1,314 research outputs found
Neurobehavioural Mechanisms of Resilience and Vulnerability in Addictive Disorders
No full textSubstance-Related and Addictive Disorders as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM 5), entail dramatic health, economic and social problems for developed countries. Behavioral and psychopharmacological therapies currently available for these disorders show little efficacy, often limited to a subset of patients. Improving therapeutic efficacy requires a better understanding of the biological background of individual resilience and vulnerability to addictive disorders. It is well established that a subset of drug users make a transition from voluntary recreative drug intake to repeated consumption and abuse. Chronic drug exposure induces long-lasting neural adaptations resulting in drug craving, in compulsive drug seeking and intake, and in a high propensity to relapse. Similar neural adaptations have been observed in individuals suffering from behavioral addictions such as gambling or food addiction.
The goal of this Research Topic is to improve our understanding of the neurobiological mechanisms underlying individual variables that drive drug and behavioral addictions. To understand why some people intensify pathologically a behavior (and others do not) can help to design future interventions intended to prevent or treat addictive disorders. Age and sex are individual variables that modulate the effects of drugs of abuse. Adolescence has been recognized as a critical developmental period in which the still-developing brain is highly vulnerable to the impact of vital experiences, including drug or stress exposure. Furthermore, it is well established that ovarian hormones are involved in sex differences to drugs of abuse and to the greater vulnerability of females to addiction. Similarly, age and sex can influence behavioral addictions. In addition, recent studies have also demonstrated the existence of endophenotypes related to addictive behaviors. Impulsivity, novelty-seeking, harm avoidance and reward dependence are traits correlated with increased risk of addiction. Current research is heading towards an understanding of the neurobiological substrates underlying these individual differences. This body of research includes genetic and epigenetic mechanisms, neural pathways, neurotransmitter systems, molecular mechanisms, immune mediators, etc.
This Research Topic will discuss the latest advances in our understanding of the neurobiological mechanisms underlying resilience or vulnerability to addiction. In addition to finding “risk biomarkers”, it is essential to know which individual variables confer resilience to addiction. This is the first step to develop strategies to increase resilience in patients and subjects at risk. We aim to generate a translational perspective of these issues through research and review articles ranging in scope from animal models to human studies.
The contributions must cover, but are not limited to, the following subtopics:
- Adolescence and addiction
- Animal models of behavioral and drug addictions
- Behavioral strategies or pharmacological approaches increasing resilience to drug addiction
- Genetic and epigenetic mechanisms of vulnerability or resilience to addictive behaviors
- Individual physiological or psychological risk factors to behavioral or substance-related addictions
- Neurobehavioural or personality traits preventing behavioral or substance-related addictions
- Personalized prevention and/or treatment interventions in addictive disorders
Keywords: Behavioural addictions, drug addiction, individual variability, animal models, neurobiolog
Coordinated prefrontal state transition leads extinction of reward-seeking behaviors
No full textExtinction learning suppresses conditioned reward responses and is thus fundamental to adapt to changing environmental demands and to control excessive reward seeking. The medial prefrontal cortex (mPFC) monitors and controls conditioned reward responses. Abrupt transitions in mPFC activity anticipate changes in conditioned responses to altered contingencies. It remains, however, unknown whether such transitions are driven by the extinction of old behavioral strategies or by the acquisition of new competing ones. Using in vivo multiple single-unit recordings of mPFC in male rats, we studied the relationship between single-unit and population dynamics during extinction learning, using alcohol as a positive reinforcer in an operant conditioning paradigm. To examine the fine temporal relation between neural activity and behavior, we developed a novel behavioral model that allowed us to identify the number, onset, and duration of extinction-learning episodes in the behavior of each animal. We found that single-unit responses to conditioned stimuli changed even under stable experimental conditions and behavior. However, when behavioral responses to task contingencies had to be updated, unit-specific modulations became coordinated across the whole population, pushing the network into a new stable attractor state. Thus, extinction learning is not associated with suppressed mPFC responses to conditioned stimuli, but is anticipated by single-unit coordination into population-wide transitions of the internal state of the animal
Nicotine self-administration and ERK signaling are altered in RasGRF2 knockout mice
No full textRas/Raf/MEK/ERK (Ras-ERK) signaling has been demonstrated to play a role in the effects of drugs of abuse such as cocaine and alcohol, but has not been extensively examined in nicotine-related reward behaviors. We examined the role of Ras Guanine Nucleotide Releasing Factor 2 (RasGRF2), an upstream mediator of the Ras-ERK signaling pathway, on nicotine self-administration (SA) in RasGRF2 KO and WT mice. We first demonstrated that acute nicotine exposure (0.4 mg/kg) resulted in an increase in phosphorylated ERK1/2 (pERK1/2) in the striatum, consistent with previous reports. We also demonstrated that increases in pERK1/2 resulting from acute (0.4 mg/kg) and repeated (0.4 mg/kg, 10 daily injections) exposure to nicotine in WT mice were not present in RasGRF2 KO mice, confirming that RasGRF2 at least partly regulates the activity of the Ras-ERK signaling pathway following nicotine exposure. We then performed intravenous nicotine SA (0.03 mg/kg/infusion for 10 days) in RasGRF2 KO and WT mice. Consistent with a previous report using cocaine SA, RasGRF2 KO mice demonstrated an increase in nicotine SA relative to WT controls. These findings suggest a role for RasGRF2 in the reinforcing effects of nicotine, and implicate the Ras-ERK signaling pathway as a common mediator of the response to drugs of abuse
Coat Cooke & Joe Poole | Coat Cooke & Rainer Wiens: Reviews
No full textCoat Cooke album reviews by Randy Raine-Reusch. Coat Cooke (sax); Joe Poole (drums); Rainer Wiens (guitar)
Genetic deletion of neuronal PPARγ enhances the emotional response to acute stress and exacerbates anxiety: An effect reversed by rescue of amygdala PPARγ function
No full textPPARγ is one of the three isoforms of the Peroxisome Proliferator-Activated Receptors (PPARs). PPARγ is activated by thiazolidinediones such as pioglitazone, and it is targeted to treat insulin resistance. PPARγ is densely expressed in brain areas involved in regulation of motivational and emotional processes.Here, we investigated the role of PPARγ in the brain and explored its role in anxiety and stress responses in mice. The results show that stimulation of PPARγ by pioglitazone did not affect basal anxiety but fully prevented the anxiogenic effect of acute stress. Using mice with genetic ablation of neuronal PPARγ (PPARγ(NestinCre)), we demonstrated that a lack of receptors, specifically in neurons, exacerbated basal anxiety and enhanced stress sensitivity. The administration of GW9662, a selective PPARγ antagonist, elicited a marked anxiogenic response in PPARγ wild-type (Wt) but not in PPARγ(NestinCre) KO mice. Using c-Fos immunohistochemistry we observed that acute stress exposure resulted in a different pattern of neuronal activation in the amygdala and the hippocampus of PPARγ(NestinCre) KO mice compared with Wt mice. No differences were found between Wt and KO mice in hypothalamic regions responsible for hormonal response to stress, nor in blood corticosterone levels. Microinjection of pioglitazone, into the amygdala but not into the hippocampus abolished the anxiogenic response elicited by acute stress. Results also showed that in both regions PPARγ co-localizes with GABAergic cells. These findings demonstrate that neuronal PPARγ is involved the regulation of the stress response, and that the amygdala is a key substrate for the anxiolytic effect of PPARγ
Robert Rainer and Claud Garner
No full textAuthor Claud Garner, right, autographed copies of his second novel while discussing a tour of other Southwest cities with Robert Rainer, representing his publisher, Creative Age Press. Published in the Fort Worth Star - Telegram morning edition, September 29, 1950.https://mavmatrix.uta.edu/specialcollections_startelegram1950s/6596/thumbnail.jp
Chronic viral hepatitis is a significant contributor to the immunosenescent phenotype of parenteral drug addiction
No full textIntravenous drug addiction is known to be associated with an inordinate morbidity and mortality. As our previous report had identified an immune phenotype consistent with accelerated ageing, we wished to investigate how much of this change may have been related to chronic viral hepatitis. A total of 12 409 clinical pathology results from the period 1995–2007 were reviewed. To control for the differences in age, only patients less than 48 years of age were considered. A total of 636 substance use disorder (SUD) and 6103 non-SUD (N-SUD) patients were studied. They had comparable ages (mean ± SD 31.32 ± 6.90 versus 31.57 ± 9.23, P-value not significant), but the SUD group had more males (74.37% versus 53.20%, P < 0.001). For most of the changes examined splitting the two SUD groups into hepatitis C positive (HCV+) and hepatitis C negative (HCV−) demonstrated that the majority of the described changes were most marked in the HCV+ group. The globulins were higher in the HCV+ group and the albumin was lower and fell more markedly with age than in N-SUD or HCV− (all P < 0.001). The globulin/albumin ratio was significantly higher in HCV+ than HCV− or N-SUD (both P < 0.0001) and rose more with age. These changes were paralleled by the ESR, elevations in the CRP and lymphocyte count. Transaminases were elevated in SUD and HCV+ groups compared with N-SUD (all P < 0.02). At multivariate analysis ESR, lymphocyte count, dual hepatitis B and C seropositivity, AST and HCVAb were significant predictors of the serum globulin level and accounted for 21% of the variance. These data extend our earlier report and show that much of the immunosenescent phenotype of SUD, encompassing the known immunosuppression and the observed immunostimulation, is statistically related to chronic viral hepatitis. Important theoretical and practical management (vaccination) implications ensue
Author response
No full textRas-ERK signalling in the brain plays a central role in drug addiction. However, to date, no clinically relevant inhibitor of this cascade has been tested in experimental models of addiction, a necessary step toward clinical trials. We designed two new cell-penetrating peptides - RB1 and RB3 - that penetrate the brain and, in the micromolar range, inhibit phosphorylation of ERK, histone H3 and S6 ribosomal protein in striatal slices. Furthermore, a screening of small therapeutics currently in clinical trials for cancer therapy revealed PD325901 as a brain-penetrating drug that blocks ERK signalling in the nanomolar range. All three compounds have an inhibitory effect on cocaine-induced ERK activation and reward in mice. In particular, PD325901 persistently blocks cocaine-induced place preference and accelerates extinction following cocaine self- administration. Thus, clinically relevant, systemically administered drugs that attenuate Ras-ERK signalling in the brain may be valuable tools for the treatment of cocaine addiction
Quantum chemistry of 2D-nanomaterials : investigation of graphene, hBN and α-borophene on SiO2 (001)
No full textAuthor: Felix Rainer Serafin Purtscher, BScMasterarbeit University of Innsbruck 202
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