The effects of alcohol and cannabinoid exposure during the brain growth spurt on behavioral development in rats

Breit, Kristen R.; Zamudio, Brandonn; Thomas, Jennifer D.

doi:10.1002/bdr2.1487

Cited by 31 publications

(31 citation statements)

References 111 publications

(135 reference statements)

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“…Thus, the augmentation in locomotion could be the result of a decreased habituation to a novel environment compared to the CTRL group. Since habituation per se represents a learning process of the environmental setting, one could speculate that the hyper-locomotor effect observed in this study may underlie a delay in simple learning (Breit et al, 2019) rather than a prominent effect on emotionality. Further investigation of spatial learning abilities (Cannizzaro et al, 2007) of PCE progeny will clarify this point.…”

Section: Discussionmentioning

confidence: 90%

In utero Δ9-tetrahydrocannabinol exposure confers vulnerability towards cognitive impairments and alcohol drinking in the adolescent offspring: Is there a role for neuropeptide Y?

et al. 2020

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Background: Cannabinoid consumption during pregnancy has been increasing on the wave of the broad-based legalisation of cannabis in Western countries, raising concern about the putative detrimental outcomes on foetal neurodevelopment. Indeed, since the endocannabinoid system regulates synaptic plasticity, emotional and cognitive processes from early stages of life interfering with it and other excitability endogenous modulators, such as neuropeptide Y (NPY), might contribute to the occurrence of a vulnerable phenotype later in life. Aims: This research investigated whether in utero exposure to Δ9-tetrahydrocannabinol (THC) may induce deficits in emotional/cognitive processes and alcohol vulnerability in adolescent offspring. NPY and excitatory postsynaptic density (PSD) machinery were measured as markers of neurobiological vulnerability. Methods: Following in utero THC exposure (2 mg/kg delivered subcutaneously), preadolescent male rat offspring were assessed for: behavioural reactivity in the open field test, neutral declarative memory and aversive limbic memory in the Novel Object and Emotional Object Recognition tests, immunofluorescence for NPY neurons and the PSD proteins Homer-1, 1b/c and 2 in the prefrontal cortex, amygdala and nucleus accumbens at adolescence (cohort 1); and instrumental learning, alcohol taking, relapse and conflict behaviour in the operant chamber throughout adolescence until early adulthood (cohort 2). Results: In utero THC-exposed adolescent rats showed: (a) increased locomotor activity; (b) no alteration in neutral declarative memory; (c) impaired aversive limbic memory; (d) decreased NPY-positive neurons in limbic regions; (e) region-specific variations in Homer-1, 1b/c and 2 immunoreactivity; (f) decreased instrumental learning and increased alcohol drinking, relapse and conflict behaviour in the operant chamber. Conclusion: Gestational THC impaired the formation of memory traces when integration between environmental encoding and emotional/motivational processing was required and promoted the development of alcohol-addictive behaviours. The abnormalities in NPY signalling and PSD make-up may represent the common neurobiological background, suggesting new targets for future research.

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Section: Discussionmentioning

confidence: 90%

In utero Δ9-tetrahydrocannabinol exposure confers vulnerability towards cognitive impairments and alcohol drinking in the adolescent offspring: Is there a role for neuropeptide Y?

et al. 2020

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“…Previous findings from our group demonstrated that perinatal exposure to THC (GD 15 to PND 9) altered social play and induced anxiety‐like behaviours in the male rat offspring (Trezza et al, ). Moreover, it has been recently shown that the postnatal exposure to the cannabinoid receptor agonist CP 55,940 from PND 4 to PND 10, a period of brain development equivalent to the third trimester in human, increased the time spent in the open arms of the elevated plus‐maze in offspring of both sexes at prepubertal period (Breit, Zamudio, & Thomas, ). We here showed that prenatally WIN‐exposed animals of both sexes did not exhibit anxious‐like behaviours in the elevated plus‐maze.…”

Section: Discussionmentioning

confidence: 99%

Sex‐specific behavioural deficits induced at early life by prenatal exposure to the cannabinoid receptor agonist WIN55, 212‐2 depend on mGlu5 receptor signalling

Manduca

Servadio

Melancia

et al. 2020

British J Pharmacology

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Background and Purpose:Marijuana is the illicit drug most commonly used among pregnant and breastfeeding women. Different studies reported long-term adverse effects induced by in utero exposure to the main component of marijuana, Δ 9tetrahydrocannabinol (THC), both in rodents and in humans. However, little is known about any potential sex-dependent effects of marijuana consumption during pregnancy on newborns at early developmental ages. Experimental Approach:We studied the effects of prenatal exposure to the cannabinoid receptor agonist WIN55,212-2 (WIN; 0.5 mgÁkg −1 from GD5 to GD20) on the emotional reactivity and cognitive performance of male and female rat offspring from infancy through adolescence and tested the role of mGlu 5 receptor signalling in the observed effects.Key Results: Prenatally WIN-exposed male infant pups emitted less isolationinduced ultrasonic vocalizations compared with male control pups, when separated from the dam and siblings and showed increased locomotor activity while females were spared. These effects were normalized when male pups were treated with the positive allosteric modulator of mGlu 5 receptor CDPPB. When tested at the prepubertal and pubertal periods, WIN-prenatally exposed rats of both sexes did not show any difference in social play behaviour, anxiety and temporal order memory. Conclusions and Implications:We reveal a previously undisclosed sexual divergence in the consequences of fetal cannabinoids on newborns at early developmental ages, which is dependent on mGlu 5 receptor signalling. These results provide new impetus for the urgent need to investigate the functional and behavioural substrates of prenatal cannabinoid exposure in both the male offspring and the female offspring. Abbreviations: % OE, percentage of open arm entries; % TO, percentage of time spent in the open arms; CDPPB, the positive allosteric modulator of mGlu 5 receptors; CTRL, control; GD, gestational day; HDIPS, number of exploratory head dips; PND, postnatal day; SAP, number of stretched-attend postures; USVs, isolation-induced ultrasonic vocalizations; VEH, vehicle; WIN, the cannabinoid receptor agonist WIN 55,212-2.

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“…Importantly, the BAC achieved is the critical factor, particularly since alcohol and THC were not administered simultaneously. Moreover, we have previously reported synergistic effects of alcohol and cannabinoids (both on BAC and offspring behavior) when they are administered via different routes during the neonatal period (Breit et al, 2019b(Breit et al, , 2019c, suggesting that synergistic effects are not reliant on a single route of administration. Thus, although this is the first study to administer polydrug exposure via vapor inhalation during the prenatal period, these factors collectively suggest that consequences of prenatal alcohol, as well as the synergistic effects of alcohol and THC, observed in the current study are not due to the route of administration.…”

Section: **mentioning

confidence: 94%

Combined vapor exposure to THC and alcohol in pregnant rats: Maternal outcomes and pharmacokinetic effects

Breit

Rodriguez

Lei

et al. 2020

Neurotoxicology and Teratology

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Cannabis is the most frequently used illicit drug among pregnant women, yet the potential consequences of prenatal cannabis exposure on development are not well understood. Electronic cigarettes have become an increasingly popular route of administration among pregnant women, in part to user's perception that e-cigarettes are a safer route for consuming cannabis products. Importantly, half of pregnant women who consume cannabis also report consuming alcohol, but research investigating co-consumption of these drugs is limited, particularly with current routes of administration.The purpose of this study was to establish a co-exposure vapor inhalation model of alcohol and THC in pregnant rats, to ultimately determine the effects on fetal development. Pregnant Sprague-Dawley rats were exposed to moderate doses of THC via e-cigarettes, alcohol, the combination, or vehicle daily from gestational days 5-20. Importantly, pharmacokinetic interactions of alcohol and THC were observed during pregnancy. Combined exposure consistently increased blood alcohol concentrations, indicating that THC alters alcohol metabolism. In addition, THC levels also increased over the course of pregnancy and THC metabolism was altered by alcohol. Alcohol, but not THC, exposure during pregnancy reduced maternal weight gain, despite no group differences in food intake. Neither prenatal alcohol nor THC exposure altered gestational length, litter size, sex ratio or birth weight. However, prenatal alcohol exposure delayed eye opening, and prenatal THC exposure decreased body weights during adolescence among offspring. These individual and synergistic effects suggest that this novel co-exposure vapor inhalation paradigm can effectively be used to expose pregnant dams, exerting some effects on fetal development, while avoiding nutritional confounds, birth complications, or changes in litter size. With this model, we have demonstrated that combining THC and alcohol alters drug metabolism, which could have important consequences on prenatal development.

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The effects of alcohol and cannabinoid exposure during the brain growth spurt on behavioral development in rats

Cited by 31 publications

References 111 publications

In utero Δ9-tetrahydrocannabinol exposure confers vulnerability towards cognitive impairments and alcohol drinking in the adolescent offspring: Is there a role for neuropeptide Y?

In utero Δ9-tetrahydrocannabinol exposure confers vulnerability towards cognitive impairments and alcohol drinking in the adolescent offspring: Is there a role for neuropeptide Y?

Sex‐specific behavioural deficits induced at early life by prenatal exposure to the cannabinoid receptor agonist WIN55, 212‐2 depend on mGlu5 receptor signalling

Combined vapor exposure to THC and alcohol in pregnant rats: Maternal outcomes and pharmacokinetic effects

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