Table 1. Intravenous Self-Administration Studies with Cannabimimetics in Laboratory Animals.
| Study | Subjects Gender Drug Experience | Reinforcer | Dose/infusion | Vehicle | Schedule | Procedure | Results IVSA | Results Reinstatement (drug priming-induced) |
|---|---|---|---|---|---|---|---|---|
| Rodent studies | ||||||||
| Van Ree et al (1978) | Wistar rats FEM Naive | THC | 7.5–300 μg/kg | Tween 20 (1%)/saline | FR1 | Initial forced injections No food restriction IVSA acquisition | +/− Low incidence of lever pressing 40% Rats responded | |
| Takahashi and Singer (1979, 1980) | Wistar rats Male Naive | THC | 6.25–50 μg/kg | Tween 80 (0.6%)/saline | FR | Automatic food pellet delivery (FT-1 min) IVSA acquisition and maintenance | +/− Behavior maintained only with food pellet delivery and food deprivation | |
| Martellotta et al (1998) | CD1 mice Male Naive | WIN 55,212-2 | 10–500 μg/kg | Cremophor (10%)/heparinized saline | FR1 | Restrained mice used for single IVSA session | +/− Max resp. at 100 μg/kg | |
| Ledent et al (1999) | CD1 mice-WT or CB1 KO Male Naive | WIN 55,212-2 | 100 μg/kg | Cremophor (10%)/heparinized saline | FR1 | Restrained mice used for single IVSA session | +WT mice −CB1 KO mice | |
| Navarro et al (2001) | CD1 Mice Naive | WIN 55,212-2 HU-210 | 10–100 μg/kg 5 μg/kg | Tween 80/ heparinized saline | FR1 | Restrained mice used for single IVSA session | +/−WIN Max resp. at 50 and 100 μg/kg +/−HU-210 Max resp. at 5 μg/kg | |
| Fattore et al (2001) | L-E rats Male Naive | WIN 55,212-2 | 6.25–50 μg/kg | Tween 80/heparinized saline | FR1 | IVSA acquisition, maintenance, extinction | + Max resp. at 12.5 μg/kg 87% Rats acquired | |
| Spano et al (2004) | L-E rats Male Naive | WIN 55,212-2 | 12.5 μg/kg | Tween 80/heparinized saline | FR1 | IVSA acquisition and extinction Drug-induced reinstatement | + | + WIN + Heroin −Cocaine |
| Fadda et al (2006) | L-E rats L-H rats Male Naive | WIN 55,212-2 | 12.5 μg/kg | Tween 80/heparinized saline | FR1 | IVSA acquisition Simultaneous microdialysis | + ↑ DA in NAc shell | |
| Lecca et al (2006) | S-D rats Male Naive | WIN 55,212-2 | 12.5 μg/kg | Tween 80 (0.3%)/saline | FR1-2 | IVSA acquisition, maintenance, extinction Simultaneous microdialysis | + 90% Rats acquired ↑ DA (NAc shell >core) | |
| Mendizabal et al (2006) | CD1 mice C57BL/6 J mice – WT or pro-dynorphin KO Male Naive | WIN 55,212-2 | 3.125–12.5 μg/kg | Tween 80/saline | FR1 | Freely moving mice IVSA acquisition, maintenance | + 90% rats acquired WT: max resp. at 12.5 μg/kg KO: max resp. at 6.25 μg/kg | |
| Deiana et al (2007) | L-E rats L-H rats S-D rats Male Naive | WIN 55,212-2 | 6.25–25 μg/kg | Tween 80/heparinized saline | FR1 | IVSA acquisition, maintenance, extinction | +L-E rats +L-H rats −S-D rats Max resp. at 12.5 μg/kg | |
| Fattore et al (2007) | L-E rats L-H rats S-D rats FEM (OVX or intact) Male Naive | WIN 55,212-2 | 12.5 μg/kg | Tween 80/saline | FR1 | IVSA acquisition, maintenance, extinction | +L-E rats Intact FEM >males or OVX FEM +L-H rats Intact FEM >males or OVX FEM −S-D rats | |
| Solinas et al (2007) | L-E rats Male Naive | WIN 55,212-2 | 12.5–25 μg/kg | Tween 80/saline | FR1-5 | IVSA acquisition and maintenance | + | |
| Fattore et al (2010) | L-H rats FEM (OVX or intact) Male Naive | WIN 55,212-2 | 12.5 μg/kg | Tween 80/heparinized saline | FR1 | IVSA acquisition, maintenance, extinction Drug-induced reinstatement Cue-induced reinstatement | + Intact FEM>males or OVX FEM | + WIN Intact FEM>males or OVX FEM + Cue Intact FEM>males or OVX FEM |
| Justinova et al (2013) | L-H rats Male Naive | WIN 55,212-2 | 12.5 μg/kg | Tween 80/heparinized saline | FR1 | IVSA acquisition, maintenance Drug-induced reinstatement | + | + WIN |
| De Luca et al (2014) | S-D rats Male Naive | 2-AG | 12.5–50 μg/kg | Tween 80 (2%)/ethanol (2%)/saline | FR1-2 | IVSA acquisition, extinction, reacquisition | + Max resp. at 25 μg/kg 90% Rats acquired | |
| Lefever et al (2014) | L-E rats Male WIN SA | THC | 3–100 μg/kg | Polysorbate 80 (1%)/saline | FR3 | IVSA (Substitution for WIN55,212) | − | |
| Vallée et al (2014) | CD1 mice Naive | WIN 55,212-2 | 12.5 μg/kg | Tween 80/saline | FR1 PR | IVSA acquisition, maintenance | + | |
| De Luca et al (2015) | S-D rats C57BL/6 Mice Male Naive | JWH-018 | Rats: 10–20 μg/kg Mice: 15–30 μg/kg | Tween 80 (2%)/ethanol (2%)/saline | FR1-3 (rats) FR1 and PR (mice) | IVSA acquisition, extinction, reacquisition | + Rats Max resp. at 20 μg/kg, 90% acquired + Mice Max resp. at 30 μg/kg, 90% acquired | |
| Scherma et al (2016) | L-H rats Male Naive | WIN 55,212-2 | 12.5 μg/kg | Tween 80/heparinized saline | FR1 | THC exposure in adolescence IVSA acquisition, maintenance | + THC-exposed >vehicle-exposed rats | |
| Struik et al (2017) | L-H rats Male Naive | WIN 55,212-2 | 12.5 μg/kg | Tween 80/saline | FR1 | Prior NDL exposure IVSA acquisition, maintenance, extinction Drug-induced reinstatement Cue-induced reinstatement | + NDL exposed>vehicle exposed rats | + WIN NDL exposed=vehicle exposed +Cue NDL exposed=vehicle exposed |
| Kirschmann et al (2017) | S-D rats Male Naive | WIN 55,212-2 | 12.5 μg/kg | Tween 80/saline | FR1 | Short (2 h) and long (6 h) access IVSA in adolescence Cue-induced reinstatement | + 2 h intake=6 h intake | + Cue + Incubation of craving |
| Non-human primate studies | ||||||||
| Deneau and Kaymakcalan (1971; Kaymakcalan (1972) | Rhesus m. Male FEM Naive | THC | 100-400 μg/kg | Tween 80 (0.2–0.8%)/saline | FR | Automatic THC injections Cocaine IVSA training IVSA acquisition | −Naive subjects +/− Responding occurred only after physical dependence to THC developed or after cocaine SA | |
| Pickens et al (1973) | Rhesus m. Phencyclidine SA | THC | 25–100 μg/kg | PVP/saline | FR1 | IVSA substitution for phencyclidine | − | |
| Harris et al (1974) | Rhesus m. Male Naive | THC | 25–300 μg/kg | PVP/saline | FR | Naive then cocaine SA—substitution for cocaine Automated THC injections | −Naive subjects −When substituted for cocaine −After chronic THC exposure | |
| Carney et al (1977) | Rhesus m. Male Cocaine SA | THC | 3–300 μg/kg | EL-620/ Ethanol/saline | FR10 | IVSA substitution for cocaine | − | |
| Mansbach et al (1994) | Rhesus m. Male Cocaine SA | THC CP 55,940 | 17–100 μg/kg 0.3–3 μg/kg | EL-620/ Ethanol/saline | FR | IVSA substitution for phencyclidine | −THC −CP 55,940 | |
| Tanda et al (2000) | Squirrel m. Male Cocaine SA | THC | 1–8 μg/kg | Tween 80(0.4–1%)/Ethanol (0.4–1%)/saline | FR10 | IVSA (Substitution for cocaine), extinction, reacquisition | + Max resp. at 4 μg/kg | |
| Justinova et al (2003) | Squirrel m. Male Naive | THC | 1–16 μg/kg | Tween 80 (0.4-1%)/Ethanol (0.4-1%)/saline | FR10 | IVSA acquisition, extinction, reacquisition | + Max resp. at 4 μg/kg | |
| Justinova et al (2004) | Squirrel m. Male THC or cocaine SA | THC | 2–8 μg/kg | Tween 80 (0.4–1%)/Ethanol (0.4–1%)/saline | FR10 | IVSA maintenance | + Max resp. at 4 μg/kg | |
| Justinova et al (2005) | Squirrel m. Male Naive or THC SA | AEA MethAEA | 2.5–160 μg/kg 2.5–80 μg/kg | Water-soluble emulsion or Tween 80 (0.125–4%)/ Ethanol/Saline | FR10 | IVSA acquisition, maintenance, extinction | +AEA Max resp. at 40 μg/kg +MethAEA Max resp. at 40 μg/kg | |
| Justinova et al (2008a) | Squirrel m. Male THC or AEA SA | AEA THC URB597 | 3–100 μg/kg 1–8 μg/kg 1–100 μg/kg | AEA, THC: Tween 80 (0.125–4%)/ Ethanol/Saline URB597: Tween 80 (5%)/ PEG (5%)/Saline | FR10 | IVSA acquisition, maintenance, extinction Drug-induced reinstatement | + AEA Max resp. at 30 μg/kg + THC Max resp. at 4 μg/kg − URB597 | + THC − URB597 |
| Justinova et al (2008b) | Squirrel m. Male Amphetamine or cocaine SA | THC | 10–80 μg/kg at the end of the session | Tween 80(0.4–1%)/Ethanol (0.4–1%)/saline | SOS FI 30 min (FR10:S) | IVSA acquisition, maintenance, extinction Drug-induced reinstatement Cue-induced reinstatement | + Max resp. at 40 μg/kg at the end of the session | +THC +Morphine +AEA +MethAEA +AM404 − Cocaine +Cue |
| Justinova et al (2011a) | Squirrel m. Male THC or AEA SA | THC AEA | 0.5–8 μg/kg 1–80 μg/kg | Tween 80(1%)/ Ethanol (1%)/ saline | FR10 | IVSA maintenance, extinction Drug-induced reinstatement | +THC Max resp. at 4 μg/kg + AEA Max resp. at 40 μg/kg | +THC |
| Justinova et al (2011b) | Squirrel m. Male AEA or nicotine SA | 2-AG | 0.1–100 μg/kg | Tween 80(5%)/Ethanol (3%)/sterile water (Stock solution 1.5 mg/ml) | FR10 | Substitution for AEA or nicotine IVSA acquisition, maintenance, extinction | + Max resp. at 3 μg/kg | |
| Li et al (2012b) | Rhesus m. Females Males Naive | THC | 3.2–32 μg/kg | EL-620/ Ethanol/saline | FR30 | Substitution for heroin IVSA acquisition | − | |
| Justinova et al (2013) | Squirrel m. Male THC SA | THC | 0.5–16 μg/kg | Tween 80(1%)/ Ethanol (1%)/ saline | FR10 | IVSA maintenance, extinction Drug-induced reinstatement Cue-induced reinstatement | + Max resp. at 4 μg/kg | +THC + Cue |
| Justinova et al (2014) | Squirrel m. Male THC SA | THC | 0.1–32 μg/kg | Tween 80(1%)/ Ethanol (1%)/ saline (Stock solution 0.4 mg/ml) | FR10 | IVSA maintenance | + Max resp. at 4 μg/kg | |
| Justinova et al (2015) | Squirrel m. Male AEA, THC, or cocaine SA | URB694 | 0.3–30 μg/kg | AEA: Tween 80(1%)/ Ethanol (1%)/ saline URB694: DMSO (5%)/Tween 80(5%)/saline | FR10 | Substitution for AEA, THC, or cocaine IVSA acquisition, maintenance, extinction Drug-induced reinstatement | + Regardless of SA history Max resp. at 1 μg/kg | +THC − URB694 |
| Schindler et al (2016a) | Squirrel m. Male THC SA | THC | 1–8 μg/kg | Tween 80(1%)/ Ethanol (1%)/ saline (Stock solution 0.4 mg/ml) | FR10 | IVSA maintenance Drug-induced reinstatement Cue-induced reinstatement | + Max resp. at 4 μg/kg | +THC +Nicotine +Cocaine +Cue |
| Schindler et al (2016b) | Squirrel m. Male AEA, THC or cocaine SA | AM404 VDM11 AEA | 1–100 μg/kg 0.3–56 μg/kg 2.5–80 μg/kg | AM404, AEA: Tween 80(2%)/ Ethanol (2%)/ saline VDM11: Tween 80(2%)/ Ethanol (6%)/ saline | FR10 | Substitution for AEA or cocaine IVSA acquisition, maintenance, extinction Drug-induced reinstatement | +AM404 Max resp. at 10 μg/kg + VDM11 Max resp. at 10 μg/kg + AEA Max resp. at 40 μg/kg | +AEA + THC + AM404 |
| John et al (2017) | Rhesus m. Male Naive or METH or cocaine SA Cynomolgus m. Male Cocaine SA | THC CP 55,940 | 0.01–10 μg/kg 0.001–3 μg/kg | Tween 80 (1%)/Ethanol (1%)/ Saline | FR10 (Rhesus) SOS FI 600- s [FR30:S] (Cynomolgus) | Rhesus: Food SA training, THC, and CP 55,940 substituted for food pellets Cynomolgus: THC substituted for cocaine | − THC FR: low rates of resp. only after chronic THC exposure +/−THC SOS: 50% of animals resp. above vehicle +/− CP 55,940 | |
Abbreviations:: 2-AG, 2-archidonoylglycerol; AEA, anandamide; DA, dopamine; DMSO, dimethyl sulfoxide; EL-620, emulphor; FEM, female; FR, fixed ratio; FT-1, fixed-time 1 min schedule; Inf., infusion; IVSA, intravenous self-administration; KO, knockout; L-E, Long-Evans; L-H, Lister-Hooded; m., monkeys; METH, methamphetamine; NDL, nandrolone; OVX, ovariectomy; PEG, polyethylene glycol; PR, progressive ratio; PVP, polyvinylpyrollidone; Resp., responding; SA, self-administration; SOS, second-order schedule; S-D, Sprague-Dawley; WT, wild type; WIN, WIN 55,212-2.
Symbols: +/−, <50% Animals responded, low incidence of lever pressing, or special conditions (eg, single session use, movement restriction); +, reliable self-administration behavior or significant reinstatement of drug seeking; −, no self-administration above vehicle levels or no reinstatement of drug seeking; >, higher self-administration rates, faster acquisition, or preferential dopamine increase; =, identical effect; ↑, increase; ↓, decrease.