Antiaversive Effects of Cannabinoids: Is the Periaqueductal Gray Involved?

Table 2

Effects of Cannabinoid-related drugs injected into the PAG of rats submitted to animal models of anxiety-related behaviors. (AEA: anandamide; ACEA: arachidonyl-2-chloro-ethylamide; CBD: cannabidiol; EPM: elevated plus-maze; VCT: Vogel conflict test; CFC: contextual fear conditioning; dlPAG: dorsolateral PAG; dPAG: dorsal (dorsolateral + dorsomedial) PAG; dmPAG: dorsomedial PAG; unpub: unpublished data.)

	Drug	PAG column	Test	Doses tested	Effect (effective dose)	Ref.
Phytocannabinoids	CBD	dlPAG	EPM, VCT	15–60 nmol	Anxiolytic (30 nmol^*)	[86]
Endocannabinoids	AEA	dlPAG	EPM	0.05–50 pmol	Anxiolytic (5 pmol^*,1)	[71]
			VCT	5 pmol	Anxiolytic	[73]
			CFC	5 pmol	Anxiolytic	[78]
CB1 receptor agonists	ACEA	dlPAG	EPM	0.05–5 pmol	Anxiolytic (0.05 pmol^*)	[71]
	HU210	dPAG	dPAG chemical stimulation	0.1–5𝜇g	Attenuated flight responses (0.1–5𝜇g)	[36]
	HU210	dmPAG	Ultrasound-induced hyperlocomotion and freezing	5𝜇g	Decreased hyperlocomotion, but increased freezing^**	[70]
CB1 receptor antagonist	AM251	dlPAG	EPM, VCT, CFC	1–300 pmol	No effect by itself, but blocked AEA and AM404 anxiolytic effects	[71, 73, 78]
	Rimonabant	dPAG	Ultrasom-induced hyperlocomotion and freezing	30𝜇g	No effect by itself	[70]
AEA uptake inhibitor	AM404	dlPAG	EPM	0.5–50 pmol	No effect by itself; potentiated the anxiolytic effect of AEA	[71]
			VCT	50 pmol	Anxiolytic	[73]
			CFC	50 pmol	Anxiolytic	[78]
AEA metabolism inhibitor	URB597	dlPAG	VCT	0.01–0.1 nmol	Anxiolytic (0.01 pmol^*)	[73]
TRPV1 antagonists	Capsazepine	dlPAG	EPM, VCT	10–60 nmol	Anxiolytic (60 nmol)^+	[87]

^*Bell-shaped dose-response curve. Anxiolytic effect blocked by AM251 (100 pmol) and potentiated by AM404 (50 pmol).⁺Capsazepine 10 nmol turned the higher, ineffective dose of CBD (60 nmol) into an anxiolytic one in the EPM [85].^**Not blocked by rimonabant 30𝜇g.