Endocannabinoid signaling in social functioning: an RDoC perspective

Abstract

Core deficits in social functioning are associated with various neuropsychiatric and neurodevelopmental disorders, yet biomarker identification and the development of effective pharmacological interventions has been limited. Recent data suggest the intriguing possibility that endogenous cannabinoids, a class of lipid neuromodulators generally implicated in the regulation of neurotransmitter release, may contribute to species-typical social functioning. Systematic study of the endogenous cannabinoid signaling could, therefore, yield novel approaches to understand the neurobiological underpinnings of atypical social functioning. This article provides a critical review of the major components of the endogenous cannabinoid system (for example, primary receptors and effectors--Δ9-tetrahydrocannabinol, cannabidiol, anandamide and 2-arachidonoylglycerol) and the contributions of cannabinoid signaling to social functioning. Data are evaluated in the context of Research Domain Criteria constructs (for example, anxiety, chronic stress, reward learning, motivation, declarative and working memory, affiliation and attachment, and social communication) to enable interrogation of endogenous cannabinoid signaling in social functioning across diagnostic categories. The empirical evidence reviewed strongly supports the role for dysregulated cannabinoid signaling in the pathophysiology of social functioning deficits observed in brain disorders, such as autism spectrum disorder, schizophrenia, major depressive disorder, posttraumatic stress disorder and bipolar disorder. Moreover, these findings indicate that the endogenous cannabinoid system holds exceptional promise as a biological marker of, and potential treatment target for, neuropsychiatric and neurodevelopmental disorders characterized by impairments in social functioning.

OPEN

Citation: Transl Psychiatry (2016) 6, e905; doi:http://dx.doi.org/10.1038/tp.2016.169

Web End =10.1038/tp.2016.169

http://www.nature.com/tp

Web End =www.nature.com/tp

REVIEW

Endocannabinoid signaling in social functioning: an RDoC perspective

DS Karhson1,2, AY Hardan2 and KJ Parker2

Core decits in social functioning are associated with various neuropsychiatric and neurodevelopmental disorders, yet biomarker identication and the development of effective pharmacological interventions has been limited. Recent data suggest the intriguing possibility that endogenous cannabinoids, a class of lipid neuromodulators generally implicated in the regulation of neurotransmitter release, may contribute to species-typical social functioning. Systematic study of the endogenous cannabinoid signaling could, therefore, yield novel approaches to understand the neurobiological underpinnings of atypical social functioning. This article provides a critical review of the major components of the endogenous cannabinoid system (for example, primary receptors and effectors9-tetrahydrocannabinol, cannabidiol, anandamide and 2-arachidonoylglycerol) and the contributions of cannabinoid signaling to social functioning. Data are evaluated in the context of Research Domain Criteria constructs (for example, anxiety, chronic stress, reward learning, motivation, declarative and working memory, afliation and attachment, and social communication) to enable interrogation of endogenous cannabinoid signaling in social functioning across diagnostic categories. The empirical evidence reviewed strongly supports the role for dysregulated cannabinoid signaling in the pathophysiology of social functioning decits observed in brain disorders, such as autism spectrum disorder, schizophrenia, major depressive disorder, posttraumatic stress disorder and bipolar disorder. Moreover, these ndings indicate that the endogenous cannabinoid system holds exceptional promise as a biological marker of, and potential treatment target for, neuropsychiatric and neurodevelopmental

disorders characterized by impairments in social functioning.

Translational Psychiatry (2016) 6, e905; doi:http://dx.doi.org/10.1038/tp.2016.169

Web End =10.1038/tp.2016.169 ; published online 27 September 2016

INTRODUCTIONSocial functioning impairments are frequently cited as core features of neuropsychiatric and neurodevelopmental disorders, yet progress in biomarker identication and development of targeted pharmacotherapies has been extremely limited. Delays in progress are attributed to social decit heterogeneity and use of the Diagnostic and Statistical Manual of Mental Disorders (DSM) for investigational research.13 The DSM is a categorical classication system intended to provide clinicians with a common language for diagnosis, but its use in empirical research confers a top-down design. Clinicians categorize patients phenomenologically using the DSM, then researchers attempt to identify pathophysiological mechanisms in patient-participants. However, congruence in phenomenology between patients does not necessarily signify similarity in endophenotypes or genotypes, confounding explicit links to pathology.3,4 To address the disparity in our current understanding of brain dysfunction with clinical phenomenology, a paradigm shift towards a dimensional bottom-up design in research has been adopted. The Research Domain Criteria (RDoC) is a translational research approach that utilizes a matrix framework to facilitate studies that cut across diagnostic boundaries by probing functional constructs associated with neural circuits. The RDoC provides a comprehensive infrastructure to interrogate social functioning impairments and strongly emphasizes the appropriate experimental classication of patients to support direct translation of research ndings for clinical use.2

Social competence is an emergent property, inter- and intra-dependent on functional integrity of three of the RDoC domains: negative valence systems, positive valence systems and cognitive systems. Initial stages of social interaction require overcoming negative valence systems (for example, fear, anxiety) to initiate the interaction and are reinforced by positive valence systems (for example, reward learning, reward valuation). Cognitive Systems (that is, attention, perception, working memory) guide the exchange after social interaction has commenced. Social process systems (that is, afliation and attachment, social communication, perception of self and others) exert supramodal control to coordinate germane practices. Dysfunction in one construct intrinsically affects social information processing and impacts the ability to function typically. In addition, the RDoC framework encourages experimental inquiry at multiple levels of analysis (that is, genes, molecules, cells, circuits, physiology, behavior) to foster research within and across constructs, which fundamentally highlights neuromodulatory systems that operate in multiple constructs, such as the cannabinoid system. The functional heterogeneity of the endogenous cannabinoid system recapitulates the diversity of social functioning abilities in neuropsychiatric and neurodevelopmental disorder patients and parallels dimensional analysis of the RDoC.

The rst reports on cannabinoid involvement in social functioning are from the nineteenth century psychiatrist Dr. Jacques Moreau de Tours for the treatment of distributed neurological

1Center for Interdisciplinary Brain Sciences Research, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA and

2Division of Child and Adolescent Psychiatry, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA. Correspondence: Dr DS Karhson, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 1201 Welch Road, MSLS P-104, Stanford, CA 94305, USA.

E-mail: mailto:[email protected]

Web End [email protected] Received 5 July 2016; accepted 18 July 2016

Endocannabinoids in social functioning DS Karhson et al

2 dysregulation and social alienation.57 Dr. Moreau noted similarities from experiences in healthy humans after ingesting North African hashish (which contains very high concentration of THC [9-tetrahydrocannabinol]5) with the diversity of behaviors in neurological dysfunction.6 Moreover, rst-person reports from hashish users detail traits that neatly map onto RDoC constructs: for example, uctuations of emotions (negative valence), extreme happiness, excitement (positive valence), errors of time and spaceand illusions and hallucinations6 (arousal/regulatory), irresistible impulsesand dissociation of ideas (cognitive domain).8,9 However, current research is focused on the use of inhibitors of endogenous cannabinoid degradation (to enhance signaling) in the study of reward-related processing in social interactions.1014 The present article reviews the basic biology of the endogenous cannabinoid system and the roles of its relevant components across each RDoC construct as it pertains to social functioning. Data reviewed within each RDoC construct are applicable to multiple neuropsychiatric and neurodevelopmental disorders, the most notable of which are highlighted as exemplars at the conclusion of each section. With development of diagnostic assessments and treatment options for social functioning decits limited due to inherent phenotypic heterogeneity, methodical research on the endogenous cannabinoid system has high potential to provide inroads in identifying underlying mechanisms shared across disorders.

ENDOCANNABINOID SIGNALING: EFFECTORS IN NEUROPSYCHIATRIC AND NEURODEVELOPMENTAL DISORDERS

ReceptorsCannabinergic effects is chiey mediated by stimulation of cannabinoid receptors, type 1 and 2 (CB1R and CB2R),15 which are distributed throughout the central nervous system8,16 (see

Table 1). Both types are seven-transmembrane G-protein-coupled receptors. These receptors stimulate Gi/o proteins in the regulation of ion channels, inhibit adenylyl cyclase, which through downstream signaling increase cyclic AMP in the modulation of neuro-transmission, activate protein kinase A to govern cellular function and regulate mitogen-activated protein kinases in control of transcriptional factors.8,17,18 Mainly expressed in presynaptic

axonal segments of inhibitory and excitatory neurons of the

brain, CB1Rs are implicated in regulation of synaptic strength.16,17

CB1Rs control the probability of neurotransmitter release at glutamate and -aminobutyric acid (GABA) synapses, mediating GABA suppression or glutamate release and reuptake,18,19

thereby contributing to the homeostatic maintenance of the brains excitatory-inhibitory balance.17,20,21 CB1R activation also

suppresses release of serotonin, dopamine, acetylcholine and noradrenaline,18,21 thereby mediating the characteristic cognitive and antidepressant effects.16,18 CB2Rs, in contrast, were initially

considered a peripheral nervous system receptor as they were originally from immune cells and gene expression levels were highest in inammatory responses.15,22 The presence of brain

CB2Rs was rst detected after harm, insult or neuroinammation, which breaks down the bloodbrain barrier and allows for non-neuronal immunocytes to inltrate the central nervous system, thereby increasing CB2R expression.23 Accordingly, expression levels of brain CB2R represent brain health,22,23 as

very low expression indicates a t brain.23,24 At homeostasis, low CB2R expression25 is observed in cell bodies and dendrites of neural progenitor cells, neurons, oligodendrocytes, astrocytes23,26

and stimulated microgliaresident macrophages of the central nervous system.22 Activation of CB2Rs upregulates cell-surface factors in regeneration and degeneration, functions in migration and proliferation, as well as neural cell maturation and survival,16,23,27 but the underlying mechanisms remain unclear.

LigandsElucidation of the delta-9 double bond in plant-derived cannabinoid (phytocannabinoid), 9-tetrahydrocannabinol (THC), in the early 1960s instigated the search for endogenously synthesized cannabinoids (endocannabinoids) and led to the detection of anandamide (AEA) and 2-arachidonoylglycerol (2-AG).65,66 Each

cannabinoid class and type is distinct in mechanisms of action, behavioral proles and action in neural circuits. Phytocannabinoids are produced in secretory cells of glandular trichomes at high concentrations in unfertilized female Cannabis owers. THC is a low potency partial agonist at CB1R and CB2R.8,65 The non

psychoactive analog of THC, cannabidiol (CBD), is of burgeoning clinical interest for its very low efcacy and partial agonism at CB1R and CB2R. At low molar concentrations, CBD acts as an antagonist or inverse agonist (particularly at CB2R) to limit THC effects and contributes to the upregulation of endogenous cannabinoid signaling.67 Clinically, CBD is a neuroprotectant used as an anti-inammatory, anticonvulsant, antiepileptic and antipsychotic.8 CBDs effects are attributed to the full agonism it exhibits for non-cannabinoid G-protein-coupled receptors (for example, peroxisome proliferator-activated and nuclear receptors) and interactions with serotonergic, adenosinergic and vanilloid systems.8,15 Notably, the most efcacious therapeutics are observed with formulations combining THC and CBD (two to four times greater than single cannabinoid preparations68) as CBD

enhances the therapeutic action of THC by potentiating its psychotropic effects, augmenting THC tolerability, and widening the therapeutic window.67 Enhanced efcacy is attributed to the entourage effect,65,68 the synergistic action of the more than 480 biologically active and inactive compounds in Cannabis. It is likely that the as-yet identied major and minor cannabinoids in plant extracts may further enhance the therapeutic benet observed with THC and CBD through improved stimulation of the endogenous cannabinoid system.65

Endocannabinoids (eCBs) are small (o400 Da) lipophilic activity-dependent retrograde messengers in the brain. Produced post-synaptically on demand through de novo synthesis from membrane phospholipids in response to increased intracellular Ca2+ via depolarization,69 eCBs act presynaptically to inhibit GABA and glutamate release.17 The physiological endpoints of AEA and 2-AG are comparable to THC,69 but are functionally and temporally distinct from one another. AEA has high binding afnity (CB1R: Ki = 239 nmol l1, CB2R: 440 nmol l1),70 but low efcacy for cannabinoid receptors. It is most active during steady-state conditions and regulates basal synaptic neurotransmission. Data from rodent autism spectrum disorder (ASD) models demonstrate that genetic mutations in the neuroligin gene disrupt tonic eCB signaling71 and intimate the importance of eCB signaling mode (tonic or phasic) in neurodevelopment and neuropsychiatric disorders. 2-AG is the more prevalent eCB (~4 nmol g1 in brain tissue vs AEA at o100 pmol g1)70 and regulates synaptic plasticity.17,69 It is representative of phasic signaling evoked in sustained depolarization. The greater overall efcacy and binding afnity of 2-AG (CB1R: Ki = 3424nmol l1, CB2R: 1194 nmol l1),70 particularly at CB2R,72 is likely related to the enhanced native tone and role in adaptive response. Inactivation of AEA and 2-AG is primarily through enzymatic degradation. AEA is transported across the transmembrane proteins47,73 and hydrolyzed via fatty acid amide hydrolase (FAAH),47 whereas 2-AG can be hydrolyzed by FAAH or monoacylglycerol lipase.74

ENDOCANNABINOID SIGNALING IN SOCIAL FUNCTIONING: AN RDOC PERSPECTIVE

The endocannabinoid system provides a consummate model to examine social functioning decits across multiple clinical populations. The distribution of eCB components is congruent

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inamygdala(viaFAAH)30

inNAc dopamine

inNAc dopamine

inbrainanxiolytic30 inbrainanxiogenic30

RDoCconstructMediatingcircuitCB1RincircuitryCB2Rincircuitry2-AGAEA

AnxietyInterpret:BNST,HPC,amygdala

HPC,amygdala,NAc59,60 NotyetknownNotyetknown(viaFAAH)

USVs61

Abbreviations:AEA,anandamide;2-AG,2-arachidonoylglycerol;BNST,bednucleusofthestriaterminalis;FAAH,fattyacidamidehydrolase;GABA,glutamateand-aminobutyricacid;HPA,hypothalamus

pituitaryadrenalglandaxis;HPC,hippocampus;NAc,nucleusaccumbens;PFC,prefrontalcortex;PVN,paraventricularnucleus;RDoC,ResearchDomainCriteria;SON,supraopticnucleus;USV,ultrasonic

vocalization;VTA,ventraltegmentalarea.CB1RisthemostabundantG-protein-coupledreceptor(a highestlevels/densities,b lowest)inthemammalianbrain,contributingtocannabinergiceffectson

movement,affectiveresponding,cognition,temperature,appetiteandneuroendocrinefunction.8,18 HumanmRNAexpressionforaCB2Risoformhasbeenfoundinamygdala,striatum,HPC,cortexand

cerebellum,25 withrodentsshowingadditionalexpressioninthecerebralcortex,brainstem,thalamicnucleiandperiaqueductalgrey.64 AEAbindingelicitssub-maximalreceptorsignaling,whereas2-AGbinds

withmuchgreaterefcacy,42 necessarytoproducerobustphasicsignalingresponses.

HPC18 (viaFAAH)

acquisition47,48

(viaFAAH)

acquisition47,48

Afliationand

attachment

Play:amygdalaand

NAc12,36

63

Amygdalarimpairmentin

synthesis,30 inPFC36

inNAc

dopamine38,41,42

inNAc

dopamine38,41,42

HPCCB1Rbinding

GABA45,46

encoding/consolidation51

inamygdalaplay36

dopaminergicneurons16,31

HPC23 HPCCB2Rbinding

HPC23,56 inHPCcare54,57

a PFC,a HPC,a NAc,amygdala,HPAa,19,35 Rats:amygdala,HPC,PFC,

hypothalamus25

Microglia,30 VTAandNAc

VTAdopaminergic

neurons31,40

VTAdopaminergic

neurons31

HPCinterneuron

cholecystokinin(+)basket

cells45

BNSTa ,a HPC,amygdala,a PFC,a NAcmedium

spinyneurons,hypothalamusa,5,8,18

a HPC,VTAanda NAc

dopaminergicneurons38,40,41

a NAcmediumspinyneurons,a HPC,

amygdala,VTAanda NAcdopaminergic

neurons,hypothalamusa ,a PFC40,42,43

a PFC,amygdala,GABAergicinterneurons,

a HPC(dentategyrus,CA1andCA3).18,19

a NAcmediumspinyneuron,GABAergic

hippocampalinterneurons46

34 SON,55 HPA,a,13 BNSTa ,amygdala,

NAc12,56

Table1.EndocannabinoidsystemcomponentinRDoCdomains

Evaluateandresponseinitiation:

PFC,NAc,VTA,hypothalamus28,29

39Amygdala,

MotivationOrbitofrontalcortex,amygdala,

VTA,NAc37

DeclarativememoryPFC,amygdala,HPC(dentategyrus,

CA1,CA3),VTA,NAc44

54PVN,

ChronicstressHPA,amygdalamedialPFC

striatum32

RewardlearningVTA,NAc,PFC,hypothalamus,

amygdala40,42

WorkingmemoryPFCparietalcingulatethalamus

NAc,HPC49,50

Amygdala,VTA,NAc,PVN,SON,

HPA,BNST52

SocialcommunicationAmygdala,NAc,orbitofrontal

cortex,corticobasalganglia

thalamonetwork58

34

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with affected neuroanatomy in neuropsychiatric and neuro-developmental disorders with social functioning impairments (see Table 1). Changes in eCB components and function contribute to impairments in RDoC constructs critical to social behavior, resulting in a spectrum of atypical social endopheno-types. The next sections review the role of the eCB system in RDoC constructs subserving social functioning and which are characteristically observed as affected in neuropsychiatric and neurodevelopmental disorders.

eCB SIGNALING AND NEGATIVE VALENCE SYSTEMSAnxietyAnxiety, fear, and stress as terms are often semantically interchangeable, though each is independently characterized by the nature of the eliciting event and magnitude of response.28,29

Anxiety is elicited by putatively dangerous, uncertain, imminent situations or events that lead to an acute behavioral response in preparation for threats to individual integrity that is disproportional in intensity or chronicity.29 Anxiety is physiologically manifested as an exaggerated startle response, increased muscle tension, decreased motion, avoidance behaviors and autonomic hyperactivity. With regard to social functioning, pathological anxiety can impede competent functioning in the absence of triggering stimuli. Major components of the neurocircuitry mediating anxiety, such as the prefrontal cortex (PFC), hippocampus, amygdala and hypothalamus are rich in CB1R and CB2R expression (see Table 1). In animal models, genetic deletion of CB1R increases anxiety-like behaviors, but only under highly aversive conditions, whereas deletion of CB2R modulate vulnerability to anxiogensis.30,75 Overexpression of CB2Rs in mouse models increases resistance to anxiogenic stimuli, mediated by increased 2-AG and GABA signaling.30 Exogenous cannabinoids exert an inverted U-shaped effect on anxiety, that is both anxiolytic and anxiogenic, dependent on concentration and context.76 Acute administration of THC and CBD in preclinical models and patient populations commonly produces an anxiolytic response, likely due to inhibition of the glutamatergic ring in neural networks involved in anxiety.28,29 Similarly, eCB signaling, such as blockade of AEA hydrolysis77,78 or inhibition of

monoacylglycerol lipase8 also elicits an anxiolytic response. Anxiogensis can be observed via eCB signaling suppression of glutamate outow in the hippocampus and periaqueductal gray, as well as in its inhibition of corticolimbic release of noradrenaline, dopamine and serotonin.30,76 These data are pertinent to a myriad

of neurodevelopmental and neuropsychiatric disorders (for example, posttraumatic stress disorder, depression, schizophrenia, obsessive compulsive disorder, ASD, bipolar disorder, phobias and so on), but further study is needed to clarify how best to leverage neurocircuitry modulation with precision to ensure anxiolytic function of cannabinergic pharmacologic interventions and the potential restoration of homeostatic eCB signaling.

Chronic stressStress is an adaptive response to a specic internal or external stressor in preparation for injury or threat. Denitions of stress emphasize the physiological and emotional consequences to relate acute parallel activation of autonomic and endocrine systems. Chronic stress is a response to persistent stressors, like social threat or defeat, which reduces social motivation and social interactions by intensifying fear towards (an emotional reaction) and avoidance (anxiogenic behavior) of unknown conspecics.32,79 Across development, protracted exposure to stressors imposes a progressive pattern of dysfunction in social functioning, beginning as asociality and culminating in antisociality.79 Persistent activation (44 weeks, 48 weeks) of stress neurocircuitry breaks down homeostatic balance32,33 and

creates a 'hypocannabinergic state' through downregulation of CB1R expression in the hippocampus, hypothalamus, striatum and dorsal root ganglion.33,34 No signicant change in CB2R expression

was observed in three separate mouse lines, following exposure to chronic stressors, but without analogous data in humans, few conclusions can be made about CB2R function under chronic stress.25 Alterations in CB1R expression are concurrent with changes in eCB signaling in the hippocampus, striatum, dorsal raphe nucleus, hypothalamus, nucleus accumbens (NAc), PFC (at GABAergic terminals) and the amygdala. In the absence of stressors, AEA tone suppresses activity of the hypothalamic pituitaryadrenal (HPA) axis (the chief modulator of the stress response80,81) and disruption of this suppression initiates HPA-axis activation.35,81 Chronic stressor exposure impairs AEA signaling and elevates 2-AG content within the amygdala (and increases glucocorticoid hormone secretion), hippocampus, hypothalamus and PFC,33 likely due to altered FAAH and monoacylglycerol lipase-mediated hydrolysis, as the synthesis of these eCBs is unimpaired.34,82 Glucocorticoid feedback inhibition of HPA-axis activity is suggested to occur on two temporal scales, rapidly via the PFC and 2-AG tone enhancement, or less rapidly via negative feedback inhibition at the paraventricular nucleus of the hypothalamus.34,82 Glucocorticoids then normalize the amygdalar AEA levels to support basal HPA function.34 The enhancement of 2-AG signaling is perceived as an attempt to habituate to the chronic stress exposure and may be crucial in understanding how to properly engage eCB signaling in the modulation of the HPA axis to guarantee a positive adaptive response.34 However, the presence of a mechanism to examine maladaptive responses to chronic stress exposure highlights novel areas for social decits in which exposure to a chronic stressor is unavoidable (for example, social anxiety and mood disorders).

eCB SIGNALING AND POSITIVE VALENCE SYSTEMSReward learningReward attainment is one of the only RDoC constructs to explicitly detail eCBs as candidate modulators of reward learning, valuation and processing.43 Recent data linking reward and social neuropeptides with eCBs highlight a novel, potential intervention specic to social functioning decits.13 Adaptive reinforcement of social interactions requires long-term synaptic plasticity at excitatory synapses of the NAc and is dependent on oxytocin (OT), a neuropeptide that regulates prosocial behavior and its dysregulation has been implicated in social impairments.83,84 In

the examination of neural circuits of socialization, Wei et al.13

demonstrated an obligatory role of AEA in a socially isolated rodent model. Salience and reward were modulated by AEA mobilization in the NAc and hippocampus via activation of OT receptors by endogenously released OT following social contact. Additional experiments to control for the anxiogenic induction of AEA release during stressful social situations found the observed effects were independent of the stress response and specic to social reward.13 Data suggest that OT acts as a social reinforcement signal to induce long-term depression in medium spiny neurons and requires specic activation of CB1Rs by AEA to regulate social incentive salience. These preclinical data provide insight into the mechanisms associated with OT in social functioning in clinical populations. If improvement in social functioning requires OT-evoked AEA signaling as data suggest, then enhancement of OT to improve social decits must be sufcient to engage AEA mobilization for proper functioning of the neural circuit. Researchers have advocated that these ndings are of particular relevance to ASD, although these results can also be broadly applied to neuropsychiatric disorders characterized by dysregulated OT and impaired social functioning (for example, schizophrenia and mood, anxiety, or personality disorders85,86).

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Social motivationSocial motivation leads to enhancement of social development by promoting social interactions. Abnormal motivation precludes procient social interaction and has negative consequences on the acquisition of higher-order social abilities.37 The inability to separate motivation from social interest has contributed to the assumption that decits in social functioning are a cause of disrupted social interest, as opposed to a consequence of them.37

Motivation is necessary to attend to social information, seek and engage in social interaction, as well as foster and maintain social bonds, whereas interest does not necessitate action. Individual differences in social motivation are associated with alterations in the activity of neurocircuitry that overlap with reward learning; high social motivation is correlated with enhanced activation of the amygdala and orbital frontal cortex, whereas weaker activation is related to lower social motivation. Opioid and dopaminergic neurons in the ventral tegmental area have complementary roles in motivated behaviors and require eCB signaling to ne-tune dopamine release in incentive-related reward learning.40,52

Concomitantly, enhanced motivation is observed following CB1R stimulation and with increased AEA signaling in the amygdala, NAc and dorsal striatum and 2-AG in the NAc.38,41,42 Diminished

motivation is associated with CB1R blockade.38,39 Wei et al.87

suggest increased AEA content in the forebrain in animal models of ASD can ameliorate social motivation decits. Extending previous results in rats in which modulation of CB1R or genetic removal of FAAH negatively impacted social interactions,79,88

researchers examined the inuence of AEA on social behaviors via FAAH modulation.13 A social approach task and elevated plus maze were used to assess the effects of increased AEA (via FAAH inhibition) on social motivation in BTBR mice (an idiopathic ASD model with known decits in social approach, reciprocal social interaction, and juvenile play) and Fragile X Syndrome mice (a syndromic ASD model with persistent social approach decits). Increased AEA signaling in the forebrains of ASD mouse models correlated with increased time in the social chamber and preferential interaction with novel animals compared with untreated and control mice.87 Effects were not associated with decreased anxiogenic responses, as no change in behavior on the elevated plus maze was observed. Improved prosocial behaviors were generalizable87 and suggest common neural circuitry of social motivation between idiopathic and syndromic ASD.

eCB SIGNALING AND COGNITIVE SYSTEMSDeclarative memoryDeclarative memory (that is, encoding, consolidation, storage and retrieval of factual information44) supports social interactions by providing biographical and episodic recall.49 It functions as a store of experience-outcomes and integrates previous conclusions with new input, as well as emotion, motivation and perception.44

Stimulation of cannabinoid receptors in hippocampal circuits diminishes glutamate release to below-threshold levels, inhibiting long-term potentiation necessary for encoding.89,90 In animal

models, stimulation of receptors before or after learning induces impaired performance on water maze, contextual fear conditioning and object recognition memory assessments.89,91 In humans,

decits were not observed in the retrieval of previously stored information, and learning impairments were transient as after a 3-month abstinence from phytocannabinoids, decits were no longer observed.8,92 Importantly, cannabinergic modulation of cognitive effects can vary on the basis of the use of exogenous or endogenous cannabinoids. AEA and 2-AG are both robust modulators of early-stage acquisition, consolidation and extinction,49,66,90 but it is the enhancement of 2-AG that is

correlated with disrupted encoding in spatial memory.51,93,94 An

abundance of evidence demonstrates transient, dose-dependent

THC-induced memory impairments (with a tolerance effect in heavy users) and the contrasting absence of memory decits following CBD administration. Data also suggest that CBD is protective against THC-induced impairments in episodic and spatial memory.65,66,92 Explicit control of eCB signaling in

declarative memory for social functioning decits must account for individual differences in abilities. Brain disorders characterized by difculties in uncontrolled recall (for example, ASD, posttraumatic stress disorder, phobia disorders) may benet from control over extinction, whereas disrupting short-term memory consolidation may be advantageous for other disorders (for example, OCD, anxiety disorders).

Working memoryMore immediate information processing involves working memory, which actively maintains and updates relevant information, but is capacity-limited.50 In social interactions, working memory tracks social information, like the characteristics of, or relationships among, people necessary to competently socially interact. THC exposure in humans negatively impacts working memory via CB1R activation and inhibition of AEA reuptake.48,51 Correspondingly, rodent models with upregulated CB1R expression in the PFC, as well as CB1R knockout mice, demonstrate changes in cognitive exibility. Low doses of CB1R antagonists improved task switching (a measure of cognitive exibility) and inhibitory control via inhibition of PFC glutamatergic activity, whereas CB1R agonists increased impulsive behaviors. A neuroimaging study90 suggests that THC impacts activity in cerebral inhibition response circuits causing increased hyperactivity in the PFC and anterior cingulate cortices. Acute administration of THC reduces response inhibition49,89 (that is, increases behavioral impulsivity) and causes hyperactivity at dopaminergic synapses in the PFC.90 Data from animal models suggest that cannabinoid signaling interacts with dopaminergic, GABAergic and glutamatergic pathways to mediate behavioral changes. Data in FAAH knockout mice demonstrate that AEA-biased tone improves acquisition in working memory tasks, but the effects are transient and do not persist into later trials.65,66 This evidence suggests that strategies to improve components of working memory (for disorders such as prosopagnosia, schizophrenia and/or depression) should focus on control of AEA tone and local modulation of 2-AG signaling.

eCB SIGNALING AND SOCIAL PROCESSING SYSTEMS Afliation and attachmentMaternal care is a newborns rst social experience and variation in maternal care has been shown to dramatically inuence social development.56,57 Mouse pups that receive intensive maternal

care demonstrate enhanced maternal behavior in adulthood demonstrating the enduring effects of maternal care on adult social functioning.95,96 Disruption of the motherinfant bond has lasting consequences on neuroendocrine and cognitive functioning, increasing the risk for subsequent psychopathology.56 OT is a

primary regulator of social behavior,53,83,84 particularly in maternal care,53,54 and is associated with eCB signaling.57,95,97 Schechter et al.57,95 performed several studies examining eCB and OT signaling in maternal care and demonstrated that genetic ablation of CB1R negatively affected maternal care. This impairment correlated with decreased hippocampal OT receptor expression and increased hippocampal levels of 2-AG.54,57,95 Results are

consistent with observations from socially isolated animals. These studies demonstrated that region-specic CB1R expression in the supraoptic nucleus of socially isolated animals can reduce social play and social interaction compared with those that were pair-housed and handled daily.36,55 Changes in receptor density affect GABAergic and glutamatergic input to OT-synthesizing neurons for mobilization of OT release,55,57 which is necessary for social

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bonding. Valproate-exposed rats, another animal model of social decits used in ASD research, demonstrate similarly reduced sociability, but changes in CB1R expression were also correlated with reduced hippocampal 2-AG expression.98 Moreover, after social play, increased AEA and 2-AG levels in the NAc and the amygdala were observed.12,88 These data demonstrate that

perturbation of eCB signaling is an elegant potential causal effector in the regulation of maternal care and afliative behaviors. These results are pertinent to better understanding how cannabinoid modulation contributes to the neurocircuitry of psychiatric disorders related to early-life adversity, such as depression, bipolar disorder and schizophrenia.56,96

Social communicationIn humans, high concentrations of cannabinoid receptors are found in the left hemisphere cortical regions that are associated with verbal language function,16,18 which suggests a role for eCB signaling in social communication. However, current ndings only supports a role for eCB signaling in nonverbal motor-related aspects of social communication (that is, eye-gaze or body language). Genetic variants (that is, single-nucleotide polymorphisms) in CB1Rs are correlated with greater gaze duration to happy faces and are considered a putative endophenotype for communication decits, particularly in ASD research.99 Animal models of social communication impairments demonstrate a direct connection to cannabinergic function, which interacts with the forkhead box (FOXP) protein family.58 Interestingly, FOXP are instrumental in ultrasonic vocalizations (USVs) production and vocal learning.58,100 In rodents, USVs serve a communicatory function

to elicit social interaction61,62 or to share socially relevant

information with known conspecics.63 Moreover, USVs are developmental- and context-dependent62 relating identity, emotionality,6163 receptivity to afliative and sexual behaviors, and changes in the environment.56 Persistent activation of CB1R, via agonists or inhibitors of enzymatic degradation, decrease emission of USVs in rodent pups. Cannabinoids modulate USVs induced by maternal separation in pups,61 whereas in adult rodents, cannabinoids increase the emission of USVs when exposed to anxiogenic stimuli.61,63 Moreover, CB1R knockout mice have low USV emission throughout development,56 which parallels the communication impairments associated with disorders such as ASD.62 For clinical populations with impairments in language acquisition, especially nonverbal patients with social decits, cannabinergic modulation of USVs offers a novel and viable area of biomedical intervention in support of communication acquisition and development.59,60,100

CONCLUSIONSThe diversity of social functioning decits present in neuropsychiatric and neurodevelopmental disorders confounds the efcacy and specicity of treatment for affected individuals. However, the recent shift in psychiatric research towards examining the underlying dysregulated neural circuits of brain disorders has allowed consideration herein of novel aspects of the functionally diverse eCB signaling system. This article reviewed the eCB signaling system and the role of its components (that is, cannabinoid receptors, functional ligands) in varied, but convergent, RDoC domains of social functioning. From a molecular level of analysis, the cannabinoid system is implicated in negative and positive valence systems to restore homeostatic balance, increase the salience of reward learning and motivate social interactions. Behavioral and physiological effects of the eCB system are observed in cognitive systems. Social process systems show evidence of cannabinergic modulation, and as an emergent domain, rely on appropriate eCB function in the aforementioned RDoC domains. Although further work is needed to clarify the

discrete roles of cannabinoid signaling in each RDoC domain, the extant evidence strongly supports the contribution of dysregulated cannabinoid signaling to the pathophysiology of social functioning impairments. With regard to the development of pharmacological interventions, although there is a diverse set of methods to enhance endogenous signaling or receptor stimulation in vivo, the lack of evidence on direct endocannabinoid (AEA or 2-AG)66 highlights the need for further research. Moreover, in the pursuit of precision health,2 although each component of the eCB system can be targeted for therapeutic development, appropriate targeting with respect to the intersection of the eCB system and a disorders neurocircuitry must be carefully considered to achieve optimal outcomes. It is clear, though, that the eCB system holds exceptional promise as a biological marker of, and treatment target6 for, neuropsychiatric and neurodevelop-mental disorders characterized by pronounced abnormalities in social functioning.

CONFLICT OF INTEREST

The authors declare no conict of interest.

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