Maladaptive cue-controlled cocaine-seeking habits promote increased relapse severity in rats

AbstractThe inflexible pursuit of drug-seeking and great tendency to relapse that characterize addiction has been associated with the recruitment of the dorsolateral striatum-dependent habit system. However, the mechanisms by which maladaptive drug-seeking habits influence subsequent relapse are obscure. Here, we show that rats with a long history of cocaine-seeking, controlled by drug-paired cues and mediated by the habit system, show highly exacerbated drug-seeking at relapse that is not mediated by cocaine withdrawal. This heightened tendency to relapse is underpinned by transient engagement of the dorsomedial striatum goal-directed system and reflects emergent negative urgency resulting from the prevention of enacting the seeking habit during abstinence. These results reveal a novel mechanism underlying the pressure to relapse and indicate a target for preventing it.One Sentence SummaryInstrumental deprivation triggers flexibility in the well-established cue-controlled cocaine-seeking behaviour.

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Administration of orexin A in the posterior paraventricular nucleus of the thalamus promotes cocaine-seeking behavior and is associated with hypothalamic activation

10.1101/185538 ◽

2017 ◽

Author(s):

Alessandra Matzeu ◽

Rémi Martin-Fardon

Keyword(s):

Paraventricular Nucleus ◽

Priming Effect ◽

Cocaine Dependence ◽

Activation Pattern ◽

Neuronal Activation ◽

Drug Seeking ◽

Protracted Abstinence ◽

Cocaine Seeking ◽

Seeking Behavior ◽

History Of

ABSTRACTHypothalamic orexin (Orx) neurons that project to the paraventricular nucleus of the thalamus (PVT) have received growing interest because of their role in drug-seeking behavior. When injected in the posterior PVT (pPVT), OrxA reinstated extinguished cocaine-seeking behavior in rats that had long access (LgA) to cocaine for 6 h/day after an intermediate period of abstinence (I-Abst, 2-3 weeks). Considering the long-lasting nature of drug-seeking behavior and that the PVT sends projections to the hypothalamus, the present study examined whether (i) OrxA’s priming effect is preserved after a period of protracted abstinence (P-Abst, 4-5 weeks) in LgA rats and (ii) the neural activation pattern (i.e., Fos+ and Fos+/Orx+ cells) in the lateral hypothalamus (LH), dorsomedial hypothalamus (DMH), and perifornical area (PFA) following intra-pPVT OrxA administration that may explain OrxA-induced reinstatement in LgA animals. As reported previously, OrxA administration in the pPVT triggered cocaine-seeking behavior after I-Abst. With P-Abst, the priming effect of OrxA was absent. An intra-pPVT injection of OrxA produced a strong increase in neuronal activation (i.e., Fos expression) in the LH/DMH/PFA at I-Abst but not at P-Abst. The analysis of the activation (Fos+) of Orx neurons (Orx+) revealed an increase in Fos+/Orx+ expression in the LH/DMH/PFA at I-Abst only, thus paralleling the behavioral data. These data indicate that shortly after abstinence, PVT↔LH/DMH/PFA connections are strongly recruited in animals with a history of cocaine dependence. The lack of effect at P-Abst suggests that the function of Orx receptors and connectivity of the PVT↔LH/DMH/PFA circuit undergo significant neuroadaptations following P-Abst.SIGNIFICANCE STATEMENTA better understanding of the pathophysiological changes associated with cocaine addiction is needed to develop efficient pharmacotherapies. The paraventricular nucleus of the thalamus (PVT) and orexin (Orx) transmission within the PVT have been implicated in maladaptive (compulsive) behavior that is characteristic of drug addiction. The present study shows OrxA injections in the posterior PVT reinstates cocaine-seeking behavior in animals with a history of cocaine dependence, and this effect disappears after protracted abstinence, paralleled by the neuronal activation pattern in the hypothalamus. In subjects with a history of cocaine dependence, the function of Orx receptors and connectivity of the PVT↔ LH/DMH/PFA circuit undergo significant neuroadaptations.

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

Current Psychopharmacologye ◽

10.2174/2211556009666210108112737 ◽

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.

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A history of bingeing on fat enhances cocaine seeking and taking.

Behavioral Neuroscience ◽

10.1037/a0025759 ◽

2011 ◽

Vol 125 (6) ◽

pp. 930-942 ◽

Cited By ~ 37

Author(s):

Matthew D. Puhl ◽

Angie M. Cason ◽

Francis H. E. Wojnicki ◽

Rebecca L. Corwin ◽

Patricia S. Grigson

Keyword(s):

Cocaine Seeking ◽

History Of

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Discriminative Stimulus- vs. Conditioned Reinforcer-Induced Reinstatement of Drug-Seeking Behavior and arc mRNA Expression in Dorsolateral Striatum

Advances in Behavioral Biology - The Basal Ganglia IX ◽

10.1007/978-1-4419-0340-2_21 ◽

2009 ◽

pp. 269-284 ◽

Cited By ~ 1

Author(s):

Matthew D. Riedy ◽

Raymond P. Kesner ◽

Glen R. Hanson ◽

Kristen A. Keefe

Keyword(s):

Mrna Expression ◽

Discriminative Stimulus ◽

Conditioned Reinforcer ◽

Drug Seeking ◽

Dorsolateral Striatum ◽

Seeking Behavior

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Drug-seeking motivation level in male rats determines offspring susceptibility or resistance to cocaine-seeking behaviour

Nature Communications ◽

10.1038/ncomms15527 ◽

2017 ◽

Vol 8 (1) ◽

Cited By ~ 25

Author(s):

Qiumin Le ◽

Biao Yan ◽

Xiangchen Yu ◽

Yanqing Li ◽

Haikun Song ◽

...

Keyword(s):

Male Rats ◽

Drug Seeking ◽

Cocaine Seeking ◽

Motivation Level

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Application of Tree-Based Solutions

Cases on Information Technology Series - Annals of Cases on Information Technology ◽

10.4018/978-1-93070-840-2.ch018 ◽

2011 ◽

pp. 260-271

Author(s):

David Paper ◽

Kenneth B. Tingey

Keyword(s):

Subject Matter ◽

Subject Matter Expert ◽

Major Theme ◽

Working Environments ◽

Compliance Requirements ◽

Environmental Laboratory ◽

History Of ◽

Directed System ◽

Design Projects ◽

Computerized System

This case is a study of the application of tree-based solutions to Idaho National Engineering and Environmental Laboratory (INEEL) challenges in the development of a computerized system to meet complex, yet exacting compliance requirements extended to thousands of employees in a largescale organization. We rehearse the history of the project and include information on the theoretical structure of the tree-based solution used. Using primary research documentation, we use a constructivist approach to the issue of subject matter expert empowerment, a major theme of the case. Of particular interest is how the engineer in question was able to modify his work paradigm to incorporate a new role as digital content designer and overseer of the project. Additionally, the study concentrates on the overall effects of the project on other INEEL systems and working environments at the INEEL. Implications of management- and subject matter expert-directed system design projects using tree-based tools are considered with respect to all aspects of enterprise systems development.

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Behavioral History of Withdrawal Influences Regulation of Cocaine Seeking by Glutamate Re-Uptake

PLoS ONE ◽

10.1371/journal.pone.0163784 ◽

2016 ◽

Vol 11 (9) ◽

pp. e0163784

Author(s):

Luyi Zhou ◽

Haley Andersen ◽

Adrian C. Arreola ◽

Jill R. Turner ◽

Pavel I. Ortinski

Keyword(s):

Behavioral History ◽

Cocaine Seeking ◽

History Of

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An extended history of drug self-administration results in multiple sources of control over drug seeking behavior

Progress in Neuro-Psychopharmacology and Biological Psychiatry ◽

10.1016/j.pnpbp.2017.11.011 ◽

2018 ◽

Vol 87 ◽

pp. 48-55 ◽

Cited By ~ 3

Author(s):

Kelly J. Clemens ◽

Nathan M. Holmes

Keyword(s):

Multiple Sources ◽

Self Administration ◽

Drug Seeking ◽

Seeking Behavior ◽

History Of

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Context-induced relapse to drug seeking: a review

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2008.0090 ◽

2008 ◽

Vol 363 (1507) ◽

pp. 3233-3243 ◽

Cited By ~ 306

Author(s):

Hans S Crombag ◽

Jennifer M Bossert ◽

Eisuke Koya ◽

Yavin Shaham

Keyword(s):

Basolateral Amygdala ◽

Dorsal Hippocampus ◽

Dorsal Striatum ◽

Self Administration ◽

Occasion Setting ◽

Drug Seeking ◽

Psychological Mechanisms ◽

History Of ◽

Study Context

In humans, exposure to environmental contexts previously associated with drug intake often provokes relapse to drug use, but the mechanisms mediating this relapse are unknown. Based on early studies by Bouton & Bolles on context-induced ‘renewal’ of learned behaviours, we developed a procedure to study context-induced relapse to drug seeking. In this procedure, rats are first trained to self-administer drug in one context. Next, drug-reinforced lever responding is extinguished in a different (non-drug) context. Subsequently, context-induced reinstatement of drug seeking is assessed by re-exposing rats to the drug-associated context. Using variations of this procedure, we and others reported reliable context-induced reinstatement in rats with a history of heroin, cocaine, heroin–cocaine combination, alcohol and nicotine self-administration. Here, we first discuss potential psychological mechanisms of context-induced reinstatement, including excitatory and inhibitory Pavlovian conditioning, and occasion setting. We then summarize results from pharmacological and neuroanatomical studies on the role of several neurotransmitter systems (dopamine, glutamate, serotonin and opioids) and brain areas (ventral tegmental area, accumbens shell, dorsal striatum, basolateral amygdala, prefrontal cortex, dorsal hippocampus and lateral hypothalamus) in context-induced reinstatement. We conclude by discussing the clinical implications of rat studies on context-induced reinstatement of drug seeking.

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