Isoxazole‐9 reduces enhanced fear responses and retrieval in ethanol‐dependent male rats

Abstract

Plasticity in the dentate gyrus (DG) is strongly influenced by ethanol, and ethanol experience alters long-term memory consolidation dependent on the DG. However, it is unclear if DG plasticity plays a role in dysregulation of long-term memory consolidation during abstinence from chronic ethanol experience. Outbred male Wistar rats experienced 7 weeks of chronic intermittent ethanol vapor exposure (CIE). Seventytwo hours after CIE cessation, CIE and age-matched ethanol-naïve Air controls experienced auditory trace fear conditioning (TFC). Rats were tested for cue-mediated retrieval in the fear context either twenty-four hours (24 hr), ten days (10 days), or twenty-one days (21 days) later. CIE rats showed enhanced freezing behavior during TFC acquisition compared to Air rats. Air rats showed significant fear retrieval, and this behavior did not differ at the three time points. In CIE rats, fear retrieval increased over time during abstinence, indicating an incubation in fear responses.Enhanced retrieval at 21 days was associated with reduced structural and functional plasticity of ventral granule cell neurons (GCNs) and reduced expression of synaptic proteins important for neuronal plasticity. Systemic treatment with the drug Isoxazole-9 (Isx-9; small molecule that stimulates DG plasticity) during the last week and a half of CIE blocked altered acquisition and retrieval of fear memories in CIE rats during abstinence. Concurrently, Isx-9 modulated the structural and functional plasticity of ventral GCNs and the expression of synaptic proteins in the ventral DG.These findings identify that abstinence-induced disruption of fear memory consolidation occurs via altered plasticity within the ventral DG, and that Isx-9 prevented these effects.

Social stress under binge-like alcohol withdrawal in adolescence: evidence of cannabidiol effect on maladaptive plasticity in rats

“…Our evidence is consistent with studies showing that male rats exposed to chronic alcohol displayed heightened freezing in context-induced memory tasks indicating the occurrence of a maladaptive coping to adverse stimuli (Rorick, Finn, & Steinmetz, 2003; Staples et al, 2021). Notably, the only report available, to our knowledge, on the response to social stress in a human population exposed to alcohol during adolescence highlighted a significant association between early alcohol use and impaired stress perception and HPA axis reactivity during a social stress procedure (Evans, Greaves-Lord, Euser, Franken, & Huizink, 2012).…”

ISX-9 potentiates CaMKIIδ-mediated BMAL1 activation to enhance circadian amplitude

“…ISX-9 was then proposed in a few applications related to neurogenesis, for instance, to potentiate cell proliferation and neuronal commitment in the dentate gyrus in vivo 46 . Interestingly, besides the primary role as a neurogenesis inducer, ISX-9 was reported to be useful in treating neuropsychiatric conditions, such as lowering the relapse of methamphetamine abuse 47 and fear response in ethanol-dependent rat model 48 . In an age-related perspective, ISX-9 was shown to rescue the loss of cortico-striatal synapse, thus improving cognition in Huntington's disease model R6/2 strain 49 .…”

Isoxazole 9 (ISX9), a small molecule targeting Axin, activates Wnt/β‐catenin signalling and promotes hair regrowth

“…Kalwat et al also reported that ISX9 could alter β‐cell metabolites, protect glucose‐responsive signalling pathways under lipotoxic conditions and improve glycemia in a mouse model of β‐cell regeneration (Kalwat et al, 2016). In ethanol‐dependent male rats, ISX9 was found to decrease enhanced fear responses and retrieval (Staples et al, 2021). Recently, Li et al demonstrated that ISX9 could promote circadian amplitude via potentiation of CaMKIIδ‐mediated brain and muscle ARNT‐Like 1 (BMAL1; aryl hydrocarbon receptor nuclear translocator‐like protein 1/ARNTL) activation (Li et al, 2022).…”