Table 1.
NAC and SUD—preclinical research
| Model/procedure | Species, sex | NAC (dose, route, treatment) | Change | References | |
|---|---|---|---|---|---|
| In vivo | Ex vivo | ||||
| Alcohol | |||||
| Chronic alcohol exposure | Wistar rats, male |
2 g/L po; 45 day |
↓ alcohol intake |
↓ TG rise (serum) ↓ VLDL rise (serum) ↓ ox-LDL rise (serum) ↑ HDL/TG ratio (serum) |
[26] |
| Chronic alcohol exposure/deprivation | Wistar rats, male | 2 g/L po; 15 days during deprivation | ↓ TG rise (serum) | ||
| Chronic alcohol/withdrawal | Wistar rats, male | 60, 90 mg/kg, ip | ↓ alcohol withdrawal-induced anxiety (60–90) |
↓ CORT rise (serum) ↓ leptin rise (serum) |
[32] |
| Repeated alcohol in sensitization paradigm | Swiss mice, male |
60, 120 mg/kg, ip; 15 days |
↓ development of alcohol sensitization (120) |
↓ ΔFosB rise (PFC) ↑ xCT drop (NAcc) |
[29] |
| Chronic alcohol access to high alcohol drinkers/deprivation/relapse | Wistar rats, male |
100 mg/kg, po; 14 days |
↓ alcohol intake ↓ alcohol relapse |
↓ GSSG/GSH and GFAP rises (HIP) | [27] |
| Alcohol self-administration/seeking/reacquisition | Long Evans rats, male | 25, 50, 100 mg/kg, ip |
↓ alcohol self-administration (25–100) ↓ alcohol seeking (25–100) ↓ reacquisition of alcohol self-administration (25–100) |
[30] | |
| Chronic (15 days) voluntary alcohol drinking | Sprague–Dawley rats, male | 25, 50, 100 mg/kg, ip; 3 days | ↓ depression (50–100) |
↑ 5-HT drop (25–100; HIP) ↑ 5-HT drop (100; PFC) ↓ GRIN2A and GRIN2B rise (50–100; HIP) ↓ SGPT, SGOT, GGT rises (50–100) ↓ ALP, MCV rises (50–100) |
[33] |
| Chronic (10 week) intermittent alcohol vapor/extinction/reacquisition | Wistar rats, male | 25, 50, 100 mg/kg, ip |
↓ alcohol reward (25–100) ↓ alcohol motivation (25) ↓ extinction responding (50) ↓ reacquisition of alcohol self-administration (50) |
∅ xCT (100; NAc) ∅ GLT-1 (100; NAc) |
[30] |
| Chronic alcohol access to high alcohol consumers/deprivation/relapse | Wistar rats, female |
70 mg/kg, ip; 2 days + 40 mg/kg, po; 11 days |
↓ alcohol intake ↓ alcohol relapse |
↑ Nrf2-ARE pathway (HIP) ↓ GSSG/GSH (HIP) |
[28] |
| Alcohol deprivation effect (ADE) model | Wistar rats, male |
2 mg/h, sc (pumps); 14 days |
↓ alcohol relapse | [31] | |
| 60–100 mg/kg, sc | ↓ alcohol relapse (60) | ||||
| Cannabinoids | |||||
| THC + CBD self-administration/extinction/reinstatement | Sprague–Dawley rats, male |
60 mg/kg, ip; 5 days |
↓ THC induced- reinstatement |
[34] | |
| Nicotine | |||||
| Nicotine self-administration | Wistar rats, male | 30, 60, and 90 mg/kg, ip | ↓ nicotine reward (30–90) | [37] | |
| Nicotine self-administration |
60 mg/kg; ip; 14 days |
↓ nicotine reward (no tolerance) |
|||
| Nicotine self-administration/extinction/reinstatement | 30, 60, 90 mg/kg, ip | ↓ cue-induced reinstatement (60–90) | |||
| Nicotine conditional place preference | ICR mice, male | 5, 15, 30, 60 mg/kg, ip | ↓ nicotine reward (5–60) | [36] | |
| 2-week continuous nicotine treatment/withdrawal | 15, 30, 120 mg/kg, ip |
↓ nicotine withdrawal (15–120) ∅ withdrawal-induced anxiety (15–120) |
|||
| Neonatal vHIP lesion + nicotine self-administration | Sprague–Dawley rats, male |
100 mg/kg, ip; PND 42-PND 91 |
↓ nicotine reward | [35] | |
| Neonatal vHIP lesion + nicotine self-administration, extinction/reinstatement |
100 mg/kg, ip; PND 42-PND 126 |
↓ nicotine-induced reinstatement | |||
| Nicotine vs. saccharin discrimination/extinction/reinstatement | Wistar rats, male | 30, 60, 100 mg/kg, ip | ↓ cue-induced reinstatement (100) | [39] | |
| Nicotine conditioned place preference | Wistar rats, female bred as high ethanol drinkers |
100 mg/kg, po; 9 days |
↓ nicotine intake | [27] | |
| Nicotine conditioned place preference/reinstatement | ↓ reinstatement of nicotine place preference | ↓ GSSG/GSH and GFAP rises (HIP) | |||
| Nicotine self-administration/extinction/reinstatement | Sprague–Dawley rats, male |
100 mg/kg ip; 4 days |
∅ cue-induced reinstatement | ∅ dendritic spine morphology rised or mRNA/protein of relevant glutamatergic genes rises (NAcc core) | [42] |
|
100 mg/kg ip; 15 days |
↓ extinction ↓ cue-induced reinstatement |
||||
| Nicotine self-administration/extinction/reinstatement | Sprague–Dawley rats, male |
100 mg/kg ip; 4 days |
↓ cue-induced reinstatement | [41] | |
| Sprague–Dawley rats, female |
∅ cue-induced reinstatement (during estrous or met/diestrus) |
||||
| Nicotine self-administration/extinction/reinstatement | Sprague–Dawley rats, male |
60, 100 mg/kg ip; 14 days |
↓ cue-induced reinstatement (100) | [40] | |
| Nicotine self-administration/cue-exposure extinction/reinstatement | ↓ cue-induced nicotine reinstatement (100) |
↑ GLT-1 drop and ↓ GluN2B rise (NAcc shell; 7 days after) ↑ xCT drop (NAcc shell; 50 days after) ↑ mGluR2 (NAcc shell + core; 50 days after) |
|||
| Nicotine self-administration/home abstinence/relapse | ∅ cue-induced nicotine relapse (100) | ||||
| Nicotine self-administration/extinction/reinstatement | Sprague–Dawley rats, male |
100 mg/kg, ip; 5 days |
↓ cue-induced nicotine reinstatement (100) |
↓ AMPA/NMDA ratio, ↓ TNFα and ↑ GFAP (NAcc core) |
[38] |
| Opioids | |||||
| Heroin self-administration/extinction/reinstatement | Sprague–Dawley rats, male |
100 mg/kg, ip; 15 days |
↓ cue-induced reinstatement ↓ heroin-induced reinstatement |
[44] | |
| Heroin self-administration/extinction/reinstatement | Lister Hooded rats, male | 30, 60, 90 mg/kg, ip |
∅ early cue-induced reinstatement ↓ late cue-induced reinstatement (90) |
[43] | |
| Repeated, systemic morphine administration + naloxone-precipitated withdrawal | Swiss–Webster mice, male | 50 mg/kg, ip | ↓ withdrawal symptoms (in combination with Nigella sativa oil) |
↓ NO (brain) ↑ GSH (brain) |
[45] |
| ↓ withdrawal symptoms (in combination with α-lipic acid) |
↓ NO, GLU, MDA ↑ GSH, GSH-Px |
[46] | |||
| Psychostimulants | |||||
| Amphetamine self-administration | Squirrel monkey, male | 10, 30 mg/kg, im |
∅ amphetamine reward ∅ cocaine reward ∅ cocaine reinstatement |
[47] | |
| Repeated amphetamine in sensitization paradigm | Sprague–Dawley rats, male |
90 mg/kg, ip; 1 or 10 days |
∅ re-expression of amphetamine sensitization | [48] | |
| Cocaine self-administration/extinction/reinstatement | Sprague–Dawley rats, male |
60 mg/kg, ip; 4 days |
↓ cocaine-induced reinstatement | ↓ GLU release rise and ↑ xCT activity drop (NAcc) | [10] |
| Cocaine self-administration/extinction/reinstatement | Sprague–Dawley rats, male | 60 mg/kg, sc | ↓ cocaine-induced reinstatement | [50] | |
| Cocaine self-administration | Sprague–Dawley rats, male |
60 mg/kg, ip; 11 days |
∅ cocaine reward acqusition ∅ cocaine reward |
[21] | |
| Cocaine self-administration in escalation paradigm |
60 mg/kg, ip; 11 days |
↓ cocaine-induced escalation of drug intake | |||
| Cocaine self-administration/extinction/reinstatement |
60 mg/kg, ip; 10–11 days |
↓ cocaine-induced reinstatement |
↑ xCT and basal GLU (NAcc) ↓ cocaine-evoked GLU release (NAcc) |
||
| Repeated cocaine in sensitization paradigm |
60 mg/kg, ip; 7 days |
↓ cocaine-induced development of behavioral sensitization | |||
| Cocaine self-administration in extended paradigm/extinction/reinstatement | Sprague–Dawley rats, male | 30, 60 mg/kg, ip |
↓ cocaine-induced reinstatement (30, 60) |
[14] | |
| Cocaine self-administration/extinction/reinstatement |
90 mg/kg, ip; 12 days (acquisition of self-administration) |
↓ cocaine-induced reinstatement | |||
| Cocaine self-administration/extinction/reinstatement | Sprague–Dawley rats, male |
33, 100 mg/kg, ip; 12 days |
↓ cocaine-induced reinstatement (100) | ↑ AMPA/NMDA ratio drop (NAcc) | [51] |
| Cocaine self-administration/extinction | Sprague–Dawley rats, male |
100 mg/kg, ip; 7 days |
↑ xCT and GLT-1 drop (NAcc) | [8] | |
| Cocaine self-administration | Sprague–Dawley rats, male |
60 mg/kg, ip; 12 days |
∅ cocaine reward | [78] | |
| Cocaine self-administration/extinction/reinstatement |
60 mg/kg, ip; 7 days |
↓ cocaine-induced reinstatement | |||
| Cocaine self-administration/extinction/reinstatement | Sprague–Dawley rats, male |
60, 100 mg/kg, ip; 12 days |
↓ cocaine-induced reinstatement (100) ↓ cue + cocaine-induced reinstatement (100) |
[52] | |
| Cocaine self-administration/home abstinence/relapse | ↓ context-induced relapse (100) | ||||
| Cocaine self-administration | Squirrel monkeys, male | 10 mg/kg, im | ∅ cocaine reward | [47] | |
| Cocaine self-administration/extinction/reinstatement | ∅ cocaine-induced reinstatement | ||||
| Cocaine self-administration/extinction/reinstatement | Sprague–Dawley rats, male |
1, 10 ug/side, intra-NAcc |
↓cocaine-induced reinstatement (1–10) ↓ cue + cocaine-induced reinstatement (1–10) |
[53] | |
| Cocaine self-administration/extinction/reinstatement | 10 mg/kg, ip |
∅ cocaine-induced reinstatement ↓ cocaine-induced reinstatement (in combination with MTEP) |
|||
| Cocaine self-administration | Lister Hooded rats, male | 30, 60, 90 mg/kg, ip | ∅ cocaine reward | [54] | |
| Cocaine self-administration/extinction | 15, 30, 60, 90 mg/kg, ip | ↓ early cocaine-induced seeking (30–90) | |||
| Cocaine self-administration | Wistar rats, male | 25–100 mg/kg, ip | ∅ cocaine reward | [55] | |
|
100 mg/kg, ip; 6 days |
∅ cocaine reward | ||||
| Cocaine self-administration/extinction/reinstatement | 12.5–50 mg/kg, ip |
↓ cue-induced reinstatement (12.5–50) ↓ cocaine-induced reinstatement (25–50) |
|||
| Cocaine self-administration/extinction/reinstatement | Sprague–Dawley rats, male |
100 mg/kg, ip; 5 days |
↓ cue-induced reinstatement | ↑ GLT-1 drop (NAcc) | [58] |
| Cocaine self-administration | Sprague–Dawley rats, male |
60 mg/kg, ip; 19 days |
∅ cocaine reward | ↓ Zif268 drop (NAcc, DSTR) | [57] |
| Cocaine self-administration in escalation paradigm |
∅ cocaine reward ↑ abstinence |
↑ GLT-1 drop and ↑ Zif268 drop (NAcc, DSTR) |
|||
| Cocaine self-administration/extinction/reinstatement | Wistar rats, male |
100 mg/kg, ip; 10 days |
↓ cue-induced reinstatement ↓ cocaine-induced reinstatement |
[19] | |
| Bulbectomy + cocaine self-administration/extinction/reinstatement |
∅ cue-induced reinstatement ∅ cocaine-induced reinstatement |
||||
| Neonatal vHIP lesion + repeated cocaine in sensitization paradigm | Sprague–Dawley rats, male |
100 mg/kg, ip; PND 28-PND 84 |
∅ development of cocaine behavioral sensitization | [35] | |
| Cocaine self-administration | Squirrel monkeys, male |
10 mg/kg, im; 10 days |
∅ cocaine reward | [56] | |
| Cocaine self-administration/extinction/reinstatement |
10 mg/kg, im; 15 days |
↑ extinction ∅ cocaine-induced reinstatement |
|||
| Methamphetamine self-administration/extinction/reinstatement | Sprague–Dawley rats, female | 30, 60, 120 mg/kg, ip |
∅ methamphetamine reward ∅ methamphetamine-induced reinstatement |
[49] | |
↑ increased, ∅ no changed, ↓ decreased, ΔFosB protein encoded by the FBJ murine osteosarcoma viral oncogene homolog B (FOSB) gene, 5-HT serotonin, ALP alkaline phosphatase, AMPA α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor, CBD cannabidiol, CORT corticosterone, DSTR dorsal striatum, GFAP glial fibrillary acidic protein, GGT gamma-glutamyl transferase, GLT-1 glial glutamate transporter 1, GLU glutamate, GluN2B NMDA receptor subunit 2B, GRIN2A gene encoding NMDA receptor subunit 2A, GRIN2B gene encoding NMDA receptor subunit 2B, GSH glutathione, GSH-Px glutathione peroxidase, GSSG oxidized glutathione, HDL high-density lipoprotein, HIP hippocampus, MCV mean corpuscular volume, MDA malondialdehyde, mGluR2 metabotropic glutamate receptor type 2, MTEP 3-((2-Methyl-4-thiazolyl)ethynyl)pyridine, a selective allosteric antagonist of the metabotropic glutamate receptor subtype 5, NAC N-acetylcysteine, NAcc nucleus acumbens, NMDA N-methyl-d-aspartate receptor, NO nitric oxide, Nrf2-ARE transcription NF-E2-related factor 2 binds to antioxidant responsive element, ox-LDL oxidized-low-density lipoprotein, PFC prefrontal cortex, PND postnatal day, SGOT serum glutamic oxaloacetic transaminase, SGPT serum glutamic pyruvic transaminase, TG triacylglycerol, THC tetrahydrocannabinol, TNFα tumor necrosis factor alpha, vHIP ventral hippocamapus, VLDL very low-density lipoprotein, xCT cystine-glutamate antiporter, Zif268 zinc finger protein 268