Table 1.

Compilation of methods and results of studies using P2X7R antagonistic drugs in murine depression models based on CPSS/CPPS application

Stress model and animal characteristics						P2X7R-antagonist and behavioural assessment			Main results	References
Stress paradigm/individual stressors		Stressor application	Paradigm duration	Species/strain	Sex/age	P2X7R antagonist and dosage/application and timing		Behavioural tests and timing/experimenter blinding
Unpredictable Chronic Mild Stress (UCMS)	Social stress, wet bedding, frequent bedding change, cage tilting at 45°, place rat droppings in mice cages, playing predator sounds, altering day and night cycles, restraint stress (30 min)	Two stressors per day, over time increased to four or five stressors per day; random order	9 weeks	Mouse/BALB/cByJ	Male/7 weeks	BBG 50 mg/kg i.p	Application commenced 2 weeks after the UCMS start; performed until the end of UCMS	CSS (once weekly during the UCMS), NBS (assessed during the last week of UCMS; for more details see [138]) Experimenters were blinded to the treatment status for the CSS	UCMS resulted in (a) impaired CSS and NBS at weeks 8 and 9; improved by BBG (p < 0.01 vs. UCMS + saline group) (b) increased microglial activation and P2X7R expression in limbic and cortical areas; ameliorated by BBG (p < 0.05 vs. UCMS + saline group) (c) HPA dysfunction; attenuated by BBG (p < 0.05 vs. UCMS + saline group)	[139]
Unpredictable Chronic Mild Stress (UCMS)	Cage tilting (24 h), wet bedding (24 h), swimming in 4 °C cold or in 45 °C hot water (each 5 min), pairing with other stressed animal (48 h), level shaking (10 min), nip tail (1 min), inversion light/dark cycle (24 h)	One stressor per day; each stressor applied 5–6 times in total; the same stressor was not applied two days in a row; random order	6 weeks	Rat/Wistar-Albino	Male/8–10 weeks	BBG 25 mg/kg i.p BBG 50 mg/kg i.p	Application every 24 h during the last 3 weeks of UCMS	FST, SPT (both performed after UCMS ended) Experimenters were blinded to the treatment status for the FST	UCMS resulted in (a) anhedonic behaviour in SPT; attenuated by 25 and 50 mg BBG (p < 0.01 vs. UCMS + saline) (b) elevated immobility in the FST; recovered by 50 mg but not 25 mg BBG (p < 0.01 vs. UCMS + saline) (c) mRNA level increase of P2X7R, caspase-1, ASC, NFƙB, IL-1β, IL-6; attenuated by 50 mg BBG (p < 0.05 vs. UCMS + saline); microglia activation (Iba-1 in IHC; hippocampus) in the UCMS group; reduced by both 25 and 50 mg BBG (p < 0.01 vs. UCMS + saline)	[140]
Chronic Unpredictable Stressors (CUS)	Water/food deprivation (each 40 h), light–dark cycle reversal, hot environment (40 °C, 5 min), swimming in cold water (4 °C, 5 min), cage shake (30 min)	One stressor per day; random order	3 weeks	Rat/Sprague–Dawley	Male/n.a.*	BBG 1 μl (1 pM) A-438079 1 µl (1.75 nM) Bilateral microinjection into the hippocampus via an implanted cannula	Application once daily during CUS; injections were performed 30 min after each stress exposure	FST, OFT (both performed on the first day of CUS before the injection and on the last day of the CUS paradigm 30 min after the last injection occurred) Experimenters were blinded to the treatment status for all tests	CUS resulted in (a) elevated hippocampal extracellular ATP, increased cleaved-caspase-1, ASC and NLRP3 levels (p < 0.05 vs. controls); slightly raised IL-1β, unaltered P2X7R levels at weeks 1, 2 and 3 (p > 0.05 vs. controls) (b) depressive-like behaviour with reduced rearing and distance travelled in the OFT, less struggle and more immobility time in the FST (p < 0.05 vs. CUS + saline); CUS effects were attenuated by injection of BBG or A-438079 (p < 0.05 vs. CUS + saline)	[113]
Chronic Unpredictable Stressors (CUS)	Cage tilt, light–dark cycle change, crowd, odor, cold stress, no bedding, wet bedding, isolation, food/water deprivation, stroboscope, forced swim, cage rotation, immobilization stress	Two stressors per day; random order	8 weeks	Rat/Sprague–Dawley	Male/n.a	A-804598 5 mg/kg i.p	Application twice daily in the last 4 weeks of CUS (∑ 10 mg/kg/d of A-804598)	SPT, NSFT, EPM (all performed after UCMS ended) Experimenters were blinded to the treatment status for all tests	CUS resulted in (a) reduced consumption in the SPT, elevated latency to feed in the NSFT and reduced time in the open arms of the EPM (p < 0.05 vs. unstressed controls) (b) A-804598 significantly reversed the CUS effects in the SPT, NSFT and EPM (p < 0.05 vs. CUS group)	[94]

BBG brilliant blue G, i.p. intraperitoneal, n.a. not available, ASC apoptosis-associated speck-like protein containing a CARD

CSS coat state score, NBS nest building score, SPT sucrose preference test, FST forced swim test, OFT open field test, NSFT novelty suppressed feeding test, EPM elevated plus maze, SCT sucrose consumption test, IHC immunohistochemistry

*Rats were 180–200 g