Endocannabinoid Modulation of Nucleus Accumbens Microcircuitry and Terminal Dopamine Release

Tang

Intl J Eating Disorders

et al. 2023

ObjectiveAlthough studies have demonstrated the involvement of the nucleus accumbens (NAc) in the neurobiology of eating disorders, its alterations in bulimia nervosa (BN) remain largely unknown. This study investigated the structural and functional properties of NAc in patients with BN.MethodBased on the resting‐state functional MRI and high‐resolution anatomical T1‐weighted imaging data acquired from 43 right‐handed BN patients and 40 sex‐, age‐ and education‐matched right‐handed healthy controls (HCs), the group differences in gray matter volume (GMV) and fractional amplitude of low‐frequency fluctuation (fALFF) in slow‐4 and ‐5 bands and functional connectivity (FC) of NAc subregions (core and shell) were compared. The relationships between MRI and clinical data were explored in the BN group.ResultsCompared with HCs, BN patients showed preserved GMV, decreased fALFF in slow‐5 band of the left NAc core and shell, decreased FC between left NAc core and right caudate, and increased FC between all NAc subregions and frontal regions, between all NAc subregions (except the right NAc core) and the supramarginal gyrus (SMG), and between right NAc shell and left middle temporal gyrus. FC between the NAc and SMG was correlated with emotional eating behaviors.DiscussionOur study revealed preserved GMV, local neuronal activity reduction and functional network reorganization of the NAc in BN. The functional network reorganization of the NAc mainly occurred in the frontal cortex and was correlated with emotional eating behavior. These findings may provide novel insights into the BN using NAc as an entry point.Public significanceAlthough studies have demonstrated the involvement of the nucleus accumbens (NAc) in the neurobiology of eating disorders, its alterations in bulimia nervosa (BN) remain largely unknown. We used a multimodal MRI technique to systematically investigate structural and functional alterations in NAc subregions of BN patients and explored the associations between such alterations and maladaptive eating behaviors, hoping to provide novel insights into BN.

Section: Discussionmentioning

confidence: 99%

The role of functional and structural properties of the nucleus accumbens subregions in eating behavior regulation of bulimia nervosa

Tang

Intl J Eating Disorders

et al. 2023

“…4 ). GLUT/GABAergic substrates are functionally involved in regulation of mesolimbic DAergic function and directly modulate intra-NAc DA neurotransmission ( Rey et al, 2012 ; Covey and Yocky, 2021 ). Critically, CB1Rs are located primarily on GLUT axons and GABA presynaptic terminals in both the VTA and NAc ( Rey et al, 2012 ; Guzman et al, 2021 ); suggesting a particular susceptibility of both systems to PCE which may result in the observed long-term dysregulation of the mesolimbic circuit.…”

Section: Discussionmentioning

confidence: 99%

Prenatal THC Exposure Induces Sex-Dependent Neuropsychiatric Endophenotypes in Offspring and Long-Term Disruptions in Fatty-Acid Signaling Pathways Directly in the Mesolimbic Circuitry

Sarikahya

Cousineau

Felice

et al. 2022

eNeuro

Despite increased prevalence of maternal cannabis use, little is understood regarding potential long-term effects of prenatal cannabis exposure (PCE) on neurodevelopmental outcomes. While neurodevelopmental cannabis exposure increases the risk of developing affective/mood disorders in adulthood, the precise neuropathophysiological mechanisms in male and female offspring are largely unknown. Given the interconnectivity of the endocannabinoid system and the brain's fatty acid pathways, we hypothesized that prenatal exposure to Δ9-tetrahydrocannabinol (THC) may dysregulate fetal neurodevelopment through alterations of fatty-acid dependent synaptic and neuronal function in the mesolimbic system. To investigate this, pregnant Wistar rats were exposed to vehicle or THC (3mg/kg) from gestational day (GD) 7 until GD22. Anxiety-like, depressive-like, and reward-seeking behaviour, electrophysiology, and molecular assays were performed on adult male/female offspring. Imaging of fatty acids using matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) was performed at prepubescence and adulthood. We report PCE induces behavioral, neuronal, and molecular alterations in the mesolimbic system in male and female offspring, resembling neuropsychiatric endophenotypes. Additionally, PCE resulted in profound dysregulation of critical fatty acid pathways in the developing brain lipidome. Female progeny exhibited greater alterations to fatty acid levels at prepubescence but recovered from these deficits by early adulthood. In contrast, males exhibited persistent fatty acid deficits into adulthood. Moreover, both sexes maintained enduring abnormalities in glutamatergic/GABAergic function in the nucleus accumbens. These findings identify several novel longterm risks of maternal cannabis use and demonstrate for the first time, sex-related effects of maternal cannabinoid exposure directly in the developing neural lipidome. Significance StatementPrenatal cannabinoid exposure (PCE) is growing in prevalence and the long-term effects on fetal brain development are largely unknown. Our study provides novel evidence that chronic prenatal THC exposure can induce long-lasting alterations in mesolimbic function that differentially impacts the male vs. female brains. We also demonstrate for the first time that PCE can induce profound lipidomic adaptations that may account for these neuropathophysiological sequelae.

acta neuropathol commun

“…Ultimately, stimulation of CB1 increases DA levels in the PfCtx while antagonism of CB1 attenuates DA release induced by palatable foods [ 45 , 46 ]. A similar mechanism also contributes to the eCB modulation of DA release in the nAc [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

α-Dystrobrevin knockout mice have increased motivation for appetitive reward and altered brain cannabinoid receptor 1 expression

Hawkes

Heath

Sharp

et al. 2022

Abstractα-Dystrobrevin (α-DB) is a major component of the dystrophin-associated protein complex (DAPC). Knockout (KO) of α-DB in the brain is associated with astrocytic abnormalities and loss of neuronal GABA receptor clustering. Mutations in DAPC proteins are associated with altered dopamine signaling and cognitive and psychiatric disorders, including schizophrenia. This study tested the hypothesis that motivation and associated underlying biological pathways are altered in the absence of α-DB expression. Male wildtype and α-DB KO mice were tested for measures of motivation, executive function and extinction in the rodent touchscreen apparatus. Subsequently, brain tissues were evaluated for mRNA and/or protein levels of dysbindin-1, dopamine transporter and receptor 1 and 2, mu opioid receptor 1 (mOR1) and cannabinoid receptor 1 (CB1). α-DB KO mice had significantly increased motivation for the appetitive reward, while measures of executive function and extinction were unaffected. No differences were observed between wildtype and KO animals on mRNA levels of dysbindin-1 or any of the dopamine markers. mRNA levels of mOR1were significantly decreased in the caudate-putamen and nucleus accumbens of α-DB KO compared to WT animals, but protein levels were unaltered. However, CB1 protein levels were significantly increased in the prefrontal cortex and decreased in the nucleus accumbens of α-DB KO mice. Triple-labelling immunohistochemistry confirmed that changes in CB1 were not specific to astrocytes. These results highlight a novel role for α-DB in the regulation of appetitive motivation that may have implications for other behaviours that involve the dopaminergic and endocannabinoid systems.