Table 2 Main effects of caffeine administration on neuroinflammatory and behavioral outcomes in animal models of depression.

Mudgal et al. 2019

LPS (E.coli 0111:B4)

1.5 mg.kg^-1, i.p.

Adult Male Swiss albino mice

Caffeine (5 mg.kg^-1

gavage Chronic (1 week)

Caffeic acid (CA 10 mg.kg^-1) & Imipramina: 15 mg.kg^-1

Caffeic acid + Caffeine: Antidepressant in the TST and FST;

Anxiolytic in OFT and DLB.

Caffeic acid + Caffeine: Anti-inflammatory (reduces IL-6, TNFα – serum/ brain)

Caffeic acid + Caffeine: decrease MDA, increase GSH

Hall et al. [32]

LPS (E. coli O111:B4)

0.83 mg.kg^-1, ip.

Adult Male C57BL/6 J mice

Caffeine (10 mg.kg^-1)

gavage Chronic (2 weeks)

Imipramine (10 mg.kg^-1), coffee samples (caffeinated and decaffeinated – 140 mg.kg^-1 each);

Caffeinated and decaffeinated coffee: Antidepressant in the TST, FST, and exploratory behavior in OFT.

Caffeinated and decaffeinated coffee - anti-inflammatory (reduces IDO activity, neopterin/biopterin ratio, slightly decreases in the brain concentrations of PGE2)

Neuroprotection - KA/3-HK and KA/KYN ratios

Mallik et al. 2021

LPS (E. coli O111:B4) 0.83 mg.kg^-1, ip.

Adult Male C57BL/6 J mice

Caffeine

(10 mg.kg^-1)

gavage Chronic (2 weeks)

Imipramine

(10 mg.kg^-1)

Caffeine: Antidepressant in the TST, FST, and exploratory behavior in OFT.

Caffeine: Anti-inflammatory (reduces IL-6, TNFα, IL-1ß, IFNγ

Caffeine: Reduces lipid peroxidation (decrease MDA); increase BDNF

Unno et al. [35]

LPS (O55:B5, L2880)

0.5 mg.kg^-1, ip.

Adult Male SAMP10/TaIdrSlc mice

Green tea with CE/TA ratios (1, 2, 4, 8, and 12 mole ratio) ~ caffeine at 60,120,120, 240,360 μmole.

oral (in the bottle)

CE/TA ratio (CE - 60,120,120, 240,360 μmole) relative to (T - 80,80,40, 40,40 μmole) (A 40,40, 20,20, 20 μmole)

Green tea (CE/TA ratio 4/5): Anti depressant in the SPT; reduces Npas.

Green tea (CE/TA ratio1/2): Anti-inflammatory (reduces TNFα, IL-1ß),

Green tea (CE/TA ratio1/2): Inhibits adrenal hypertrophy and thymic atrophy; suppression of Lcn2 expression

Zhang et al. [36]

LPS (E. coli O111:B4)

0.83 mg.kg^-1, ip.

Adult Male Sprague–Dawley rats

Caffeine (60 mg.kg^-1

gavage Chronic (4 weeks).

No

Caffeine: Antidepressant in the TST, FST, OFT, and CFT.

Caffeine: Anti-inflammatory (reduces pAKT, NFkB)

No other effect

Daubry et al. [37]

Sleep Deprivation

Male Wistar adult rats

Caffeine (200 mg.kg¹)

Gavage Chronic

(4 weeks).

Alcohol - 20%

Caffeine: Anxiogenic (hole-board test and EPM); Decrease social behavior; locomotive activity in the OFT.

Caffeine: increases inflammatory cytokines (TNF-β, IL-6, and IL-10); Decreases AChE activity;

impaired memory (SAB);

Gu et al. [38]

Chronic paradoxical sleep deprivation (PSD)

Male Wistar adult rats

Conventional coffee – (0.5 ml/100 g) & decaffeinated coffee - (200 mg.kg^-1)

Gavage

(1 week).

No

Conventional and decaffeinated coffee: Antidepressant in the TST, FST, SPT, and OFT.

Conventional coffee: Anti-inflammatory (decreases IL-6 and TNFα);

Decaffeinated coffee: Anti-inflammatory (decreases TNFα).

Conventional and decaffeinated coffee: Recovers intestinal dysbiosis; increases SOD, and GSH-Px levels

Mao et al. [39]

Chronic water immersion restraint stress (CWIRS)

(3 weeks)

Adult Male Kunming mice

Caffeine (10, 20 mg.kg^-1).

gavage Chronic (4 weeks).

CORT

(2 mg.kg^-1),

RU486

(25 mg.kg^-1),

fluoxetine

(20 mg.kg^-1),

Caffeine: Antidepressant in the TST, FST, and SPT;

Increase 5-HT and decrease 5-HIAA levels.

Caffeine: Anti-inflammatory

(suppress microglia activation (IBA1, CD68); reduces NO, TNFα, IL-1ß;pNFkB).

Caffeine: Stimulates neurogenesis (BrdU); reduces p-MEK/MEK, p-ERK1/2/ERK 1/2 e p-NFkB/GPADH ratios

Markovaa et al. [40]

Social defeat (20 days)

Adult Male C57BL/6 mice

Transplantation of immune cells pre-treated with caffeine at the dose of 100 μg per 15 × 10⁶ cells with 3% FCS (Hyclone)

No

Transplantation of cells treated with caffeine: Antidepressant in the FST, OFT, SPT, and EPM;

Transplantation of cells treated with caffeine: decreases pro-inflammatory cytokines (IL-1β, IL-6, INF-γ, and TNF-α) and increases anti-inflammatory (IL-10 and IL-4).

Transplantation of cells treated with caffeine: Increases BDNF and neurogenesis and/or survival of hippocampal neurons