scholarly journals The effects of cannabidiol on cue- and stress-induced reinstatement of cocaine seeking behavior in mice are reverted by the CB1 receptor antagonist AM4113

2020 ◽  
Author(s):  
Miguel Ángel Luján ◽  
Laia Alegre-Zurano ◽  
Ana Martín-Sánchez ◽  
Olga Valverde
Keyword(s):  
Extinction Training ◽  
Cocaine Addiction ◽  
Cb1 Receptors ◽  
Brain Disorder ◽  
Specific Effects ◽  
Cocaine Seeking ◽  
Increased Risk ◽  
Cannabinoid Antagonist ◽  
Seeking Behavior ◽  
Psychiatric Conditions

ABSTRACTCocaine addiction is a brain disorder characterized by the consumption of the drug despite harmful consequences, the loss of control over drug intake and increased risk of relapse. Albeit prolonged research efforts, there is no available medication approved for the treatment of cocaine addiction. In the last decade, cannabinoid-based compounds have drawn increased interest for its potential therapeutic applications in various psychiatric conditions. Cannabidiol, a non-psychotomimetic constituent of the C. sativa plant, shows promising results in rodent models of anxiety, schizophrenia, depression and drug addiction. However, the specific effects and mechanisms of action of cannabidiol in a rodent model of extinction-based abstinence and drug seeking relapse remain unclear. Here, we administered cannabidiol (20 mg/kg) to male CD-1 mice trained to self-administer cocaine (0.75 mg/kg/inf) during extinction training (8–12 days). Then, we evaluated the reinstatement of cocaine seeking induced by cues, stress and drug priming. To ascertain the participation of CB1 receptors in these behavioral responses, we systemically administered the neutral cannabinoid antagonist AM4113 (5 mg/kg) before each reinstatement session. The results document that cannabidiol (20 mg/kg) does not modulate extinction training but attenuates ‘extinction burst’ responding after one cannabidiol injection. Furthermore, cannabidiol specifically blocked the reinstatement of cocaine seeking triggered by a cue presentation, an effect prevented by AM4113 (5 mg/kg). Unexpectedly, cannabidiol facilitated stress-induced reinstatement of cocaine seeking behavior, also by a CB1-dependent mechanism. Finally, cannabidiol did not affect cocaine-primed (10 mg/kg) precipitation of cocaine seeking. Our results reveal a series of complex changes induced by cannabidiol treatment with opposite implications for the reinstatement of cocaine seeking behavior that may limit therapeutic opportunities. The activity of CB1 receptors seems to play a crucial role in the expression of cannabidiol-induced neuroplasticity underlying both the desirable and undesirable reinstatement effects here detailed.

scholarly journals Subthalamic low-frequency oscillations predict vulnerability to cocaine addiction

2021 ◽  
Vol 118 (14) ◽  
pp. e2024121118
Author(s):  
Mickael Degoulet ◽  
Alix Tiran-Cappello ◽  
Etienne Combrisson ◽  
Christelle Baunez ◽  
Yann Pelloux
Keyword(s):  
Low Frequency ◽  
Cocaine Addiction ◽  
Oscillatory Activity ◽  
Prevention Strategies ◽  
Core Component ◽  
Low Frequency Oscillations ◽  
Cocaine Seeking ◽  
Seeking Behavior ◽  
Stn Dbs ◽  
Deep Brain

Identifying vulnerable individuals before they transition to a compulsive pattern of drug seeking and taking is a key challenge in addiction to develop efficient prevention strategies. Oscillatory activity within the subthalamic nucleus (STN) has been associated with compulsive-related disorders. To study compulsive cocaine-seeking behavior, a core component of drug addiction, we have used a rat model in which cocaine seeking despite a foot-shock contingency only emerges in some vulnerable individuals having escalated their cocaine intake. We show that abnormal oscillatory activity within the alpha/theta and low-beta bands during the escalation of cocaine intake phase predicts the subsequent emergence of compulsive-like seeking behavior. In fact, mimicking STN pathological activity in noncompulsive rats during cocaine escalation turns them into compulsive ones. We also find that 30 Hz, but not 130 Hz, STN deep brain stimulation (DBS) reduces pathological cocaine seeking in compulsive individuals. Our results identify an early electrical signature of future compulsive-like cocaine-seeking behavior and further advocates the use of frequency-dependent STN DBS for the treatment of addiction.

scholarly journals Reduced cue-induced reinstatement of cocaine-seeking behavior in Plcb1+/- mice

2020 ◽  
Author(s):  
Judit Cabana-Domínguez ◽  
Elena Martín-García ◽  
Ana Gallego-Roman ◽  
Rafael Maldonado ◽  
Noèlia Fernàndez-Castillo ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Medial Prefrontal Cortex ◽  
Short Term Memory ◽  
Long Term Potentiation ◽  
Cocaine Addiction ◽  
Cocaine Exposure ◽  
Self Administration ◽  
Normal Behavior ◽  
Cocaine Seeking ◽  
Seeking Behavior

ABSTRACTBackground and PurposeCocaine addiction causes serious health problems and no effective treatment is available yet. We previously identified a genetic risk variant for cocaine addiction in the PLCB1 gene and found this gene upregulated in postmortem brains of cocaine abusers and in human dopaminergic neuron-like cells after an acute cocaine exposure. Here, we functionally tested the contribution of PLCB1 gene to cocaine addictive properties in mice.Experimental approachWe used heterozygous Plcb1 knockout mice (Plcb1+/-) and characterized their behavioral phenotype. Subsequently, mice were trained for operant conditioning and self-administered cocaine for 10 days. Plcb1+/- mice were assessed for cocaine motivation, followed by 26 days of extinction and finally evaluated for cue-induced reinstatement of cocaine seeking. Gene expression alterations after reinstatement were assessed in medial prefrontal cortex (mPFC) and hippocampus (HPC) by RNAseq.Key ResultsPlcb1+/- mice showed normal behavior, although they had increased anxiety and impaired short-term memory. Importantly, after cocaine self-administration and extinction, we found a reduction in the cue-induced reinstatement of cocaine-seeking behavior in Plcb1+/- mice. After reinstatement, we identified transcriptomic alterations in the medial prefrontal cortex of Plcb1+/- mice, mostly related to pathways relevant to addiction like the dopaminergic synapse and long-term potentiation.Conclusions and ImplicationsTo conclude, we found that heterozygous deletion of the Plcb1 gene decreases cue-induced reinstatement of cocaine seeking, pointing at PLCB1 as a possible therapeutic target for preventing relapse and treating cocaine addiction.

scholarly journals Zinc potentiates dopamine neurotransmission and cocaine seeking

2020 ◽  
Author(s):  
Juan L. Gomez ◽  
Jordi Bonaventura ◽  
Jacqueline Keighron ◽  
Kelsey M. Wright ◽  
Dondre L. Marable ◽  
...  
Keyword(s):  
Conditioned Place Preference ◽  
Mechanism Of Action ◽  
Cocaine Abuse ◽  
Cocaine Addiction ◽  
Locomotor Sensitization ◽  
Self Administration ◽  
Pharmacological Mechanism ◽  
Cocaine Seeking ◽  
Seeking Behavior

AbstractCocaine binds to the dopamine transporter (DAT) in the striatum to regulate cocaine reward and seeking behavior. Zinc (Zn2+) also binds to the DAT, but the in vivo relevance of this interaction is unknown. We found that cocaine abuse in humans correlated with low postmortem striatal Zn2+ content. In mice, cocaine decreased striatal vesicular Zn2+ and increased striatal synaptic Zn2+ concentrations and Zn2+ uptake. Striatal synaptic Zn2+ increased cocaine’s in vivo potency at the DAT and was required for cocaine-induced DAT upregulation. Finally, genetic or dietary Zn2+ manipulations modulated cocaine locomotor sensitization, conditioned place preference, self-administration, and reinstatement. These findings reveal new insights into cocaine’s pharmacological mechanism of action and indicate that Zn2+ can serve as a critical environmentally derived regulator of human cocaine addiction.

scholarly journals The NMDA Receptor Subunit (GluN1 and GluN2A) Modulation Following Different Conditions of Cocaine Abstinence in Rat Brain Structures

2021 ◽  
Author(s):  
Irena Smaga ◽  
Karolina Wydra ◽  
Agata Suder ◽  
Małgorzata Frankowska ◽  
Marek Sanak ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nmda Receptor ◽  
Rat Brain ◽  
Brain Structures ◽  
Extinction Training ◽  
Receptor Subunit ◽  
Nmda Receptor Subunit ◽  
Cocaine Seeking ◽  
Instrumental Task ◽  
Seeking Behavior

AbstractDifferent neuronal alterations within glutamatergic system seem to be crucial for developing of cocaine-seeking behavior. Cocaine exposure provokes a modulation of the NMDA receptor subunit expression in rodents, which probably contributes to cocaine-induced behavioral alterations. The aim of this study was to examine the composition of the NMDA receptor subunits in the brain structures in rats with the history of cocaine self-administration after cocaine abstinence (i) in an enriched environment, (ii) in an isolated condition, (iii) with extinction training, or (iv) without instrumental task, as well as the Grin1 (encoding GluN1) and Grin2A (encoding GluN2A) gene expression were evaluated after 10-day extinction training in rat brain structures. In the present study, we observed changes only following cocaine abstinence with extinction training, when the increased GluN2A subunit levels were seen in the postsynaptic density fraction but not in the whole homogenate of the prelimbic cortex (PLC) and dorsal hippocampus (dHIP) in rats previously self-administered cocaine. At the same time, extinction training did not change the Grin1 and Grin2A gene expression in these structures. In conclusion, NMDA receptor subunit modulation observed following cocaine abstinence with extinction training may represent a potential target in cocaine-seeking behavior.

scholarly journals Reduced cue-induced reinstatement of cocaine-seeking behavior in Plcb1 +/− mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Judit Cabana-Domínguez ◽  
Elena Martín-García ◽  
Ana Gallego-Roman ◽  
Rafael Maldonado ◽  
Noèlia Fernàndez-Castillo ◽  
...  
Keyword(s):  
Short Term Memory ◽  
Long Term Potentiation ◽  
Cocaine Addiction ◽  
Phenotypic Characterization ◽  
Cocaine Exposure ◽  
Normal Behavior ◽  
Term Potentiation ◽  
Cocaine Seeking ◽  
Seeking Behavior ◽  
Postmortem Brains

AbstractCocaine addiction causes serious health problems, and no effective treatment is available yet. We previously identified a genetic risk variant for cocaine addiction in the PLCB1 gene and found this gene upregulated in postmortem brains of cocaine abusers and in human dopaminergic neuron-like cells after an acute cocaine exposure. Here, we functionally tested the contribution of the PLCB1 gene to cocaine addictive properties using Plcb1+/− mice. First, we performed a general phenotypic characterization and found that Plcb1+/− mice showed normal behavior, although they had increased anxiety and impaired short-term memory. Subsequently, mice were trained for operant conditioning, self-administered cocaine for 10 days, and were tested for cocaine motivation. After extinction, we found a reduction in the cue-induced reinstatement of cocaine-seeking behavior in Plcb1+/− mice. After reinstatement, we identified transcriptomic alterations in the medial prefrontal cortex of Plcb1+/− mice, mostly related to pathways relevant to addiction like the dopaminergic synapse and long-term potentiation. To conclude, we found that heterozygous deletion of the Plcb1 gene decreases cue-induced reinstatement of cocaine-seeking, pointing at PLCB1 as a possible therapeutic target for preventing relapse and treating cocaine addiction.

Dopaminylation in Psychostimulant use Disorder Protects Against Psychostimulant Seeking Behavior by Normalizing Nucleus Accumbens (NAc) Dopamine Expression

2021 ◽  
Vol 09 ◽  
Author(s):  
Kenneth Blum ◽  
Mark S Gold ◽  
Jean L. Cadet ◽  
David Baron ◽  
Abdalla Bowirrat ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Histone H3 ◽  
D2 Receptor ◽  
Reward Processing ◽  
Allelic Polymorphism ◽  
Cocaine Withdrawal ◽  
Src Signaling ◽  
Chronic Cocaine ◽  
Cocaine Seeking ◽  
Seeking Behavior

Background: Repeated cocaine administration changes histone acetylation and methylation on Lys residues and Deoxyribonucleic acid (DNA) within the nucleus accumbens (NAc). Recently Nestler’s group explored histone Arg (R) methylation in reward processing models. Damez-Werno et al. (2016) reported that during investigator and selfadministration experiments, the histone mark protein-R-methyltransferase-6 (PRMT6) and asymmetric dimethylation of R2 on histone H3 (H3R2me2a) decreased in the rodent and cocaine-dependent human NAc. Overexpression of PRMT6 in D2-MSNs in all NAc neurons increased cocaine seeking, whereas PRMT6 overexpression in D1-MSNs protects against cocaine-seeking. Hypothesis: Hypothesizing that dopaminylation (H3R2me2a binding) occurs in psychostimulant use disorder (PSU), and the binding inhibitor Srcin1, like the major DRD2 A2 allelic polymorphism, protects against psychostimulant seeking behavior by normalizing nucleus accumbens (NAc) dopamine expression. Discussion: Numerous publications confirmed the association between the DRD2 Taq A1 allele (30-40 lower D2 receptor numbers) and severe cocaine dependence. Lepack et al. (2020) found that acute cocaine increases dopamine in NAc synapses, results in histone H3 glutamine 5 dopaminylation (H3Q5dop), and consequent inhibition of D2 expression. The inhibition increases with chronic cocaine use and accompanies cocaine withdrawal. They also found that the Src kinase sig-naling inhibitor 1 (Srcin1 or p140CAP) during cocaine withdrawal reduced H3R2me2a binding. Consequently, this inhibited dopaminylation induced a “homeostatic brake.” Conclusion: The decrease in Src signaling in NAc D2-MSNs, like the DRD2 Taq A2 allele, a well-known genetic mechanism protective against SUD normalized nucleus accumbens (NAc) dopamine expression and decreased cocaine reward and motivation to self-administer cocaine. The Srcin1 may be an important therapeutic target.

scholarly journals 302 - The Effectiveness and Safety of Electroconvulsive Therapy for Treatment Refractory Agitation or Aggression in Major Neurocognitive Disorder

2020 ◽  
Vol 32 (S1) ◽  
pp. 58-58
Author(s):  
Simon Woo ◽  
Peter Chan ◽  
Robyn E Waxman ◽  
Sarah Elmi ◽  
Mafalda Musacchio ◽  
...  
Keyword(s):  
Neuropsychiatric Symptoms ◽  
Symptom Clusters ◽  
Decision Makers ◽  
Neurocognitive Disorder ◽  
Increased Risk ◽  
Valuable Treatment ◽  
Psychiatric Conditions ◽  
Treatment Refractory ◽  
Refractory Symptom ◽  
Inpatient Units

Introduction:Fifty to ninety percent of individuals with Major Neurocognitive Disorder (MNCD) have Neuropsychiatric Symptoms (NPS)1. Agitation and aggression are amongst the most persistent and treatment-refractory symptom clusters. Patients with these NPS are associated with increased risk of institutionalization, psychotropic medication use, caregiver burden, and mortality2.Safe and effective treatments for NPS are lacking. Consensus guidelines emphasize the initial use of non-pharmacologic approaches though supportive evidence is limited3.Extensive research has established the safety and efficacy of ECT in elderly patients with depression and other psychiatric conditions6. Clinical experience suggests that ECT is a valuable treatment option in MNCD-related treatment refractory NPS cases7-10. However, data supporting the efficacy and safety of this practice is scant.Materials and Method:Patients admitted to the geriatric psychiatry inpatient units who meet the inclusion criteria, were recruited from 2 Vancouver sites and 3 unit at Ontario Shores. These patients had an anesthesia consultation to evaluate their safety of going through ECT. Consent was obtained from their substitute decision makers. All patients enrolled are already on psychotropic medications.

scholarly journals Mental health and suicidal ideation in US military veterans with histories of COVID-19 infection

2021 ◽  
pp. bmjmilitary-2021-001846
Author(s):  
Peter Na ◽  
J Tsai ◽  
I Harpaz-Rotem ◽  
R Pietrzak
Keyword(s):  
Suicidal Ideation ◽  
Protective Factors ◽  
Community Integration ◽  
Military Veterans ◽  
Risk And Protective Factors ◽  
Stress Disorders ◽  
Us Military ◽  
Increased Risk ◽  
Psychiatric Conditions ◽  
Internalising Disorders

IntroductionThere have been reports of increased prevalence in psychiatric conditions in non-veteran survivors of COVID-19. To date, however, no known study has examined the prevalence, risk and protective factors of psychiatric conditions among US military veterans who survived COVID-19.MethodsData were analysed from the 2019 to 2020 National Health and Resilience in Veterans Study, which surveyed a nationally representative, prospective cohort of 3078 US veterans. Prepandemic and 1-year peripandemic risk and protective factors associated with positive screens for peripandemic internalising (major depressive, generalised anxiety and/or posttraumatic stress disorders) and externalising psychiatric disorders (alcohol and/or drug use disorders) and suicidal ideation were examined using bivariate and multivariate logistic regression analyses.ResultsA total of 233 veterans (8.6%) reported having been infected with COVID-19. Relative to veterans who were not infected, veterans who were infected were more likely to screen positive for internalising disorders (20.5% vs 13.9%, p=0.005), externalising disorders (23.2% vs 14.8%, p=0.001) and current suicidal ideation (12.0% vs 7.6%, p=0.015) at peripandemic. Multivariable analyses revealed that greater prepandemic psychiatric symptom severity and COVID-related stressors were the strongest independent predictors of peripandemic internalising disorders, while prepandemic trauma burden was protective. Prepandemic suicidal ideation, greater loneliness and lower household income were the strongest independent predictors of peripandemic suicidal ideation, whereas prepandemic community integration was protective.ConclusionPsychiatric symptoms and suicidal ideation are prevalent in veterans who have survived COVID-19. Veterans with greater prepandemic psychiatric and substance use problems, COVID-related stressors and fewer psychosocial resources may be at increased risk of these outcomes.

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