Cannabinoid receptor type 1 antagonists alter aspects of risk/reward decision making independent of toluene-mediated effects

Braunscheidel, Kevin M; Okas, Michael P; Floresco, Stan B.; Woodward, John J.

doi:10.1007/s00213-021-05914-8

Cited by 5 publications

(3 citation statements)

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“…This was manifested as a delayed shift in their choice behavior as the odds of receving a large/risky reward changed suggesting that a persistent CB1R-mediated suppression of mPFC or BLA excitatory signaling may have contributed to the reduction in behavioral flexibility in toluene treated animals. However, in a follow-up study, systemic or intra-mPFC infusion of CB1R antagonists failed to prevent changes in risk behavior in rats acutely exposed to toluene vapor despite producing selective effects on choice behavior and latency on their own ( Braunscheidel et al, 2021 ). While these results do not rule out a role for toluene-induced inhibition of mPFC-BLA synaptic activity in this effect, future studies using intra-BLA infusion of CB1R antagonists or genetic manipulation of BLA CB1R signaling are needed to fully address this issue.…”

Section: Discussionmentioning

confidence: 99%

Toluene alters the intrinsic excitability and excitatory synaptic transmission of basolateral amygdala neurons

Braunscheidel,

Okas,

Woodward

2024

Front. Neurosci.

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IntroductionInhalant abuse is an important health issue especially among children and adolescents who often encounter these agents in the home. Research into the neurobiological targets of inhalants has lagged behind that of other drugs such as alcohol and psychostimulants. However, studies from our lab and others have begun to reveal how inhalants such as the organic solvent toluene affect neurons in key addiction related areas of the brain including the ventral tegmental area, nucleus accumbens and medial prefrontal cortex. In the present study, we extend these findings and examine the effect of toluene on electrophysiological responses of pyramidal neurons in the basolateral amygdala BLA, a region important for generating emotional and reward based information needed to guide future behavior.MethodsWhole-cell patch-clamp electrophysiology recordings of BLA pyramidal neurons in rat brain slices were used to assess toluene effects on intrinsic excitability and excitatory glutamatergic synaptic transmission.ResultsAcute application of 3 mM but not 0.3 mM toluene produced a small but significant (~20%) increase in current-evoked action potential (AP) firing that reversed following washout of the toluene containing solution. The change in firing during exposure to 3 mM toluene was accompanied by selective changes in AP parameters including reduced latency to first spike, increased AP rise time and decay and a reduction in the fast after-hyperpolization. To examine whether toluene also affects excitatory synaptic signaling, we expressed channelrhodopsin-2 in medial prefrontal cortex neurons and elicited synaptic currents in BLA neurons via light pulses. Toluene (3 mM) reduced light-evoked AMPA-mediated synaptic currents while a lower concentration (0.3 mM) had no effect. The toluene-induced reduction in AMPA-mediated BLA synaptic currents was prevented by the cannabinoid receptor-1 antagonist AM281.DiscussionThese findings are the first to demonstrate effects of acute toluene on BLA pyramidal neurons and add to existing findings showing that abused inhalants such as toluene have significant effects on neurons in brain regions involved in natural and drug induced reward.

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Section: Discussionmentioning

confidence: 99%

Toluene alters the intrinsic excitability and excitatory synaptic transmission of basolateral amygdala neurons

Braunscheidel,

Okas,

Woodward

2024

Front. Neurosci.

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“…This mechanism is often referred to as endocannabinoidmediated negative feedback. Interestingly, CB1Rs were found to be expressed in the nucleus accumbens of vervet monkeys (Kucera et al, 2018), thus highlighting the role of these receptors in the reward circuitry (Méndez-Díaz et al, 2019;Braunscheidel et al, 2022;Ceccarini et al, 2022;Han et al, 2023). Dysfunction of CB1Rs has been linked to a wide array of neurological disorders such as Parkinson's Disease, Alzheimer's Disease, Huntington Disease and multiple sclerosis [reviewed in Cristino et al (2020)].…”

Section: Discussionmentioning

confidence: 99%

In silico analyses of the involvement of GPR55, CB1R and TRPV1: response to THC, contribution to temporal lobe epilepsy, structural modeling and updated evolution

Cherry,

Wheeler,

Mathisova

et al. 2024

Front. Neuroinform.

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IntroductionThe endocannabinoid (eCB) system is named after the discovery that endogenous cannabinoids bind to the same receptors as the phytochemical compounds found in Cannabis. While endogenous cannabinoids include anandamide (AEA) and 2-arachidonoylglycerol (2-AG), exogenous phytocannabinoids include Δ-9 tetrahydrocannabinol (THC) and cannabidiol (CBD). These compounds finely tune neurotransmission following synapse activation, via retrograde signaling that activates cannabinoid receptor 1 (CB1R) and/or transient receptor potential cation channel subfamily V member 1 (TRPV1). Recently, the eCB system has been linked to several neurological diseases, such as neuro-ocular abnormalities, pain insensitivity, migraine, epilepsy, addiction and neurodevelopmental disorders. In the current study, we aim to: (i) highlight a potential link between the eCB system and neurological disorders, (ii) assess if THC exposure alters the expression of eCB-related genes, and (iii) identify evolutionary-conserved residues in CB1R or TRPV1 in light of their function.MethodsTo address this, we used several bioinformatic approaches, such as transcriptomic (Gene Expression Omnibus), protein–protein (STRING), phylogenic (BLASTP, MEGA) and structural (Phyre2, AutoDock, Vina, PyMol) analyzes.ResultsUsing RNA sequencing datasets, we did not observe any dysregulation of eCB-related transcripts in major depressive disorders, bipolar disorder or schizophrenia in the anterior cingulate cortex, nucleus accumbens or dorsolateral striatum. Following in vivo THC exposure in adolescent mice, GPR55 was significantly upregulated in neurons from the ventral tegmental area, while other transcripts involved in the eCB system were not affected by THC exposure. Our results also suggest that THC likely induces neuroinflammation following in vitro application on mice microglia. Significant downregulation of TPRV1 occurred in the hippocampi of mice in which a model of temporal lobe epilepsy was induced, confirming previous observations. In addition, several transcriptomic dysregulations were observed in neurons of both epileptic mice and humans, which included transcripts involved in neuronal death. When scanning known interactions for transcripts involved in the eCB system (n = 13), we observed branching between the eCB system and neurophysiology, including proteins involved in the dopaminergic system. Our protein phylogenic analyzes revealed that CB1R forms a clade with CB2R, which is distinct from related paralogues such as sphingosine-1-phosphate, receptors, lysophosphatidic acid receptors and melanocortin receptors. As expected, several conserved residues were identified, which are crucial for CB1R receptor function. The anandamide-binding pocket seems to have appeared later in evolution. Similar results were observed for TRPV1, with conserved residues involved in receptor activation.ConclusionThe current study found that GPR55 is upregulated in neurons following THC exposure, while TRPV1 is downregulated in temporal lobe epilepsy. Caution is advised when interpreting the present results, as we have employed secondary analyzes. Common ancestors for CB1R and TRPV1 diverged from jawless vertebrates during the late Ordovician, 450 million years ago. Conserved residues are identified, which mediate crucial receptor functions.

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“…8 Cannabinoids and synthetic cannabinoids will not be considered by this paper as extensive investigation has been conducted into their use in vaporization by many other researchers, given their ubiquity in the area. [9][10][11][12] There are several areas of concern with respect to vaping in general. First, there is increasing evidence suggesting a direct correlation between young people, vaping and polydrug abuse.…”

Section: Introductionmentioning

confidence: 99%

'Tick, Tick, BOOM! Recent updates in the use of electronic cigarette technology as an illicit drug delivery system' - A multimodal review of how licit harm reduction devices are being co-opted into potential lethal weapons.

Dooley¹

2022

Preprint

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The vaporization of illicit drugs can be traced back to ancient times, to snuff boxes with traces of psychedelic drugs in Aztec tombs and opium pipes being found in the remains of many great ancient Chinese societies. The advancement of e-cigarette technology has resulted in a new and novel way to vaporize drugs, and while nicotine vaping remains their primary use, meta-analysis of online forums and statistical analysis indicates this is trend which is increasing in popularity. This paper aims to provide an update on the state of e-cigarettes being used as an illicit drug delivery system, the potential public health consequences of this kind of appropriation and a toxicological assessment of the most popular drugs being vaporised. A systematic review of online dark web marketplaces and online drug forums have formed the basis of this review. It can be concluded that this is a growing area of public health concern and one which should be continued to be monitored closely, particularly with respect to Novel Psychoactive Substances due to their continued and abundant proliferation and lack of research with respect to their toxicological profiles.

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Cannabinoid receptor type 1 antagonists alter aspects of risk/reward decision making independent of toluene-mediated effects

Cited by 5 publications

References 50 publications

Toluene alters the intrinsic excitability and excitatory synaptic transmission of basolateral amygdala neurons

Toluene alters the intrinsic excitability and excitatory synaptic transmission of basolateral amygdala neurons

In silico analyses of the involvement of GPR55, CB1R and TRPV1: response to THC, contribution to temporal lobe epilepsy, structural modeling and updated evolution

'Tick, Tick, BOOM! Recent updates in the use of electronic cigarette technology as an illicit drug delivery system' - A multimodal review of how licit harm reduction devices are being co-opted into potential lethal weapons.

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