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. 2022 Sep 26;16:1002223. doi: 10.3389/fnbeh.2022.1002223

TABLE 1.

N-acetylcysteine-induced therapeutic effects in psychiatrically relevant rodent models.

 1a. Schizophrenia-related rat models

Model NAC application Cognitive domain Negative domain Other changes References
BSO Chronic p.o. 10 and 30 mg/kg/d P68–89 ↑OM (NOR) ↑ Social interaction ↑ Efficacy of aripiprazole
↑ BDNF
Rogóż et al., 2022
SIR Chronic i.p. 150 mg/kg/d P63–77 ↑OM (NOR) ↑Social interaction ↑Rearing, ↑ PPI
↑ Clozapine efficacy
↓ proInflam. cytokines
↓ KYN/KYN-A
↓ DA (STR); ↑DA (FC)
Möller et al., 2013
NVHL Chronic 0.9 g/l d-water P5–50 ↑ PVI and PNNs
↓ Oxidative stress
↑MMN, PPI
Cabungcal et al., 2014
MIA + MA Chronic s.c. 150 mg/kg/d P51–64 ↑OM (NOR) ↑Social interaction ↑ PPI
↑ NA (FC, STR)
↓ Oxidative stress
Swanepoel et al., 2018
Poly-I:C and PUS Chronic i.p. 220 mg/kg/d P30–59 ↑WM (alternation) ↑Social interaction ↑ PPI (♀ only)
↓ LMA
↓ Oxidative stress
↑ PVI (♀ only)
Monte et al., 2020
APO-SUS Chronic, 0.9 g/l d-water P5–40, 2 g/l P40–90 ↑Cognitive flexibility
↓ Oxidative stress
↑ myelination
Maas et al., 2021
MAM Chronic 0.9 g/l d-water P11–25 ↑ PVI and PNNs
↓ Oxidative stress
Zhu et al., 2021
MAM Chronic i.p. 250 mg/kg/d P75–90 ↑Social interaction ↓ MK801-induced LMA
Lopes-Rocha et al., 2022
MAM Acute i.p. 150–500 mg/kg ↑Social interaction ↓ MK801-induced LMA Lopes-Rocha et al., 2022
PCP Acute i.p. 90 mg/kg ↑WM (alternation) ↑Social interaction ↓ Glutamate release Baker et al., 2008
MA Acute i.p. 100 and 300 mg/kg ↓ MA-induced LMA Fukami et al., 2004

 1b. Schizophrenia-related mouse models

Model NAC application Cognitive domain Negative domain Other changes References

G72Tg Chronic 1 g/l d-water 3–8 weeks ↑SLTM (MWM) Otte et al., 2011
ketamine Chronic s.c. 10 mg/kg P5–21; 1 g/l d-water from P22; or P35–56 ↑WM (alternation)
↑Cognitive flexibility
↑OM (NOR)
↑Social interaction
↑ Social novelty pref.
↑ PPI
↑ PVI
↓ Oxidative stress
Phensy et al., 2017a,b
Gclm KO Chronic 0.9 g/l d-water P20–35 ↓ MMP9/RAGE
↑ PVI and PNNs
Dwir et al., 2021
-/KYN 7 days i.p. 100 mg/kg/d ↑SLTM (food location) ↓ KYN/KYN-A
↓ Oxidative stress
Blanco Ayala et al., 2021
Grm5 KO Acute i.p. 50 and 100 mg/kg ↑ PPI Chen et al., 2010
Amph Acute i.p. 60 mg/kg ↓ Amphetamine sensitization-induced LMA Herrmann et al., 2017

1c. Models related to other brain disorders

Primary disorder Species Model NAC application Cognitive domain Negative domain Other changes References

MDD Rat CLI Chronic i.p. 100 mg/kg/d, P76–89 ↑WM (alternation) ↓Depression
↓Anhedonia (SPT)
↑ HC volume
↑ HC monoamines
↓ Anxiety
Chakraborty et al., 2020b
Rat CLI Chronic i.p. 100 mg/kg/d, P76–89 ↓Anhedonia (SPT)
↓ Anxiety
↓ Adrenal and spleen volume
↓ Corticosterone
Chakraborty et al., 2020a
Rat OBX 10 days i.p. 50 and 100 mg/kg/d ↓Depression (FST) ↑ HC and FC SOD activity
Smaga et al., 2012
Rat CUMS 1 week p.o 50 and 100 mg/kg/d ↓Depression (FST)
↓Anhedonia (SPT)
↑ HC serotonin
↓ proInflam cytokines
Fernandes and Gupta, 2019
Rat Alcohol abstinence 3 days i.p.50 and 100 mg/kg/d ↓Depression (FST, TST) ↓ GRIN2A/B
↑ HC serotonin
Yawalkar et al., 2018
Rat - Acute i.p. 15–150 mg/kg ↓Depression (FST) Ferreira et al., 2008
Rat OBX Acute i.p. 25–100 mg/kg ↓ Cocaine-seeking Frankowska et al., 2014
Mouse Repeated audible noise Chronic p.o. 325 mg/kg/d for 30 days ↓Depression (TST)
↓anhedonia (SPT)
↓Anxiety
↑ Exploration
↓ Oxidative stress
Mahmoodzadeh et al., 2021
Mouse Acute i.p. 25 mg/kg ↓Depression (TST) ↑Efficacy of imipramine and escitalopram Costa-Campos et al., 2013
OCD Mouse Acute i.p. 150 mg/kg ↓Marble burying Egashira et al., 2012
Aging Mouse Chronic 3 g/kg food, for 10 weeks ↑SLTM (MWM) Ikonne et al., 2019
AD Mouse ApoE4 Chronica, 5 g/kg food ↑WM (alternation) ↓ Aggression Shea, 2007
Mouse SAMP8 Chronic s.c. 100 mg/kg/d for 4 weeks ↑ Conditioned avoidance Farr et al., 2003
HD Mouse R6/1 Chronic i.p. 500 mg/kg/d for 8–12/17 weeks ↓Depression (FST) ↑ Motor function
↑ Mitochondrial function
↓ GluN2B
↑ Glutamate
(Wright et al., 2015, 2016)
Mouse R6/1 Acute i.p. 500 mg/kg ↓Depression (FST) Wright et al., 2016
AE Rat WAG/Rij Chronic p.o. 500 mg/kg/d for 30 days ↑OM (NOR) ↓Depression (FST) Epilepsy worsens!
↑ mGluR2
Tallarico et al., 2022

aApplied in combination with ALCAR (acetyl-L-carnitine; 1 g/kg diet) and SAM (S-adenosyl methionine; 100 mg/kg diet). AD, Alzheimer’s disease; AE, absence epilepsy; Amph, repeated amphetamine application (amphetamine sensitization); APO-SUS, apomorphine-susceptible rat; BSO, L-buthionine-(S,R)-sulfoximine developmental model of SCZ; CLI, neonatal/juvenile clomipramine application model of depression; CUMS, chronic unpredictable mild stress model of depression; DA, dopamine; d-water, drinking water; FC, frontal cortex; FST, force-swim test; Gclm, glutamate-cysteine ligase modulatory subunit; HC, hippocampus; HD, Huntington’s Disease; KYN/KYN-A, kynurenine/kynurenic acid; LMA, locomotor activity; MA, methamphetamine developmental model of SCZ; MAM, methylazoxymethanol acetate developmental model of SCZ; MDD, major depressive disorder; MMP9/RAGE, matrix-metalloprotease 9/receptor for advanced glycation end-products; MIA, developmental LPS-based maternal immune activation model of SCZ; MMN, mismatch-negativity of the auditory evoked potential; MWM, Morris water-maze; NA, noradrenaline; NOR, novel-object recognition test; NVHL, neonatal ventral hippocampal lesion model of SCZ; OBX, bulbectomization model of depression; OCD, obsessive compulsive disorder; OM, short-term object memory; PCP, phencyclidine model of SCZ; PNNs, perineuronal-nets; Poly-I:C, polyinosinic:polycytidylic acid viral mimetic developmental model of SCZ; PPI, pre-pulse inhibition of the startle response; PUS, peripubertal unpredictable stress; PVI, parvalbumin-positive interneurons; SIR, social isolation rearing; SLTM, spatial long-term memory; SOD, superoxide dismutase (anti-oxidant mechanism); SPT, sucrose-preference test; TST, tail-suspension test; WM, working memory.