The Synaptic Interactions of Alcohol and the Endogenous Cannabinoid System

Wolfe, Sarah A.

doi:10.35946/arcr.v42.1.03

Cited by 13 publications

(10 citation statements)

References 176 publications

(275 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Currently available literature on the interaction between alcohol and THC at synaptic levels is limited, but repeated co-use of the two drugs has been shown to reduce CB 1 receptor-mediated miniature excitatory postsynaptic current frequency in Purkinje cells (Zou et al, 2022). In the PFC, however, inconsistent results have been reported for the effect of chronic ethanol consumption on CB 1 receptor expression and binding affinity, as summarized in the review by Wolfe et al (2022). To investigate potential mechanisms for the long-lasting disruption in HFS-induced plasticity that we observed in drug-exposed rats, we performed additional recordings in the presence of drugs that influence GABA signaling and activity in the GSK3β signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Effects of combined exposure to ethanol and delta-9-tetrahydrocannabinol during adolescence on synaptic plasticity in the prefrontal cortex of Long Evans rats

Shi,

Kang,

Choi

et al. 2023

Preprint

View full text Add to dashboard Cite

Significant exposure to alcohol or cannabis during adolescence can induce lasting disruptions of neuronal signaling in brain regions that are later to mature, such as the medial prefrontal cortex (mPFC). Considerably less is known about the effects of alcohol and cannabis co-use, despite its common occurrence. Here, we used male and female Long-Evans rats to investigate the effects of early-life exposure to ethanol, delta-9-tetrahydrocannabinol (THC), or their combination on high frequency stimulation (HFS)-induced plasticity in the prelimbic region of the mPFC. Animals were injected daily from postnatal days 30 to 45 with vehicle or THC (escalating doses, 3-20 mg/kg) and allowed to drink vehicle (0.1% saccharin) or 10% ethanol immediately after each injection. In vitro brain slice electrophysiology was then used to record population responses of layer V neurons following HFS in layer II/III after 3-4 weeks of abstinence. We found that THC exposure reduced body weight gains observed in ad libitum fed rats, and reduced intake of saccharin and ethanol. Compared to controls, there was a significant reduction in HFS-induced long-term depression (LTD) in rats exposed to either drug alone, and an absence of LTD in rats exposed to the drug combination. Bath application of indiplon or AR-A014418, which enhance GABAA receptor function or inhibit glycogen synthase kinase 3β (GSK3β), respectively, suggested the effects of ethanol, THC or their combination were due in part to lasting adaptations in GABA and GSK3β signaling. These results suggest the potential for long-lasting adaptations in mPFC output following co-exposure to alcohol and THC.

show abstract

Section: Discussionmentioning

confidence: 99%

Effects of combined exposure to ethanol and delta-9-tetrahydrocannabinol during adolescence on synaptic plasticity in the prefrontal cortex of Long Evans rats

Shi,

Kang,

Choi

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…In human populations, the relationship between alcohol exposure and brain CNR1 levels is complex; acute exposure is associated with an increase in CNR1 availability, whereas chronic exposure results in decreased brain CNR1 54 . Studies in animal models also generally associate chronic alcohol exposure with inhibition of the endocannabinoid system, including CNR1, though acute exposures produce more variable effects (reviewed in 41 ).…”

Section: Discussionmentioning

confidence: 99%

“…Alcohol is often co-consumed with other psychoactive drugs, but the added risk for pregnancy health and infant birth outcomes due to co-consumption is seldom investigated. SAC in particular requires additional investigation, as existing literature on adult alcohol use disorders indicates that alcohol’s effects may be potentiated by endocannabinoid signaling (reviewed in 41 ). Moreover, two recently published papers in preclinical models indicate that SAC increases teratology 20,21 over alcohol or cannabinoid exposures alone.…”

Section: Discussionmentioning

confidence: 99%

Reduced fetal cerebral blood flow following prenatal drug exposure predicts perinatal mortality

Rouzer,

Sreeram,

Miranda

2023

Preprint

View full text Add to dashboard Cite

BackgroundChildren exposed prenatally to alcohol or cannabinoids individually can exhibit growth deficits and increased risk for adverse birth outcomes. However, these drugs are often co-consumed and their combined effects on early brain development are virtually unknown. The blood vessels of the fetal brain emerge and mature during the neurogenic period to support nutritional needs of the rapidly growing brain. Teratogenic exposure during this gestational window may therefore impair fetal cerebrovascular development.ObjectiveTo determine whether prenatal polysubstance exposure confers additional risk for impaired fetal-directed blood flow and offspring viability compared to each drug individually.Study DesignWe performed high resolutionin vivoultrasound imaging in C57Bl/6J pregnant mice. After pregnancy confirmation, dams (n=40) were randomly assigned to one of four groups: drug-free control, alcohol-exposed, cannabinoid-exposed or alcohol-and-cannabinoid-exposed. Drug exposure occurred daily between Gestational Days 12-15, equivalent to the transition between the first and second trimesters in humans. Dams first received an intraperitoneal injection of either cannabinoid agonist CP-55940 (750µg/kg) or volume-equivalent vehicle. Then, dams were placed in vapor chambers for 30min of inhalation of either ethanol or room air. Dams underwent ultrasound imaging on three days of pregnancy: Gestational Day 11 (pre-exposure), Gestational Day 13.5 (peri-exposure) and Gestational Day (post-exposure), and were subsequently monitored for health and delivery outcomes.ResultsOf all exposure groups, only dams co-exposed to both alcohol and cannabinoids experienced reduced gestational weight gain while undergoing drug treatments. These same co-exposed pregnant mice also demonstrated higher (+42mg/dL) blood ethanol concentrations than dams exposed to alcohol only. All drug exposures decreased fetal cranial blood flow 24-hours after the final exposure episode, though combined alcohol and cannabinoid reduced internal carotid artery blood flow relative to all other exposures. Umbilical artery metrics were not affected by drug exposure, indicating a specific vulnerability of fetal cranial circulation. Cannabinoid exposure significantly reduced cerebroplacental ratios, mirroring prior findings in marijuana-exposed human fetuses. Post-exposure cerebroplacental ratios significantly predicted subsequent perinatal mortality (p=0.019, area under the curve, 0.772; sensitivity, 81%; specificity, 85.70%) and retroactively diagnosed prior drug exposure (p=0.005; AUC, 0.861; sensitivity, 86.40%; specificity, 66.7%).Conclusion(s)Fetal cerebrovasculature is significantly impaired by exposure to alcohol or cannabinoids, and co-exposure confers additional risk for adverse birth outcomes. Considering the rising potency and global availability of cannabis products, there is an imperative for research to explore translational models of prenatal drug exposure, including polysubstance models, to inform appropriate strategies for treatment and care in pregnancies affected by drug exposure.Key PointsQuestionDoes simultaneous prenatal exposure to alcohol and cannabinoids present significant additional risk to fetal health compared to each drug individually?FindingsMaternal murine ultrasound analyses showed that alcohol and cannabinoid exposure, individually, reduced fetal cerebral arterial blood flow metrics. Notably, polysubstance-exposed fetuses demonstrate the worst cerebral hemodynamics, and reductions in fetal blood flow significantly predict subsequent perinatal offspring mortality.MeaningPrenatal drug exposure persistently reduces fetal-directed blood flow, which can disrupt normal embryonic growth and neural development, and polysubstance exposure augments deficits specifically in cerebral arterial blood flow.

show abstract

“…In contrast, stress can increase amygdala 2‐AG levels, which determines termination and adaptation to stress, as well as changes in emotional memory (Hill et al, 2010; Patel et al, 2009, 2005), suggesting that 2‐AG regulates stress signalling once the stress response is activated. Similarly, effects of alcohol exposure on eCB content have been described and the interactions between alcohol and eCB system at molecular, synaptic and behavioural levels have been reviewed recently (Kunos, 2020; Wolfe et al, 2022). For instance, acute alcohol exposure has been associated with decreased 2‐AG in prefrontal cortex (PFC) (Rubio et al, 2007), while chronic intermittent alcohol has been associated with reduction of baseline 2‐AG levels in the central nucleus of the amygdala (central amygdala [CeA]) (Serrano et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Sexually dimorphic effects of monoacylglycerol lipase inhibitor MJN110 on stress‐related behaviour and drinking in Marchigian Sardinian alcohol‐preferring rats

Vozella,

Cruz,

Feldman

et al. 2023

British J Pharmacology

View full text Add to dashboard Cite

Background and PurposeStress‐related disorders are often intertwined with alcohol use disorder (AUD). The endocannabinoid (eCB) system, which comprises the lipid mediators anandamide (AEA) and 2‐arachidonoylglycerol (2‐AG), plays an important homeostatic role in the regulation of stress circuits and has emerged as a therapeutic target to treat stress disorders and AUD. Extensive research has elucidated the role of AEA, but less is known about 2‐AG‐mediated signaling.Experimental ApproachWe pharmacologically enhanced the eCB signaling by inhibiting the 2‐AG metabolizing enzyme, monoacylglycerol lipase (MAGL), in male and female Marchigian‐Sardinian alcohol preferring (msP) rats, a model of innate alcohol preference and stress hypersensitivity, and control Wistar rats. We tested the acute effect of the selective MAGL inhibitor MJN110 in alleviating symptoms of alcohol drinking, anxiety, irritability, and fear in both male and female rats.Key ResultsA single systemic administration of MJN110 increased 2‐AG levels in the central amygdala, prelimbic, and infralimbic cortex, but did not acutely alter alcohol drinking. MAGL inhibition reduced aggressive behaviors in female msPs and increased defensive behaviors in male msPs, during the irritability test. Moreover, in the novelty‐induced hypophagia test, MJN110 selectively enhanced palatable food consumption in females, mitigating stress‐induced food suppression. Lastly, msP rats showed increased conditioned fear behavior compared to Wistar rats, and MJN110 reduced context‐associated conditioned fear responses, but not cue‐probed fear expression, in male msPs.Conclusion and ImplicationsAcute inhibition of MAGL attenuated some stress‐related responses in msP rats but not voluntary alcohol drinking. Our results provide new insights into the sex dimorphism documented in stress‐induced responses and suggest that sex‐specific endocannabinoid‐based approaches should be considered in the clinical development of therapeutics.

show abstract

The Synaptic Interactions of Alcohol and the Endogenous Cannabinoid System

Cited by 13 publications

References 176 publications

Effects of combined exposure to ethanol and delta-9-tetrahydrocannabinol during adolescence on synaptic plasticity in the prefrontal cortex of Long Evans rats

Effects of combined exposure to ethanol and delta-9-tetrahydrocannabinol during adolescence on synaptic plasticity in the prefrontal cortex of Long Evans rats

Reduced fetal cerebral blood flow following prenatal drug exposure predicts perinatal mortality

Sexually dimorphic effects of monoacylglycerol lipase inhibitor MJN110 on stress‐related behaviour and drinking in Marchigian Sardinian alcohol‐preferring rats

Contact Info

Product

Resources

About