In vivo pharmacological effects of TAAR1-selective agonists
| Study Type | Species/Test System | Pretreatment/Duration | Animals per Group (M/F) | RO5166017 Dose/Concentration | Key Results |
|---|---|---|---|---|---|
| min | n | mg/kg | |||
| Cocaine-induced hyperlocomotiona | C57Bl6 mice | 30/30 | 8 M | 0.03–3 p.o. | Attenuation at 0.3, 1, and 3 mg/kg p.o. |
| Cocaine-induced hyperlocomotiona | C57Bl6 TAAR1-KO and WT littermate mice | 30/30 | 10 M | 0.3–1 p.o. | Attenuation at 0.3 and 1 mg/kg p.o. in WT mice, no effect in TAAR1-KO mice |
| Spontaneous hyperlocomotion in DAT-KO micea | C57Bl6 DAT-KO and WT littermate mice | None/90 | 8 M | 0.2–1 p.o. | Attenuation at 0.5 and 1 mg/kg p.o. |
| L-687,414–induced hyperlocomotiona | NMRI mice | 30/30 | 8 M | 0.01–0.1 p.o. | Attenuation at 0.1 mg/kg p.o. |
| L-687,414–induced hyperlocomotiona | C57Bl6 TAAR1-KO and WT littermate mice | 60/30 | 8 M | 1 p.o. | Attenuation at 1 mg/kg p.o. in WT mice, no effect in TAAR1-KO mice |
| SIHa | NMRI mice | 45/15 | 8–16 M | 0.01–1 p.o. | Reversal of SIH (dT) at doses 0.1 and 0.3 mg/kg without affecting Tb |
| SIHa | C57Bl6 TAAR1-KO and WT littermate mice | 45/15 | 8–10 M | 0.1 p.o. | Reversal of SIH (dT) at 0.1 mg/kg in WT mice, no effect in TAAR1-KO mice |
| Cocaine-induced CPPb | Sprague-Dawley rats | 10 | 9 to 10 M | 10 i.p. | Inhibition of expression, but not retention of cocaine reward memory at 10 mg/kg i.p. |
| Abuse-related effects of nicotinec | Sprague-Dawley rats | 10 | 6–9 M | 3.2–10 i.p. | Reduction of nicotine self-administration (at 5.6 and 10 mg/kg i.p.) and attenuation of cue- and drug-induced reinstatement of nicotine-seeking (at 10 mg/kg i.p.) |
| oGTTd | C57Bl6 TAAR1-KO and WT littermate mice | 45/120 | 5–8 M | 0.3 mg/kg p.o. | Glucose-lowering effect at 0.3 mg/kg p.o. in WT mice and increased PYY and GLP-1 levels, no effect in TAAR1-KO mice |
| oGTTd | Diabetic db/db C57Bl6 mice, DIO mice, DIO Glp1R-KO mice | 45/120 | 8 M | 0.3 mg/kg p.o. | Glucose-lowering effect at 0.3 mg/kg p.o. in diabetic db/db mice |
| ivGTTd | C57Bl6 mice | 30/10 | 10 M | 3 mg/kg s.c. | Lower amount of meal emptied at 0.3 mg/kg p.o. |
| Gastric emptyingd | C57Bl6 mice | 45/30 | 8 M | 0.3 mg/kg p.o. | Lower amount of meal emptied at 0.3 mg/kg p.o. |
| Food intake and body weightd | C57Bl6 mice, DIO mice, | 45/60 | 6 M | 0.3 mg/kg s.c. | Reduction in food intake and body weight, reduced triglyceride levels, increased insulin sensitivity at 0.3 mg/kg p.o. |
| Study Type | Species/Test System | Pretreatment/Duration | Animals per Group (M/F) | RO5203648 Dose/Concentration | Key Results |
|---|---|---|---|---|---|
| min | n | mg/kg | |||
| Cocaine-induced hyperlocomotione | C57Bl6 mice | 30/30 | 8–16 M | 0.3–10 p.o. | Attenuation at 1 and 3 mg/kg p.o. |
| Cocaine-induced hyperlocomotione | Wistar rats | 60/30 | 7 to 8 M | 1–10 p.o. | Attenuation at 10 mg/kg p.o. |
| Spontaneous hyperlocomotion in DAT-KO micee | C57Bl6 DAT-KO and WT littermate mice | None/60 | 5–9 M | 1 p.o. | Attenuation at 1 mg/kg p.o. in DAT-KO mice, but no effect in DAT-KO/TAAR1-KO mice |
| Spontaneous hyperlocomotion in DAT-KO micee | C57Bl6 DAT-KO, TAAR1-KO, and WT littermate mice | None/60 | 8–11 M | 0.1–1 p.o. | Attenuation at 0.1, 0.3, and 1 mg/kg p.o. |
| L-687,414–induced hyperlocomotione | NMRI mice | 15/30 | 8 M | 0.01–0.1 p.o. | Attenuation at 0.1 mg/kg p.o. |
| Spontaneous hyperlocomotion in NR1 KD micee | C57Bl6 NR1 KD and WT littermate mice | None/60 | 6 to 7 M | 0.3–1 p.o. | Attenuation at 0.3 and 1 mg/kg p.o. in WT mice, no effect in NR1-KD mice |
| SIHe | NMRI mice | 45/15 | 6–8 M | 0.1–1 p.o. | Reversal of SIH (dT) at 0.3 mg/kg without affecting Tb |
| Forced swim stresse | Wistar rats | 24 h, 18 h, 1 h/60 | 8 F | 3–30 p.o. | Significant decrease in immobility time at 10 and 30 mg/kg p.o. |
| Cocaine self-administratione | Long-Evans rats | 60/60 | 7 to 8 M | 3–10 i.p. | Reduction of cocaine intake in rats with a stable history of intravenous cocaine self-administration at 3 and 10 mg/kg i.p. |
| min | n | mg/kg | |||
| Context-induced cocaine relapsef | Long-Evans rats | 15/90 | 6–8 M | 3–10 i.p. | Suppression of cocaine seeking after a 2-wk period of withdrawal from chronic cocaine self-administration at 3 and 10 mg/kg i.p. |
| Methamphetamine self-administrationg | Long-Evans rats | 10/60 | 6–10 M | 3–10 i.p. | Reduction of methamphetamine intake in rats with a stable history of intravenous methamphetamine self-administration at 3 and 10 mg/kg i.p. |
| Methamphetamine-stimulated hyperactivityg | Long-Evans rats | 70/60 | 5 to 6 M | 1.67–5 i.p. | Attenuation of methamphetamine-induced hyperactivity and prevention of development of methamphetamine sensitization at 1.67 and 5 mg/kg i.p. |
| Differential reinforcement of low-rate behaviore | Cynomolgus macaques | 4-h injection test interval | 5 to 6 M | 1–30 p.o. | Reduced response rate at 10 and 30 mg/kg p.o. and increased inter-response time at 30 mg/kg p.o. |
| Object retrievale | Cynomolgus macaques | 90/90 | 12 M | 1–10 p.o. | Procognitive effect at 10 mg/kg p.o. |
| Haloperidol-induced catalepsye | Wistar rats | 60/10 | 12 M | 0.3–10 p.o. | Reduction of catalepsy at 0.3, 3, and 10 mg/kg p.o. |
| Sleep/wake parameterse | Sprague-Dawley rats | 6 h | 8 M | 1–10 p.o. | Wake-promoting activity at 10 mg/kg p.o. |
| Study Type | Species/Test System | Pretreatment/Duration | Animals per Group (M/F) | RO5263397 Dose/Concentration | Key Results |
|---|---|---|---|---|---|
| min | n | mg/kg | |||
| Cocaine-induced hyperlocomotionh | C57Bl6 mice | 60/30 | 6–8 M | 0.3–3 p.o. | Attenuation at 1 and 3 mg/kg p.o. |
| PCP-induced hyperlocomotionh | C57Bl6 mice | 30/60 | 7–16 M | 0.003–1 p.o. | Attenuation at 0.01, 0.03, 0.1, and 0.3 mg/kg p.o. |
| L-687,414–induced hyperlocomotionh | NMRI mice | 15/30 | 8–24 M | 0.0003–1 p.o. | Attenuation at 0.003, 0.01, 0.03, 0.1, 0.3, and 1 mg/kg p.o. |
| Olanzapine-induced weight gainh | Sprague-Dawley rats | None/14 d | 8 M | 1 p.o. | Reduction of fat mass change induced by olanzapine at 1 mg/kg p.o. |
| ICSSi | Wistar rats | 60/20 | 8 M | 1–10 i.p. | Reversal of cocaine (1 mg/kg i.p.)–induced facilitation of changes in ICSS threshold at 1, 3, and 10 mg/kg i.p.; no significant change by RO5263397 alone and therefore no reinforcing effects and no abuse potential anticipated |
| Abuse-related effects of cocainej | Sprague-Dawley rats | 10/15 | 6–18 M | 1–10 i.p. | Reduction of expression of cocaine behavioral sensitization (at 3.2 mg/kg i.p.), cue- and cocaine prime-induced reinstatement of cocaine seeking (at 3.2 and 5.6 mg/kg i.p.), and expression but not development of cocaine-induced place preference (at 10 mg/kg i.p.) |
| Abuse-related effects of methamphetaminek | Sprague-Dawley rats | 10/15 | 7 to 8 M | 3.2–10 i.p. | Reduction of expression of behavioral sensitization (at 10 mg/kg i.p.), methamphetamine self-administration (at 3.2 mg/kg i.p.), and both cue- and a priming dose of methamphetamine-induced reinstatement of drug-seeking behaviors (at 3.2 and 10 mg/kg i.p.) |
| Chronic methamphetamine-treatment 5-CSRTTl | Sprague-Dawley rats | 3 d/60 | 8 M | 5.6 i.p. | Attenuation of forced abstinence-induced impulsivity (at 5.6 mg/kg) |
| min | n | mg/kg | |||
| Abuse-related effects of nicotinec | Sprague-Dawley rats | 10–20 | 8–10 M | 3.2–17.8 i.p | Reduction of expression and development of behavioral sensitization (at 10 mg/kg i.p.), nicotine self-administration (at 3.2 and 5.6 mg/kg i.p.) and discriminative stimulus effect of nicotine (at 10 mg/kg i.p.), attenuation of the subjective effects of nicotine (at 10 mg/kg i.p.) |
| Abuse-related effects of morphinem | Sprague-Dawley rats | 10 | 3.2–5.6 i.p | Reduction of morphine self-administration (at 3.2 and 5.6 mg/kg i.p.) and attenuation of cue- and drug-induced reinstatement of morphine-seeking) at 5.6 mg/kg i.p.); no effect on the expression of morphine-induced CPP, naltrexone precipitated withdrawal-induced jumping of CPA, or antinociceptive effect of morphine | |
| phMRIh | Sprague-Dawley rats | 90/12 | 9 M | 1–30 p.o. | Activity profile comparable to marketed antipsychotics in a dose-dependent manner. |
| Forced swim stressh | Wistar rats | 24 h, 16 h, 2 h/60 | 8 F | 3–30 p.o. | Significant decrease in immobility time at 10 and 30 mg/kg p.o. |
| Differential reinforcement of low-rate behaviorh | Cynomolgus macaques | 90/90 | 10 M | 1–10 p.o. | Number of reinforcers increased at 10 mg/kg p.o. |
| Object retrievalh | Cynomolgus macaques | 90/90 | 11 M | 0.3–10 p.o | Procognitive effect at 1, 3, and 10 mg/kg p.o. |
| Haloperidol-induced catalepsyh | Wistar rats | 60/10 | 6–12 M | 0.3–10 p.o | Reduction of catalepsy at 0.3, 1, 3, and 10 mg/kg p.o. |
| Sleep/wake parametersn | C57Bl6 TAAR1-KO, OE, and WT littermate mice | 6 h | 8 M | 0.1–1 p.o. | Wake-promoting activity and decreased REM and NREM in WT mice at 0.3 and 1 mg/kg p.o., no effect in TAAR1-KO and potentiated effect in TAAR1-OE mice |
| Sleep/wake parametersh | Sprague-Dawley rats | 6 h | 8 M | 0.3–30 p.o. | Wake-promoting activity and decreased REM at 3, 10, and 30 mg/kg p.o. |
| Study Type | Species/Test System | Pretreatment/Duration | Animals per Group (M/F) | RO5256390 Dose/Concentration | Key Results |
|---|---|---|---|---|---|
| min | n | mg/kg | |||
| Cocaine-induced hyperlocomotionh | C57Bl6 mice | 30/60 | 6–8 M | 0.3–3 p.o. | Attenuation at 0.3, 1, and 3 mg/kg p.o. |
| PCP-induced hyperlocomotionh | C57Bl6 mice | 30/60 | 7–16 M | 0.03–3 p.o. | Attenuation at 0.03, 0.1, 0.3, 1, and 3 mg/kg p.o. |
| L-687,414–induced hyperlocomotionh | NMRI mice | 15/30 | 8–24 M | 0.01–1 p.o. | Attenuation at 0.01, 0.03, 0.1, 0.3, and 1 mg/kg p.o. |
| ICSSi | Wistar rats | 60/20 | 8 M | 0.3–3 i.p. | Reversal of the cocaine (1 mg/kg i.p.)–induced facilitation of changes in ICSS threshold at 0.3, 1, and 3 mg/kg i.p.; no significant change by RO5256390 alone and therefore no reinforcing effects and no abuse potential anticipated |
| phMRIh | Sprague-Dawley rats | 90/12 | 9 M | 1–30 p.o. | Activity profile comparable to marketed antipsychotics in a dose-dependent manner |
| Attentional set-shiftingh | Long-Evans rats | 60/30 | 52 M | 1–10 p.o. | Procognitive effect: improvement of set-shifting performance at 1 and 3 mg/kg p.o. |
| Object retrievalh | Cynomolgus macaques | 60/5 | 11 M | 0.3–3 i.m. | Procognitive effect: improvement of performance during difficult trials at 3 mg/kg i.m. |
| Differential reinforcement of low-rate behaviorh | Cynomolgus macaques | 60/90 | 10 M | 0.3–3 i.m. | Increased number of reinforcers at 1 mg/kg i.m. |
| Context-induced cocaine relapsef | Long-Evans rats | 15/90 | 6–8 M | 310 i.p. | Suppression of cocaine seeking after a 2-wk period of withdrawal from chronic cocaine self-administration at 3 and 10 mg/kg i.p. |
| min | n | mg/kg | |||
| Compulsive binge-like eatingo | Wistar rats | 30/60 | 12 M | 1–10 i.p. | Inhibition of binge-like eating behavior at 3 and 10 mg/kg i.p. |
| Haloperidol-induced catalepsyh | Wistar rats | 60/10 | 6–12 M | 0.3–3 p.o | Reduction of catalepsy at 0.3 mg/kg p.o. |
| Sleep/wake parametersh | Sprague-Dawley rats | 6 h | 8 M | 1–10 p.o. | No significant effect at 1, 3, and 10 mg/kg p.o. on sleep/wake cycle and core body temperature |
5-CSRTT, five-choice serial reaction time task; F, female; ICSS, intracranial self-stimulation; ivGTT, intravenous glucose tolerance test; KD, knockdown; M, male; NMRI, Naval Medical Research Institute; oGTT, oral glucose tolerance test; REM, rapid eye movement; SIH, stress-induced hyperthermia; Tb, basal temperature; WT, wild type.
↵a Revel et al. (2011).
↵b Liu et al. (2016).
↵c Liu et al. (2018).
↵d Raab et al. (2015).
↵e Revel et al. (2012b).
↵f Pei et al. (2014).
↵g Cotter et al. (2015).
↵h Revel et al. (2013).
↵i Pei et al. (2015).
↵j Thorn et al. (2014b).
↵k Jing and Li (2015).
↵l Xue et al. (2018).
↵m Liu et al. (2017a).
↵n Schwartz et al. (2017).
↵o Ferragud et al. (2017).