Table 1.

Preclinical studies

Study	Animal	Route	Dose	Model	Effect	Receptor Involvement
Silveira Filho et al. [59]	WR	i.p.	100 mg/kg, acute	GSCT	No effect	NA
Zuardi et al. [60]	WR	i.p.	10 mg/kg, acute	CER	Anxiolytic	NA
Onaivi et al. [61]	ICR mice	i.p.	0.01, 0.10, 0.50, 1.00, 2.50, 5.00, 10.00, 50.00, 100.00 mg/kg, acute	EPM	Anxiolytic	Effects ↓ by IP flumazenil, unchanged by naloxone
Guimaraes et al. [61]	WR	i.p.	2.5, 5.0, 10.0 and 20.0 mg/kg, acute	EPM	Anxiolytic	NA
Moreira et al. [62]	WR	i.p.	2.5, 5.0 and 10.0 mg/kg, acute	VCT	Anxiolytic	Effect unchanged by IP flumazenil
Resstel et al. [63]	WR	i.p.	10 mg/kg, acute	CFC	Anxiolytic	NA
Campos et al. [64]	WR	dlPAG	15.0, 30.0, 60.0 nmol/0.2 μl, acute	EPM	Anxiolytic	Both effects ↓ by intra-dlPAG WAY100635 but not intra-dlPAG AM251
				VCT	Anxiolytic
Bitencourt et al. [65]	WR	i.c.v.	2.0 μg/μl 5 min before extinction, acute	CFC extinction	Anxiolytic	Extinction effect ↓ by SR141716A but not capsazepine
				EPM before and 24 h after CFC	No effect before CFC Anxiolytic following CFC
Campos et al. [66]	WR	dlPAG	30, 60 mg/kg, acute	EPM	Anxiolytic	Intra-dlPAG capsazepine renders 60 mg/kg anxiolytic
Resstel et al. [67]	WR	i.p.	1, 10 or 20 mg/kg, acute	RS	Anxiolytic, ↓ Pressor ↓ Tachycardia	All effects ↓ by systemic WAY100635
				EPM 24 h following RS	Anxiolytic
Soares et al. [68]	WR	dlPAG	15, 30 or 60 nmol, acute	ETM	Anxiolytic Panicolytic	All effects ↓ by intra-dlPAG WAY100635 but not AM251
				PAG E-stim	Panicolytic
Long et al. [69]	C57BL/6 J mice	i.p.	1, 5, 10, 50 mg/kg, chronic, daily/21 d	EPM	No effect	NA
				L-DT	1 mg/kg anxiolytic
				SI	No effect
				OF	50 mg/kg anxiolytic
Lemos et al. [70]	WR	i.p. PL IL	10 mg/kg IP, 30 nmol intra-PL and intra-IL, acute	CFC	IP and PL anxiolytic IL anxiogenic	NA
Casarotto et al. [71]	C57BL/6 J mice	i.p.	15, 30, and 60 mg/kg, acute, or subchronic, daily/7 d	MBT	Anticompulsive	Effect ↓ by IP AM251 but not WAY100635
Gomes et al. [72]	WR	BNST	15, 30, and 60 nmol, acute	EPM	Anxiolytic	Both effects ↓ by intra BNST WAY100635
				VCT	Anxiolytic
Granjeiro et a l. [73]	WR	Intracisternal	15, 30, and 60 nmol, acute	RS	Anxiolytic, ↓Pressor ↓Tachycardia	NA
				EPM 24 h after RS	Anxiolytic
Deiana et al. [74]	SM	i.p. Oral	120 mg/kg, acute	MBT	Anticompulsive	NA
Uribe-Marino et al. [75]	SM	i.p.	0.3, 3.0, 30.0 mg/kg, acute	PS	Panicolytic	NA
Stern et al. [76]	WR	i.p.	3, 10, 30 mg/kg immediately after retrieval, acute	Reconsolidation blockade	Anxiolytic 1 and 7 d old fear memories disrupted	Effect ↓ by AM251 but not WAY100635
Campos et al. [77]	WR	i.p.	5 mg/kg, subchronic, daily/7 d	EPM following PS	Anxiolytic	Effects ↓ by IP WAY100635
Hsiao et al. [78]	WR	CeA	1 μg/μl	REM sleep time	↓ REM sleep suppression	NA
				EPM	Anxiolytic
				OF	Anxiolytic
Gomes et al. [79]	WR	BNST	15, 30, 60 nmol, acute	CFC	Anxiolytic	Both effects ↓ by intra-BNST WAY100635
El Batsh et al. [80]	LE-H R	i.p.	10 mg/kg, chronic, daily/14 d	CFC	Anxiogenic	NA
Campos et al. [81]	C57BL/6 mice	i.p.	30 mg/kg 2 h after CUS, chronic daily/14 d	EPM	Anxiolytic	Both effects ↓ by AM251
				NSF	Anxiolytic
Do Monte et al. [82]	L-E HR	IL	1 μg or 0.4 μg/0.2 μl 5 min before extinction daily/4 d	Extinction of CFC	Anxiolytic	Effect ↓ by IP rimonabant
Campos et al. [83]	Rat	i.p.	5 mg/kg, chronic, daily/21 d	ETM	Anxiolytic Panicolytic	Panicolytic effect ↓ by intra-dlPAG WAY100635
Almeida et al. [84]	Rat	i.p.	1, 5, 15 mg/kg, acute	SI	Anxiolytic	NA
Gomes et al. [85]	WR	BNST	30 and 60 nmol, acute	RS	Anxiogenic ↑ Tachydardia	Effect ↓ by WAY100635
Twardowschy et al. [86]	SM	i.p.	3 mg/kg, acute	PS	Panicolytic	Effects ↓ by IP WAY100635
Focaga et al. [87]	WR	PL	15, 30, 60 nmol, acute	EPM	Anxiogenic	All effects ↓ by intra PL WAY100635 Anxiolytic EPM effect post-RS ↓ by IP metyrapone
				EPM after RS	Anxiolytic
				CFC	Anxiolytic
Nardo et al. [88]	SM	i.p.	30 mg/kg, acute	MBT	Anticompulsive	NA
da Silva et al. [89]	WR	SNpr	5 μg/0.2 μl	GABAA blockade in dlSC	Panicolytic	Both effects ↓ by AM251

Effective doses are in bold

Receptor specific agents: AM251 = cannabinoid receptor type 1 (CB₁R) inverse agonist; WAY100635 = 5-hydroxytryptamine 1A antagonist; SR141716A = CB₁R antagonist; rimonabant = CB₁R antagonist; capsazepine = transient receptor potential vanilloid type 1 antagonist; naloxone = opioid antagonist; flumazenil = GABA_A receptor antagonist

Anxiolytic effects in models used: CER = reduced fear response; CFC = reduced conditioned freezing; CFC extinction = reduced freezing following extinction training; EPM = reduced % time in open arm; ETM = decreased inhibitory avoidance; L-DT = increased % time in light; VCT = increased licks indicating reduced conflict; NSF = reduced latency to feed; OF = increased % time in center; SI = increased social interaction

Anticomplusive effects: MBT = reduced burying

Panicolytic effects: ETM = decreased escape; GABA_A blockade in dlSC = defensive immobility, and explosive escape; PAG-E-Stim = increased threshold for escape; PS = reduced explosive escape

WR = Wistar rats; SM = Swiss mice; L-E HR = Long–Evans hooded rats; i.p. = intraperitoneal; dlPAG = dorsolateral periaqueductal gray; i.c.v. = intracerebroventricular; PL = prelimbic; IL = infralimbic; BNST = bed nucleus of the stria terminalis; CeA = amygdala central nucleus; SNpr = substantia nigra pars reticularis; CUS = chronic unpredictable stress; GSCT = Geller–Seifter conflict test; CER = conditioned emotional response; EPM = elevated plus maze; VCT = Vogel conflict test; CFC = contextual fear conditioning; RS = restraint stress; ETM = elevated T maze; PAG E-stim = electrical stimulation of the dlPAG; L-DT = light–dark test; SI = social interaction; OF = open field; MBT = marble-burying test; PS = predator stress; NSF = novelty suppressed feeding test; GABA_A = γ-aminobutyric acid receptor A; dlSC = deep layers superior colliculus; REM = rapid eye movement; NA = not applicable