Reversing the Psychiatric Effects of Neurodevelopmental Cannabinoid Exposure: Exploring Pharmacotherapeutic Interventions for Symptom Improvement

Felice, Marta De; Laviolette, Steven R.

doi:10.3390/ijms22157861

Cited by 10 publications

(6 citation statements)

References 121 publications

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“…For instance, previous studies have shown that rats with a history of cocaine, amphetamine, or morphine exposure exhibit an increased willingness to exert effort for palatable food reward (Forouzan et al 2021; Mendez et al 2009; Nordquist et al 2007b; Rouibi and Contarino 2012), as was observed in the current study after repeated THC exposure. This heightened motivation is thought to be mediated by increased mesolimbic dopamine signaling (Berridge and Robinson 2016; Robinson and Berridge 1993), which is consistent with previous reports that repeated THC exposure causes long-lasting hyperactivity in mesolimbic dopamine neurons (De Felice and Laviolette 2021; Renard et al 2017a), and sensitizes dopamine release in the nucleus accumbens core (Cadoni et al 2008).…”

Section: Discussionsupporting

confidence: 90%

Long-term effects of THC exposure on reward learning and motivated behavior in adolescent and adult male rats

Halbout

Hutson

Hua

et al. 2022

Preprint

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Rationale: The endocannabinoid system makes critical contributions to reward processing, motivation, and behavioral control. Repeated exposure to THC or other cannabinoid drugs can cause persistent adaptions in the endocannabinoid system and associated neural circuitry. It remains unclear how such treatments affect the way rewards are processed and pursued. Objective and methods: We examined if repeated THC exposure (5 mg/kg/day for 14 days) during adolescence or adulthood led to long-term changes in rats' capacity to flexibly encode and use action-outcome associations for goal-directed decision making. Effects on hedonic feeding and progressive ratio responding were also assessed. Results: THC exposure had no effect on rats' ability to flexibly select actions following reward devaluation. However, instrumental contingency degradation learning, which involves avoiding an action that is unnecessary for reward delivery, was augmented in rats with a history of adult but not adolescent THC exposure. THC-exposed rats also displayed more vigorous instrumental behavior in this study, suggesting a motivational enhancement. A separate experiment found that while THC exposure had no effect on hedonic feeding behavior, it increased rats' willingness to work for food on a progressive ratio schedule, an effect that was more pronounced when THC was administered to adults. Adolescent and adult THC exposure had opposing effects on the CB1-receptor dependence of progressive ratio performance, decreasing and increasing sensitivity to rimonabant-induced behavioral suppression, respectively. Conclusions: Our findings reveal that exposure to a translationally relevant THC exposure regimen induces long-lasting, age-dependent alterations in cognitive and motivational processes that regulate the pursuit of rewards.

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Section: Discussionsupporting

confidence: 90%

Long-term effects of THC exposure on reward learning and motivated behavior in adolescent and adult male rats

Halbout

Hutson

Hua

et al. 2022

Preprint

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“…However, in our experiments, different sets of animals underwent PIT, Pavlovian conditioned approach, and cocaine SA, so future experiments should be performed to directly check this correlation in the same subjects. Given that dopamine transmission in the NAcc is crucial for the PIT phenomenon, with a particular role of D1 receptors ( Lex and Hauber, 2008 ), the specific enhancement of PIT in the THC-exposed males observed here may be related to the hyperdopaminergic state induced by ACE in specific circuits ( De Felice and Laviolette, 2021 ), especially the increment in D1 receptors in the NAcc shell in males but not females after ACE observed by us in a previous report ( Higuera-Matas et al, 2010 ).…”

Section: Discussionmentioning

confidence: 47%

Δ 9-Tetrahydrocannabinol During Adolescence Reprograms the Nucleus Accumbens Transcriptome, Affecting Reward Processing, Impulsivity, and Specific Aspects of Cocaine Addiction-Like Behavior in a Sex-Dependent Manner

Orihuel

Capellán

Roura-Martínez

et al. 2021

International Journal of Neuropsychopharmacology

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Background Cannabis exposure during adolescence is associated with emotional and motivational alterations that may entail an enhanced risk of developing psychiatric disorders. In rodent models, exposure to cannabinoids during adolescence leads to increased self-administration of opiates and cocaine, however, the psychological and neural mechanisms and the sex-specificity of this phenomenon are largely unknown. Methods We exposed male and female adolescent rats to Δ9-tetrahydrocannabinol (THC) and studied at adulthood the effects of such treatment on psychological processes related to reward, such as Pavlovian conditioned approach, Pavlovian to instrumental transfer, habit formation and waiting impulsivity. In the light of these data and given the involvement of the nucleus accumbens in the processes examined, we performed an RNASeq transcriptomic study and assessed cocaine addiction-like behavior. Results THC exposure increased goal-tracking (in males and females) and enhanced Pavlovian to instrumental transfer (especially in males) but did not affect habit formation. THC-exposed rats exhibited subtle, state-dependent changes in premature responding in the 2-CSRTT task. RNASeq data showed gene expression alterations in a marked sex-specific manner. While no effects were found on the acquisition of cocaine self-administration or punished drug-seeking, rats exposed to THC self-administered more cocaine under a progressive ratio schedule (males), had a higher rebound upon returning to continuous access to the drug (females) and showed reduced drug-seeking after 30 days of withdrawal (females). Conclusions Adolescent THC affects specific aspects of reward- (and cocaine-) guided behavior and the function of a key brain region mediating these effects, in a remarkable sex-specific manner.

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“…We next examined expression levels of several molecular signaling pathways known to be disrupted following neurodevelopmental adolescent THC exposure and dysregulated in neuropsychiatric disorders ( Ohtsuki et al, 2001 ; Madras, 2013 ; Urs et al, 2017 ; Renard et al, 2018 ; Szkudlarek et al, 2019 ; De Felice and Laviolette, 2021 ). Given that our VTA data revealed significant disruptions in DAergic activity states, we first characterized intra-NAc DA D1/D2R expression patterns.…”

Section: Resultsmentioning

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

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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.

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Reversing the Psychiatric Effects of Neurodevelopmental Cannabinoid Exposure: Exploring Pharmacotherapeutic Interventions for Symptom Improvement

Cited by 10 publications

References 121 publications

Long-term effects of THC exposure on reward learning and motivated behavior in adolescent and adult male rats

Long-term effects of THC exposure on reward learning and motivated behavior in adolescent and adult male rats

Δ 9-Tetrahydrocannabinol During Adolescence Reprograms the Nucleus Accumbens Transcriptome, Affecting Reward Processing, Impulsivity, and Specific Aspects of Cocaine Addiction-Like Behavior in a Sex-Dependent Manner

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

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