scholarly journals Is It Possible to Shift from Down to Top Rank? A Focus on the Mesolimbic Dopaminergic System and Cocaine Abuse

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 877
Author(s):  
Inês M. Amaral ◽  
Alex Hofer ◽  
Rana El Rawas
Keyword(s):  
Drugs Of Abuse ◽  
Coping Behavior ◽  
D2 Receptor ◽  
Social Ranking ◽  
Mesolimbic System ◽  
Positive Coping ◽  
Substance Dependent ◽  
Seeking Behavior ◽  
Substance Abuse Disorders

Impaired social behavior is a common feature of many psychiatric disorders, in particular with substance abuse disorders. Switching the preference of the substance-dependent individual toward social interaction activities remains one of the major challenges in drug dependence therapy. However, social interactions yield to the emergence of social ranking. In this review, we provide an overview of the studies that examined how social status can influence the dopaminergic mesolimbic system and how drug-seeking behavior is affected. Generally, social dominance is associated with an increase in dopamine D2/3 receptor binding in the striatum and a reduced behavioral response to drugs of abuse. However, it is not clear whether higher D2 receptor availability is a result of increased D2 receptor density and/or reduced dopamine release in the striatum. Here, we discuss the possibility of a potential shift from down to top rank via manipulation of the mesolimbic system. Identifying the neurobiology underlying a potential rank switch to a resilient phenotype is of particular interest in order to promote a positive coping behavior toward long-term abstinence from drugs of abuse and a protection against relapse to drugs. Such a shift may contribute to a more successful therapeutic approach to 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 Interactions of neuroimmune signaling and glutamate plasticity in addiction

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Cassandra D. Gipson ◽  
Scott Rawls ◽  
Michael D. Scofield ◽  
Benjamin M. Siemsen ◽  
Emma O. Bondy ◽  
...  
Keyword(s):  
Substance Use ◽  
Drug Use ◽  
Substance Use Disorders ◽  
Drugs Of Abuse ◽  
Treatment Strategies ◽  
Glutamate Signaling ◽  
Open Questions ◽  
Seeking Behavior ◽  
Glutamate System ◽  
Chronic Use

AbstractChronic use of drugs of abuse affects neuroimmune signaling; however, there are still many open questions regarding the interactions between neuroimmune mechanisms and substance use disorders (SUDs). Further, chronic use of drugs of abuse can induce glutamatergic changes in the brain, but the relationship between the glutamate system and neuroimmune signaling in addiction is not well understood. Therefore, the purpose of this review is to bring into focus the role of neuroimmune signaling and its interactions with the glutamate system following chronic drug use, and how this may guide pharmacotherapeutic treatment strategies for SUDs. In this review, we first describe neuroimmune mechanisms that may be linked to aberrant glutamate signaling in addiction. We focus specifically on the nuclear factor-kappa B (NF-κB) pathway, a potentially important neuroimmune mechanism that may be a key player in driving drug-seeking behavior. We highlight the importance of astroglial-microglial crosstalk, and how this interacts with known glutamatergic dysregulations in addiction. Then, we describe the importance of studying non-neuronal cells with unprecedented precision because understanding structure-function relationships in these cells is critical in understanding their role in addiction neurobiology. Here we propose a working model of neuroimmune-glutamate interactions that underlie drug use motivation, which we argue may aid strategies for small molecule drug development to treat substance use disorders. Together, the synthesis of this review shows that interactions between glutamate and neuroimmune signaling may play an important and understudied role in addiction processes and may be critical in developing more efficacious pharmacotherapies to treat SUDs.

scholarly journals The Adenosine A2A Receptor Activation in Nucleus Accumbens Suppress Cue-Induced Reinstatement of Propofol Self-administration in Rats

2021 ◽  
Author(s):  
Zhanglei Dong ◽  
Bingwu Huang ◽  
Chenchen Jiang ◽  
Jiangfan Chen ◽  
Han Lin ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
D2 Receptor ◽  
Fixed Ratio ◽  
Receptor Activation ◽  
Addictive Behaviors ◽  
Self Administration ◽  
A2a Receptors ◽  
Mediated Effects ◽  
Seeking Behavior ◽  
Adenosine A2a

AbstractPropofol has shown strong addictive properties in rats and humans. Adenosine A2A receptors (A2AR) in the nucleus accumbens (NAc) modulate dopamine signal and addictive behaviors such as cocaine- and amphetamine-induced self-administration. However, whether A2AR can modulate propofol addiction remains unknown. AAV-shA2AR was intra-NAc injected 3 weeks before the propofol self-administration training to test the impacts of NAc A2AR on establishing the self-administration model with fixed ratio 1 (FR1) schedule. Thereafter, the rats were withdrawal from propofol for 14 days and tested cue-induced reinstatement of propofol seeking behavior on day 15. The propofol withdrawal rats received one of the doses of CGS21680 (A2AR agonist, 2.5–10.0 ng/site), MSX-3 (A2AR antagonist, 5.0–20.0 μg/site) or eticlopride (D2 receptor (D2R) antagonist, 0.75–3.0 μg/site) or vehicle via intra-NAc injection before relapse behavior test. The numbers of active and inactive nose-poke response were recorded. Focal knockdown A2AR by shA2AR did not affect the acquisition of propofol self-administration behavior, but enhance cue-induced reinstatement of propofol self-administration compared with the AAV-shCTRLgroup. Pharmacological activation of the A2AR by CGS21680 (≥ 5.0 ng/site) attenuated cue-induced reinstatement of propofol self-administration behavior. Similarly, pharmacological blockade of D2R by eticlopride (0.75–3.0 μg/site) attenuated propofol seeking behavior. These effects were reversed by the administration of MSX-3 (5.0–20.0 μg/site). The A2AR- and D2R-mediated effects on propofol relapse were not confounded by the learning process, and motor activity as the sucrose self-administration and locomotor activity were not affected by all the treatments. This study provides genetic and pharmacological evidence that NAc A2AR activation suppresses cue-induced propofol relapse in rats, possibly by interacting with D2R.

Long-term outcome of substance-dependent youth following 12-step treatment

2007 ◽  
Vol 33 (1) ◽  
pp. 61-69 ◽  
Author(s):  
Ken C. Winters ◽  
Randy Stinchfield ◽  
William W. Latimer ◽  
Steven Lee
Keyword(s):  
Term Outcome ◽  
Long Term Outcome ◽  
Substance Dependent

Characteristics of Sexual Abuse Among Individuals With Serious Mental Illnesses

2016 ◽  
Vol 33 (17) ◽  
pp. 2725-2744 ◽  
Author(s):  
James A. Kmett ◽  
Shaun M. Eack
Keyword(s):  
Sexual Abuse ◽  
Mental Illnesses ◽  
Violence Risk ◽  
Never Married ◽  
Psychiatric Admissions ◽  
Substance Dependent ◽  
Effects Of Sexual Abuse ◽  
Serious Mental Illnesses ◽  
Multiple Samples

The deleterious effects of sexual abuse (SA) are well documented, as many studies have found that SA can increase the risk for psychiatric disorders. While SA has been examined in multiple samples, no studies have examined the characteristics of SA in individuals with severe mental illnesses (SMI). This study examined the prevalence rate and characterized the nature of SA among individuals with SMI who were under psychiatric care in three different inpatient facilities. Utilizing data from the MacArthur Violence Risk Assessment Study, 1,136 individuals with SMI were assessed for SA histories, psychiatric diagnoses, and other demographics. Nearly half of this sample ( n = 511) identified SA histories, with almost half indicating that the person was a stranger or someone outside of the family unit. One third reported SA occurred “too many times to count,” and approximately a third indicated the abuse consisted of intercourse, occurring at a mean age of 11.22 years. Results found that individuals with SA histories were often never married, Caucasian, female, had children, described themselves as psychologically unwell, and were commonly voluntary psychiatric admissions. Those with SA histories had significantly higher psychopathology and lower functioning, and were more likely to be diagnosed with depression but less likely to be substance dependent. Identifying SA characteristics in individuals with SMI is a critical component to successful treatment. Thorough screening and assessment of this common problem can help clinicians identify accompanying issues that may exacerbate SMI symptomology, and improve the prognosis for long-term outcomes.

scholarly journals The sigma-1 receptor as key common factor in cocaine and food-seeking behaviors

2019 ◽  
Vol 63 (4) ◽  
pp. R81-R92 ◽  
Author(s):  
David Aguinaga ◽  
Mireia Casanovas ◽  
Rafael Rivas-Santisteban ◽  
Irene Reyes-Resina ◽  
Gemma Navarro ◽  
...  
Keyword(s):  
Eating Disorders ◽  
Drugs Of Abuse ◽  
Common Factor ◽  
G Protein Coupled Receptors ◽  
Sigma 1 Receptor ◽  
New Findings ◽  
Sigma 1 ◽  
Seeking Behavior ◽  
Food Seeking ◽  
G Protein Coupled

Addiction and eating disorders involve brain reward circuits. Binge eating predisposes to addictive behavior, while the cessation of exposure to drugs of abuse leads to reward activities, including intake of tasty foods. Cocaine use is associated with a decrease in food intake, with reversal after drug use is discontinued. Exciting new findings show that receptors for the ‘hunger’ hormone, ghrelin, directly interact with the sigma-1 receptor (σ1R), which is a target of cocaine. σ1Rs are key players in regulating dopaminergic neurotransmission and ghrelin-mediated actions. This review focuses on the σ1 receptor as a general neuroendocrine regulator by directly interacting with neuronal G-protein-coupled receptors. This review also covers the early mechanisms by which cocaine binding to σ1 blocks the food-seeking behavior triggered by ghrelin. Those findings appear as fundamental to understand common mechanisms in drug addiction and eating disorders.

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