TABLE 8

Preclinical behavioral effects

Subeffective doses and studies that did not identify an effect are not summarized in this table; please refer to the text (section IV.A.1.b. Direct antidepressant-relevant effects of hydroxynorketamines) for these details.

Behavior or TestTime Post-TreatmentEffective DosesSpeciesReferences
Antidepressant-relevant effects
(2R,6R)-HNK
 Forced swim test1 h5–125 mg/kg, i.p.; 15–150 mg/kg, by mouthMouseZanos et al. (2016, 2019b); Highland et al. (2019); Lumsden et al., (2019); Aguilar-Valles et al. (2020)
3.62–36.2 pmol/side, intra-vlPAGRatChou et al. (2018)
24 h5–125 mg/kg, i.p.; 15–150 mg/kg, by mouth; 0.036–1 nmol/side, intra-PFCMouseZanos et al. (2016, 2019b); Highland et al. (2019); Pham et al. (2018); Fukumoto et al. (2019); Lumsden et al. (2019); Chen et al. (2020)
10 mg/kg, i.p.; 3.62 pmol/side, intra-vlPAGRatChou et al. (2018)
3 days10 mg/kg, i.p.MouseZanos et al. (2016)
10 mg/kg, i.p.; 3.62 pmol/side, intra-vlPAGRatChou et al. (2018)
5 days30 mg/kg, i.p.MouseFukumoto et al. (2019)
7 days10 mg/kg, i.p.; 3.62 pmol/side, intra-vlPAGRatChou et al. (2018)
14 days0.025–0.075 mg/kg, i.p.MouseChen et al., (2020)
21 days10 mg/kg, i.p.; 3.62 pmol/side, intra-vlPAGRatChou et al., (2018)
 Learned helplessness test24 h5–75 mg/kg, i.p.; 50–150 mg/kg, by mouth; 3–10 nmol/side, i.c.v.MouseZanos et al. (2016); Highland et al. (2019); Zanos et al. (2019a)
5 days10 nmol/side, i.c.v.MouseZanos et al. (2019a)
 Adolescent exposure to live predator prior to learned helplessness test24 h20 mg/kg, i.p.MouseElmer et al. (2020)
 Novelty-suppressed feeding test30 min10 mg/kg, i.p.MouseLumsden et al. (2019)
1 h10–20 mg/kg, i.p.MouseZanos et al. (2016); Aguilar-Valles et al. (2020)
3 days30 mg/kg, i.p.; 3.62 pmol/side, intra-PFCMouseFukumoto et al. (2019)
 Chronic CORT–induced sucrose preference deficits24 h10 mg/kg, i.p.MouseZanos et al. (2016)
 Chronic CORT–induced female urine preference deficits24 h10 mg/kg, i.p.MouseZanos et al. (2016)
 Female urine preference24 h30 mg/kg, i.p.MouseFukumoto et al. (2019)
 CSDS-induced sucrose preference deficits24 h10 mg/kg, i.p.MouseZanos et al. (2019b)
 CSDS-induced social interaction deficits24 h20 mg/kg, i.p.MouseZanos et al. (2016)
 Footshock stress–induced sucrose preference1 h10 mg/kg, i.p.; 3.62 pmol/side, intra-vlPAGRatChou et al. (2018)
24 h
3 days
7 days
21 days
2 days3–30 nmol/side, i.c.v.MouseZanos et al. (2019a)
 IBD-induced sucrose preference deficits1 h1 pg/side, intra-vlPAGMouseKo et al. (2020)
 Tail suspension test (in IBD model)1 h1 pg/side, intra-vlPAGMouseKo et al. (2020)
(2S,6S)-HNK
 Forced swim test1 h25 mg/kg, i.p.MouseZanos et al. (2016)
24 h25 mg/kg, i.p.MouseZanos et al. (2016)
 Learned helplessness test24 h75 mg/kg, i.p.MouseZanos et al. (2016)
 Forced swim test (after chronic CORT)30 min20 mg/kg, i.p.MouseYokoyama et al. (2020)
 Chronic CORT–induced sucrose preference deficits30 min20 mg/kg, i.pMouseYokoyama et al. (2020)
 Attenuation of learned fear14 days0.025–30 mg/kg, i.p.MouseaChen et al. (2020)
Analgesic effects
(2R,6R)-HNK
 Elevated von Frey threshold24 h10 mg/kg, i.p.MouseKroin et al. (2019)
 Reduced mechanical allodynia in CRPS1 model0–4 days10 mg/kg/day × 10 3 days, i.p.MouseKroin et al. (2019)
 Reduced mechanical allodynia in postoperative pain model0–5 days10 mg/kg/day × 10 3 days, i.p.MouseKroin et al. (2019)
Aggression and social dominance
(2R,6R)-HNK
 Enhanced aggression1 h10 mg/kg, i.p.; 1–10 pg/side, intra-vlPAGRatChou (2020)
24 h10 mg/kg, i.p.; 1–10 pg/side, intra-vlPAGRatYe et al. (2019); Chou (2020)
3 days10 mg/kg, i.p.; 10 pg/side, intra-vlPAGRatYe et al. (2019)
7 days
14 days
21 days
28 days
 Enhanced social dominance24 h10 mg/kg, i.p.RatYe et al. (2019)

  • CORT, corticosterone; CSDS, chronic social defeat stress; IBD, inflammatory bowel disease; vlPAG, ventrolateral periaqueductal gray.

  • ↵a Effect observed only in female, but not male, mice.