplified the decrease in active behaviors in the FST that was produced by this stressor (P?aznik et al., 1988). It has also been shown in rats that infusion of physostigmine into the ventral tegmental area (or systemic administration of low doses), raises immobility in the FST, suggesting that dysregulation of reward-related mind circuits may in part mediate the effects (Addy et al., 2015; Small et al., 2016). The therapeutic-like effects of the antidepressants, desipramine and nomifensine, in the FST can be antagonized by physostigmine (Mancinelli et al., 1988), consistent with the cholinergic-adrenergic hypothesis. An additional rat Azilsartan medoxomil monopotassium Azilsartan medoxomil monopotassium study, measuring anhedonia-related behavior through intracranial self-stimulation, found that another AChEI, Azilsartan medoxomil monopotassium donepezil, did not modulate the effects of chronic sociable defeat stress on this behavior (Gottschalk et al., 2018). This second option study raises the point that it will be important to determine if the depression-like effects of physostigmine generalize to additional AChEIs, although we have already observed depression-like effects with donepezil (Fitzgerald et al., 2020). In summary, the above studies of physostigmine in mice and rats strongly implicate this drug in promoting depression-like behavior at higher doses in the range of 0.125C2.0 mg/kg and sometimes at lower ones. Antidepressant-Like Findings in Rodent Behavioral Checks In contrast to the literature reviewed above, there are several studies, in addition to our personal on donepezil, that statement antidepressant-like effects of AChEIs in rodents. A study of swiss mice in the FST reported acute antidepressant-like properties of donepezil, including at very high doses (up Rab12 to 30 mg/kg) (Maurice et al., 2006). This group also found that the AChEIs rivastigmine and tacrine lacked an antidepressant-like response, and they hypothesized the antidepressant-like response of donepezil was not mediated through cholinergic mechanisms but rather involved the sigma-1 receptor. Maurice et al. (2006) also did not find a depression-like response to donepezil at high doses, and consequently did not suggest a Janus-faced dose-response pattern. One possibility is definitely that swiss mice do not respond similarly to donepezil in the FST as the C57BL/6J strain we used in Fitzgerald et al. (2020). A study that used chronic treatment with the AChEI, rivastigmine, in olfactory bulbectomized mice (of the DDY strain), which is a rodent model of major depression, reported antidepressant-like behavior in various tests including the FST, tail suspension test, and novelty suppressed feeding test (Islam et al., 2014). These authors suggest that the therapeutic-like effects of rivastigmine are dependent upon signaling.