. 2016 Sep 27;6(9):e905. doi: 10.1038/tp.2016.169

Table 1. Endocannabinoid system component in RDoC domains.

RDoC construct	Mediating circuit	CB1R in circuitry	CB2R in circuitry	2-AG	AEA
Anxiety	Interpret: BNST, HPC, amygdala Evaluate and response initiation: PFC, NAc, VTA, hypothalamus^28,29	BNST^a, ^aHPC, amygdala, ^aPFC, ^aNAc medium spiny neurons, hypothalamus^a,^{5, 8, 18}	Microglia,³⁰ VTA and NAc dopaminergic neurons^{16, 31}	↑in brain → anxiolytic³⁰	↓in brain → anxiogenic³⁰
Chronic stress	HPA, amygdala–medial PFC–striatum^{32, 33, 34}	^aPFC, ^aHPC, ^aNAc, amygdala, HPA^a,^{19, 35}	Rats: amygdala, HPC, PFC, hypothalamus²⁵	Amygdalar impairment in synthesis,³⁰ ↑in PFC³⁶	↓in amygdala (via↑FAAH)³⁰
Motivation	Orbitofrontal cortex, amygdala, VTA, NAc^{37, 38, 39}	Amygdala, ^aHPC, VTA and ^aNAc dopaminergic neurons^{38, 40, 41}	VTA dopaminergic neurons^{31, 40}	↑in NAc → ↑dopamine^{38, 41, 42}	↑in NAc → ↑dopamine
Reward learning	VTA, NAc, PFC, hypothalamus, amygdala^{40, 42}	^aNAc medium spiny neurons, ^aHPC, amygdala, VTA and ^aNAc dopaminergic neurons, hypothalamus^a, ^aPFC^{40, 42, 43}	VTA dopaminergic neurons³¹	↑in NAc → ↑dopamine^{38, 41, 42}	↑in NAc → ↑dopamine
Declarative memory	PFC, amygdala, HPC (dentate gyrus, CA1, CA3), VTA, NAc⁴⁴	^aPFC, amygdala, GABAergic interneurons, ^aHPC (dentate gyrus, CA1 and CA3).^{18, 19}	HPC interneuron cholecystokinin (+) basket cells⁴⁵	↓HPC CB1R binding → ↑GABA ^{45, 46}	HPC¹⁸↑(via ↓FAAH) →↑acquisition^{47, 48}
Working memory	PFC–parietal–cingulate–thalamus–NAc, HPC^{49, 50}	^aNAc medium spiny neuron, GABAergic hippocampal interneurons⁴⁶	HPC²³	↑HPC CB2R binding→ ↓encoding/consolidation⁵¹	↑ (via ↓FAAH) →↑acquisition^{47, 48}
Affiliation and attachment	Amygdala, VTA, NAc, PVN, SON, HPA, BNST^{52,53, 54}	PVN,³⁴ SON,⁵⁵ HPA,^a,13 BNST^a, amygdala, NAc^{12, 56}	HPC^{23, 56}	↑in HPC →↓ care^{54, 57} ↑in amygdala →↓play³⁶	Play: ↑amygdala and NAc^{12, 36}
Social communication	Amygdala, NAc, orbitofrontal cortex, cortico–basal ganglia–thalamo network⁵⁸	HPC, amygdala, NAc ^{59, 60}	Not yet known	Not yet known	↑ (via ↓FAAH) →↑USVs^{61, 62, 63}

Abbreviations: AEA, anandamide; 2-AG, 2-arachidonoylglycerol; BNST, bed nucleus of the stria terminalis; FAAH, fatty acid amide hydrolase; GABA, glutamate and γ-aminobutyric acid; HPA, hypothalamus–pituitary–adrenal gland axis; HPC, hippocampus; NAc, nucleus accumbens; PFC, prefrontal cortex; PVN, paraventricular nucleus; RDoC, Research Domain Criteria; SON, supraoptic nucleus; USV, ultrasonic vocalization; VTA, ventral tegmental area.

CB1R is the most abundant G-protein-coupled receptor (^ahighest levels/densities, ^blowest) in the mammalian brain, contributing to cannabinergic effects on ‘movement, affective responding, cognition, temperature, appetite and neuroendocrine function'.^{8, 18}

Human mRNA expression for a CB2R isoform has been found in amygdala, striatum, HPC, cortex and cerebellum,²⁵ with rodents showing additional expression in the cerebral cortex, brain stem, thalamic nuclei and periaqueductal grey.⁶⁴ AEA binding elicits sub-maximal receptor signaling, whereas 2-AG binds with much greater efficacy,⁴² necessary to produce robust phasic signaling responses.