Cannabidiol Modulates Behavioural and Gene Expression Alterations Induced by Spontaneous Cocaine Withdrawal

Gasparyan, Ani; Navarrete, Francisco; Rodrı́guez-Arias, Marta; Miñarro, José; Manzanares, Jorge

doi:10.1007/s13311-020-00976-6

Cited by 24 publications

(19 citation statements)

References 61 publications

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“…In particular, 1 displayed strong interactions with the key residues D138 3.32 , Y139 3.33 , M142 3.36 , and V230 5. 43 . Compound 1 also stabilized specific motifs known to aid in receptor activation via π-stacking (YYY and PIF motif), hydrogen bonding (KEY and DRY motif), or water-mediated interactions (NPxxY motif) within the compound 1-inactive-state KOR complex.…”

Section: Discussionmentioning

confidence: 99%

“…A previous study has shown that spontaneous motor behaviors are indicative of cocaine withdrawal; 43 5C). Consistent with the behaviors of cocaine withdrawal, mice in the cocaine-exposed control group traveled significantly greater distances (p = 0.003; Figure 5A) at greater velocities (p = 0.004; Figure 5B), and demonstrated more frequent rearing behavior (p = 0.02; Figure 5C) than did saline-administered controls.…”

Section: Evaluation Of 1 On Spontaneous Motor Anxiety-like and Depres...mentioning

confidence: 96%

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Alleviation of Cocaine Withdrawal and Pertinent Interactions between Salvinorin-based Antagonists and Kappa Opioid Receptor

Akins

Mohammed

Pandey

et al. 2022

Preprint

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The kappa opioid receptor (KOR) is involved in the regulation of both reward and mood processes. Recent reports find that the use of drugs of abuse increases the production of dynorphin and overall activation of KOR. Long-acting KOR antagonists, such as norbinaltorphimine (nor-BNI), JDTic, and 5'-guanidinonaltrindole (GNTI), are shown to halt depressive and anxiety-related disorders, which are the common side effects of withdrawal that can lead to the relapse of drug use. Unfortunately, these prototypical KOR antagonists are known to induce selective KOR antagonism that is delayed by hours and extremely prolonged, and their use in humans comes with serious safety concerns because they possess a large window for potential drug-drug interactions. Additionally, their persisted pharmacodynamic activities can hinder the ability to reverse unanticipated side effects instantly. Herein we report our studies on the lead selective, salvinorin-based KOR antagonist (1) as well as nor-BNI on C57BL/6N mice for spontaneous cocaine withdrawal. Assessment of pharmacokinetics showed 1 to be a short-acting compound with an average half-life of 3.75 h across different compartments (brain, spinal cord, liver, and plasma). Both 1 (5 mg/kg) and nor-BNI (5 mg/kg) were shown to reduce spontaneous withdrawal behavior in mice, with 1 producing additional anti-anxiety-like behavior in a light-dark transition test (however, no mood-related effects of 1 or nor-BNI were observed at the current dosing in an elevated plus maze or a tail suspension test). Our results support the study of selective, short-acting KOR antagonists for the treatment of psychostimulant withdrawal and the associated negative mood states that contribute to relapse. Additionally, we identified pertinent interactions between 1 and KOR via computational studies, including induced-fit docking, mutagenesis, and molecular dynamics simulations, to gain insights into the design of future selective, potent, and short-acting salvinorin-based antagonists.

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Section: Discussionmentioning

confidence: 99%

Section: Evaluation Of 1 On Spontaneous Motor Anxiety-like and Depres...mentioning

confidence: 96%

Alleviation of Cocaine Withdrawal and Pertinent Interactions between Salvinorin-based Antagonists and Kappa Opioid Receptor

Akins

Mohammed

Pandey

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…In different animal models of ethanol consumption (voluntary consumption, SA, and bingedrinking) the administration of CBD significantly reduced ethanol rewarding and the motivational actions that were associated with a reduction in the gene expression of TH in the VTA (Viudez-Martínez et al, 2018a;Viudez-Martinez et al, 2018b;Viudez-Martínez et al, 2020). Similarly, CBD significantly decreases TH in mice exposed to spontaneous cocaine withdrawal (Gasparyan et al, 2020). Nevertheless, in an animal model of spontaneous cannabinoid withdrawal CBD enhanced TH gene expression in the VTA (Navarrete et al, 2018).…”

Section: Cbd and Dopaminergic Systemmentioning

confidence: 96%

“…normalized motor and somatic signs disturbances and completely regulated anxiety-like behaviors induced by spontaneous cocaine withdrawal (progressive increasing doses of cocaine for 12 days, 15-60 mg/kg/day, i.p.). Furthermore, the administration of CBD blocked the increase of dopamine transporter (DAT) and TH gene expressions in the VTA of mice exposed to the cocaine withdrawal (Gasparyan et al, 2020).…”

Section: Cocaine Use Disordermentioning

confidence: 99%

Role of Cannabidiol in the Therapeutic Intervention for Substance Use Disorders

et al. 2021

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Drug treatments available for the management of substance use disorders (SUD) present multiple limitations in efficacy, lack of approved treatments or alarming relapse rates. These facts hamper the clinical outcome and the quality of life of the patients supporting the importance to develop new pharmacological agents. Lately, several reports suggest that cannabidiol (CBD) presents beneficial effects relevant for the management of neurological disorders such as epilepsy, multiple sclerosis, Parkinson’s, or Alzheimer’s diseases. Furthermore, there is a large body of evidence pointing out that CBD improves cognition, neurogenesis and presents anxiolytic, antidepressant, antipsychotic, and neuroprotective effects suggesting potential usefulness for the treatment of neuropsychiatric diseases and SUD. Here we review preclinical and clinical reports regarding the effects of CBD on the regulation of the reinforcing, motivational and withdrawal-related effects of different drugs of abuse such as alcohol, opioids (morphine, heroin), cannabinoids, nicotine, and psychostimulants (cocaine, amphetamine). Furthermore, a special section of the review is focused on the neurobiological mechanisms that might be underlying the ‘anti-addictive’ action of CBD through the regulation of dopaminergic, opioidergic, serotonergic, and endocannabinoid systems as well as hippocampal neurogenesis. The multimodal pharmacological profile described for CBD and the specific regulation of addictive behavior-related targets explains, at least in part, its therapeutic effects on the regulation of the reinforcing and motivational properties of different drugs of abuse. Moreover, the remarkable safety profile of CBD, its lack of reinforcing properties and the existence of approved medications containing this compound (Sativex®, Epidiolex®) increased the number of studies suggesting the potential of CBD as a therapeutic intervention for SUD. The rising number of publications with substantial results on the valuable therapeutic innovation of CBD for treating SUD, the undeniable need of new therapeutic agents to improve the clinical outcome of patients with SUD, and the upcoming clinical trials involving CBD endorse the relevance of this review.

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“…We observed increased transcript levels of CB1Rs in the NAc, DS, and HPC whereas CB2R expression decreased significantly in the PFC and DS following cocaine self-administration. In a mouse model of spontaneous cocaine withdrawal, a decrease and increase were reported in the NAc for CB1R and CB2R transcripts, respectively [87]. Opposite patterns of protein expression were reported for CBRs in basal conditions in adolescent, compared to adult, rats (CB1R higher and CB2R lower) in both the PFC and HPC.…”

Section: Opposite Role Of Cb1rs and Cb2rs In Cocaine Adaptationsmentioning

confidence: 96%

Hippocampal Cannabinoid 1 Receptors Are Modulated Following Cocaine Self-administration in Male Rats

et al. 2022

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Cocaine addiction is a complex pathology inducing long-term neuroplastic changes that, in. turn, contribute to maladaptive behaviors. This behavioral dysregulation is associated with transcriptional reprogramming in brain reward circuitry, although the mechanisms underlying this modulation remain poorly understood. The endogenous cannabinoid system may play a role in this process in that cannabinoid mechanisms modulate drug reward and contribute to cocaine-induced neural adaptations. In this study, we investigated whether cocaine selfadministration induces long-term adaptations, including transcriptional modifications and associated epigenetic processes. We first examined endocannabinoid gene expression in reward-related brain regions of the rat following self-administered (0.33mg/kg intravenous, FR1, 10 days) cocaine injections. Interestingly, we found increased Cnr1 expression in several structures, including prefrontal cortex, nucleus accumbens, dorsal striatum, hippocampus, habenula, amygdala, lateral hypothalamus, ventral tegmental area and rostromedial tegmental nucleus, with most pronounced effects in the hippocampus.Endocannabinoid levels, measured by mass spectrometry, were also altered in this structure.Chromatin immunoprecipitation followed by qPCR in the hippocampus revealed that two activating histone marks, H3K4Me3 and H3K27Ac, were enriched at specific endocannabinoid genes following cocaine intake. Targeting CB1 receptors using chromosome conformation capture, we highlighted spatial chromatin re-organization in the hippocampus, as well as in the nucleus accumbens, suggesting that destabilization of the chromatin may contribute to neuronal responses to cocaine. Overall, our results highlight a key role for the hippocampus in cocaine-induced plasticity and broaden the understanding of neuronal alterations associated with endocannabinoid signaling. The latter suggests that epigenetic modifications contribute to maladaptive behaviors associated with chronic drug use.

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Cannabidiol Modulates Behavioural and Gene Expression Alterations Induced by Spontaneous Cocaine Withdrawal

Cited by 24 publications

References 61 publications

Alleviation of Cocaine Withdrawal and Pertinent Interactions between Salvinorin-based Antagonists and Kappa Opioid Receptor

Alleviation of Cocaine Withdrawal and Pertinent Interactions between Salvinorin-based Antagonists and Kappa Opioid Receptor

Role of Cannabidiol in the Therapeutic Intervention for Substance Use Disorders

Hippocampal Cannabinoid 1 Receptors Are Modulated Following Cocaine Self-administration in Male Rats

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