Chronic harmine treatment has a delayed effect on mobility in control and socially defeated rats

Abstract

Introduction Depression is characterized by behavioral, cognitive and physiological changes, imposing a major burden on the overall wellbeing of the patient. Some evidence indicates that social stress, changes in growth factors (e.g., brain-derived neurotrophic factor (BDNF)), and neuroinflammation are involved in the development and progression of the disease. The monoamine oxidase A inhibitor drug harmine was suggested to have both antidepressant and anti-inflammatory properties and may, therefore, be a potential candidate for treatment of depression. Aim The goal of this study was to assess the effects of harmine on behavior, brain BDNF levels, and microglia activation in control rats and a rat model of social stress. Material and methods Rats were submitted to 5 consecutive days of repeated social defeat (RSD) or control conditions. Animals were treated daily with harmine (15 mg/kg) or vehicle from day 3 until the end of the experiment. To assess the effects of harmine treatment on behavior, the sucrose preference test (SPT) was performed on days 1, 6, and 15, the open field test (OFT) on days 6 and 14, and the novel object recognition test (NOR) on day 16. Brain microgliosis was assessed using [ 11 C]PBR-28 PET on day 17. Animals were terminated on day 17, and BDNF protein concentrations in the hippocampus and frontal cortex were analyzed using ELISA. Results RSD significantly decreased bodyweight and increased anxiety and anhedonia-related parameters in the OFT and SPT on day 6, but these behavioral effects were not observed anymore on day 14/15. Harmine treatment caused a significant reduction in bodyweight gain in both groups, induced anhedonia in the SPT on day 6, and significantly reduced the mobility and exploratory behavior of the animals in the OFT mainly on day 14. PET imaging and the NOR test did not show any significant effects on microglia activation and memory, respectively. BDNF protein concentrations in the hippocampus and frontal cortex were not significantly affected by either RSD or harmine treatment. Discussion Harmine was not able to reverse the acute effects of RSD on anxiety and anhedonia and even aggravated the effect of RSD on bodyweight loss. Moreover, harmine treatment caused unexpected side effects on general locomotion, both in RSD and control animals, but did not influence glial activation status and BDNF concentrations in the brain. In this model, RSD-induced stress was not strong enough to induce long-term effects on the behavior, neuroinflammation, or BDNF protein concentration. Thus, the efficacy of harmine treatment on these delayed parameters needs to be further evaluated in more severe models of chronic stress.

β-Carbolines found in cigarette smoke elevate intracranial self-stimulation thresholds in rats

“…The elevation of ICSS latencies by harmane and harmine is consistent with previous findings that these β-carbolines can suppress motor function in rats as measured using openfield locomotor activity or inactive lever pressing in an operant procedure (Giacobbo et al, 2020;Goodwin et al, 2015;Qiu et al, 2015). The lower potency of harmane and harmine to elevate ICSS latencies compared to ICSS thresholds indicates that motoric effects of these compounds did not confound their effects on thresholds, at least at lower doses.…”

“…In contrast, another study found that neither harmane nor norharmane pretreatment affected ongoing nicotine self-administration (Hall et al, 2014), and a cocktail of behaviorally active constituents including norharmane, harmane, acetaldehyde, and minor alkaloids (e.g., nornicotine, anabasine) did not alter nicotine's reinforcing effects (Smith et al, 2015). Although harmine produced anhedonic effects in a sucrose preference test (Giacobbo et al, 2020), it has not been evaluated in a model of abuse liability per se.…”

RETRACTED ARTICLE: HDAC1-Mediated MicroRNA-124-5p Regulates NPY to Affect Learning and Memory Abilities in Rats with Depression

“…Depression refers to a severe disabling psychosis that causes severe economic burdens and social consequences globally [1]. Depression is characterized by physiological, cognitive and behavioral changes that threatens patients' overall health [2]. The treatments accessible to depression have developed with the application of ketamine as a fast-acting antidepressant and the refinement of equipment capable of selectively catering to the activity of populations of neuronal subtypes [3].…”

Chronic social defeat stress mouse model: Current view on its behavioral deficits and modifications.

“…Besides, various social defeat stress rat models have been developed in recent years, including the CSDS and psychosocial witness stress rat model (Patki, Solanki, & Salim, 2014). Existing studies have shown that behavioral and physiologic characteristics of these rat models are similar to those in mouse models (Arora et al, 2018;Finnell et al, 2018;Giacobbo et al, 2020;Kochi et al, 2017;Morais-Silva et al, 2019;Zaidi et al, 2020), which further confirms the feasibility of CSDS-induced behavioral deficits among different strains.…”