The Endocannabinoid System and Autism Spectrum Disorders: Insights from Animal Models

Abstract

Autism spectrum disorder (ASD) defines a group of neurodevelopmental disorders whose symptoms include impaired communication and social interaction with restricted or repetitive motor movements, frequently associated with general cognitive deficits. Although it is among the most severe chronic childhood disorders in terms of prevalence, morbidity, and impact to the society, no effective treatment for ASD is yet available, possibly because its neurobiological basis is not clearly understood hence specific drugs have not yet been developed. The endocannabinoid (EC) system represents a major neuromodulatory system involved in the regulation of emotional responses, behavioral reactivity to context, and social interaction. Furthermore, the EC system is also affected in conditions often present in subsets of patients diagnosed with ASD, such as seizures, anxiety, intellectual disabilities, and sleep pattern disturbances. Despite the indirect evidence suggestive of an involvement of the EC system in ASD, only a few studies have specifically addressed the role of the EC system in the context of ASD. This review describes the available data on the investigation of the presence of alterations of the EC system as well as the effects of its pharmacological manipulations in animal models of ASD-like behaviors.

Sex‐specific autistic endophenotypes induced by prenatal exposure to valproic acid involve anandamide signalling

“…Indeed, a consistent number of studies indicated that endocannabinoids modulate several behaviours and processes that are compromised in ASD. Furthermore, an impaired endocannabinoid activity has been observed in preclinical models of ASD (Kerr et al ., ; Zamberletti et al ., ) and in ASD patients (Siniscalco et al ., ). Sex hormones have been found to modulate brain endocannabinoid activity, thus influencing cannabinoid‐mediated physiopathological processes (Fattore and Fratta, ; Viveros et al ., ).…”

“…Here, we have performed a longitudinal study from birth to adulthood to evaluate potential sexually dimorphic effects induced in rodents by prenatal VPA exposure on core and co‐morbid behavioural traits that are frequently impaired, often in a sex‐specific manner, in ASD patients: (i) social communication, (ii) social behaviour, (iii) social discrimination, (iv) stereotypies, (v) anxiety and (vi) cognitive performance. Furthermore, because the endocannabinoid system plays a key role in brain development (Maccarrone et al ., ), it has been recently involved in ASD (Siniscalco et al ., ; Chakrabarti et al ., ; Zamberletti et al ., ) and it is modulated by sex hormones during critical developmental ages (Viveros et al ., ). Here, we have investigated its role in the sexually dimorphic behavioural consequences of prenatal VPA exposure.…”

Medical Cannabis in Children

“…[101][102][103] Activation of the endocannabinoid system in the nucleus accumbens (anandamide mobilization and consequent activation of CB1 receptors) driven by oxytocin, a neuropeptide that reinforces social bonding, was demonstrated to be necessary and sufficient to express the rewarding properties of social interaction. 104 Reduced endocannabinoid activity was demonstrated in several animal models of ASD, 105 including monogenic (fragile-X, 106 neuroligin 3 107 ), polygenic (BTBR 105 ), and environmental (rat valproic acid 108 ) models. Activation of the endocannabinoid system [105][106][107][108] and administration of CBD 105 have been shown to restore social deficits in some models.…”

“…104 Reduced endocannabinoid activity was demonstrated in several animal models of ASD, 105 including monogenic (fragile-X, 106 neuroligin 3 107 ), polygenic (BTBR 105 ), and environmental (rat valproic acid 108 ) models. Activation of the endocannabinoid system [105][106][107][108] and administration of CBD 105 have been shown to restore social deficits in some models. A single oral administration of 600 mg CBD to 34 men (17 neurotypicals and 17 with ASD) increased prefrontal gamma-aminobutyric acid (GABA) activity in neurotypicals and decreased GABA activity in those with ASD.…”

Innovative Therapeutic Potential of Cannabinoid Receptors as Targets in Alzheimer’s Disease and Less Well-Known Diseases

“…Autism spectrum disordersAutism spectrum disorder (ASD) is formed of a heterogeneous group of neurological disorders characterised by impaired social interaction and communication skills, and is often accompanied by other behavioural symptoms such as repetitive or stereotyped behaviour and abnormal sensory processing[278,279]. Individual symptoms and cognitive functioning vary across the autism spectrum disorders.The diagnosis is made during the first three years of age; however, the onset of disease can be from birth or usually during the second year.…”