scholarly journals Involvement of the ghrelin system in the maintenance and reinstatement of cocaine-motivated behaviors: a role of adrenergic action at peripheral β1 receptors

2021 ◽  
Author(s):  
Zhi-Bing You ◽  
Ewa Galaj ◽  
Francisco Alén ◽  
Bin Wang ◽  
Guo-Hua Bi ◽  
...  
Keyword(s):  
Research Effort ◽  
Critical Role ◽  
Dopamine Neurons ◽  
Brain Stimulation Reward ◽  
Mrna Levels ◽  
Self Administration ◽  
Conditioned Stimuli ◽  
Cocaine Use ◽  
Ghrelin Receptor ◽  
Cocaine Seeking

AbstractCocaine addiction is a significant medical and public concern. Despite decades of research effort, development of pharmacotherapy for cocaine use disorder remains largely unsuccessful. This may be partially due to insufficient understanding of the complex biological mechanisms involved in the pathophysiology of this disorder. In the present study, we show that: (1) elevation of ghrelin by cocaine plays a critical role in maintenance of cocaine self-administration and cocaine-seeking motivated by cocaine-conditioned stimuli; (2) acquisition of cocaine-taking behavior is associated with the acquisition of stimulatory effects of cocaine by cocaine-conditioned stimuli on ghrelin secretion, and with an upregulation of ghrelin receptor mRNA levels in the ventral tegmental area (VTA); (3) blockade of ghrelin signaling by pretreatment with JMV2959, a selective ghrelin receptor antagonist, dose-dependently inhibits reinstatement of cocaine-seeking triggered by either cocaine or yohimbine in behaviorally extinguished animals with a history of cocaine self-administration; (4) JMV2959 pretreatment also inhibits brain stimulation reward (BSR) and cocaine-potentiated BSR maintained by optogenetic stimulation of VTA dopamine neurons in DAT-Cre mice; (5) blockade of peripheral adrenergic β1 receptors by atenolol potently attenuates the elevation in circulating ghrelin induced by cocaine and inhibits cocaine self-administration and cocaine reinstatement triggered by cocaine. These findings demonstrate that the endogenous ghrelin system plays an important role in cocaine-related addictive behaviors and suggest that manipulating and targeting this system may be viable for mitigating cocaine use disorder.

scholarly journals Genetic background and epigenetic modifications in the core of the nucleus accumbens predict addiction-like behavior in a rat model

2016 ◽  
Vol 113 (20) ◽  
pp. E2861-E2870 ◽  
Author(s):  
Shelly B. Flagel ◽  
Sraboni Chaudhury ◽  
Maria Waselus ◽  
Rebeca Kelly ◽  
Salima Sewani ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Protective Factor ◽  
Dopamine D2 Receptor ◽  
Genetic Difference ◽  
Epigenetic Modifications ◽  
Mrna Levels ◽  
Self Administration ◽  
Nucleus Accumbens Core ◽  
The Core ◽  
Cocaine Seeking

This study provides a demonstration in the rat of a clear genetic difference in the propensity for addiction-related behaviors following prolonged cocaine self-administration. It relies on the use of selectively bred high-responder (bHR) and low-responder (bLR) rat lines that differ in several characteristics associated with “temperament,” including novelty-induced locomotion and impulsivity. We show that bHR rats exhibit behaviors reminiscent of human addiction, including persistent cocaine-seeking and increased reinstatement of cocaine seeking. To uncover potential underlying mechanisms of this differential vulnerability, we focused on the core of the nucleus accumbens and examined expression and epigenetic regulation of two transcripts previously implicated in bHR/bLR differences: fibroblast growth factor (FGF2) and the dopamine D2 receptor (D2). Relative to bHRs, bLRs had lower FGF2 mRNA levels and increased association of a repressive mark on histones (H3K9me3) at the FGF2 promoter. These differences were apparent under basal conditions and persisted even following prolonged cocaine self-administration. In contrast, bHRs had lower D2 mRNA under basal conditions, with greater association of H3K9me3 at the D2 promoter and these differences were no longer apparent following prolonged cocaine self-administration. Correlational analyses indicate that the association of H3K9me3 at D2 may be a critical substrate underlying the propensity to relapse. These findings suggest that low D2 mRNA levels in the nucleus accumbens core, likely mediated via epigenetic modifications, may render individuals more susceptible to cocaine addiction. In contrast, low FGF2 levels, which appear immutable even following prolonged cocaine exposure, may serve as a protective factor.

scholarly journals Effects of acute and repeated administration of the selective M4 PAM VU0152099 on cocaine vs. food choice in male rats

2021 ◽  
Author(s):  
Morgane H Thomsen ◽  
Jill R Crittenden ◽  
Craig W. Lindsley ◽  
Ann M. Graybiel
Keyword(s):  
Acetylcholine Receptors ◽  
Repeated Administration ◽  
Muscarinic Acetylcholine Receptors ◽  
Male Rats ◽  
Contrast Effects ◽  
Self Administration ◽  
Cocaine Use ◽  
Dopamine Receptor Antagonists ◽  
Cocaine Seeking ◽  
Term Administration

Ligands that stimulate muscarinic acetylcholine receptors 1 and 4 (M1, M4) have shown promising effects as putative pharmacotherapy for cocaine use disorder in rodent assays. We have previously shown reductions in cocaine effects with acute M4 stimulation, as well as long-lasting, delayed, reductions in cocaine taking and cocaine seeking with combined M1/M4 receptor stimulation or with M1 stimulation alone. M4 stimulation opposes dopaminergic signaling acutely, but direct dopamine receptor antagonists have proved unhelpful in managing cocaine use disorder because they lose efficacy with long-term administration. It is therefore critical to determine whether M4 approaches themselves can remain effective with repeated or chronic dosing. We assessed the effects of repeated administration of the M4 positive allosteric modulator (PAM) VU0152099 in rats trained to choose between intravenous cocaine and a liquid food reinforcer, to obtain quantitative measurement of whether M4 stimulation could produce delayed and lasting reduction in cocaine taking. VU0152099 produced progressively augmenting suppression of cocaine choice and cocaine intake, but produced neither rebound nor lasting effects after treatment ended. To compare and contrast effects of M1 vs. M4 stimulation, we tested whether the M4 PAM VU0152100 suppressed cocaine self-administration in mice lacking CalDAG-GEFI signaling factor, required for M1- mediated suppression of cocaine self-administration. CalDAG-GEFI ablation had no effect on M4- mediated suppression of cocaine self-administration. These findings support the potential usefulness of M4 PAMs as pharmacotherapy to manage cocaine use disorder, alone or in combination with M1-selective ligands, and show that M1 and M4 stimulation modulate cocaine-taking behavior by distinct mechanisms.

scholarly journals Dynorphin counteracts orexin in the paraventricular nucleus of the thalamus: cellular and behavioral evidence

2017 ◽  
Author(s):  
Alessandra Matzeu ◽  
Marsida Kallupi ◽  
Olivier George ◽  
Paul Schweitzer ◽  
Rémi Martin-Fardon
Keyword(s):  
Paraventricular Nucleus ◽  
Glutamate Release ◽  
Critical Role ◽  
Brain Slices ◽  
Self Administration ◽  
Excitatory Transmission ◽  
Cocaine Seeking ◽  
Seeking Behavior ◽  
Male Wistar Rats ◽  
Behavioral Evidence

ABSTRACTThe orexin (Orx) system is known to play a critical role in drug addiction and reward-related behaviors. The dynorphin (Dyn) system, conversely, promotes depressive-like behavior and plays a key role in the aversive effects of stress. Orexin and Dyn are co-released and have opposing functions in reward and motivation in the ventral tegmental area (VTA). Earlier studies showed that microinjections of OrxA in the posterior paraventricular nucleus of the thalamus (pPVT) exerted priming-like effects and reinstated cocaine-seeking behavior, suggesting that Orx transmission in the pPVT participates in cocaine-seeking behavior. The present study sought to determine whether Orx and Dyn interact in the pPVT. Using a cellular approach, brain slices were prepared for whole-cell recordings and to study excitatory transmission in pPVT neurons. The superfusion of OrxA increased spontaneous glutamatergic transmission by increasing glutamate release onto pPVT neurons, whereas DynA decreased glutamate release. Furthermore, the augmentation of OrxA-induced glutamate release was reversed by DynA. To corroborate the electrophysiological data, separate groups of male Wistar rats were trained to self-administer cocaine or sweetened condensed milk (SCM). After self-administration training, the rats underwent extinction training and were tested with intra-pPVT administration of OrxA±DynA under extinction conditions. OrxA reinstated cocaine-and SCM-seeking behavior, with a greater effect in cocaine animals. DynA selectively blocked OrxA-induced cocaine seeking vs. SCM seeking. The data indicate that DynA in the pPVT prevents OrxA-induced cocaine seeking, perhaps by reversing the OrxA-induced increase in glutamate release, identifying a novel therapeutic target to prevent cocaine relapse.

scholarly journals Leptin protects against the development and expression of cocaine addiction-like behavior in heterogenous stock rats

2021 ◽  
Author(s):  
Lieselot Leen G Carrette ◽  
Cristina Corral ◽  
Caitlin Crook ◽  
Brent Boomhower ◽  
Molly Brennan ◽  
...  
Keyword(s):  
Individual Differences ◽  
Weight Control ◽  
Protective Factor ◽  
Causal Effect ◽  
Small Sample ◽  
Cocaine Addiction ◽  
Self Administration ◽  
Cocaine Use ◽  
Cocaine Seeking ◽  
Using Data

In addition to its pleasurable effects, weight control is a significant contributor to initiation, maintenance and relapse of cocaine use. This suggests that individual differences in bodyweight control and feeding hormones, such as leptin may contribute to the vulnerability to cocaine use disorder. While pre-clinical studies have shown a mutually inhibitory relationship between leptin and cocaine, they have used small sample sizes and did not investigate individual differences in a large heterogeneous population. Here, we tested if individual differences in bodyweight and blood leptin level is associated with high or low vulnerability to addiction-like behaviors using data from 500 heterogenous stock rats and 160 blood samples from the Cocaine Biobank, using a model of extended access to intravenous self-administration of cocaine. Finally, we tested a separate cohort to evaluate the causal effect of exogenous leptin administration on cocaine seeking. Bodyweight, while changing due to cocaine self-administration in males, was not related to the vulnerability to addiction-like behavior. Blood leptin levels after ~6 weeks of cocaine self-administration did not correlate with addiction-like behaviors, however, baseline blood leptin levels before any access to cocaine negatively predicted addiction-like behavior. Finally, administration of leptin reduced cocaine intake after acute withdrawal and cocaine seeking after 6 weeks of protracted abstinence. These results demonstrate that high blood leptin level before access to cocaine may be a protective factor against the development of cocaine addiction-like behavior, that exogenous leptin reduces the motivation to take and seek cocaine, but that blood leptin level and bodyweight changes in current users are not good biomarkers for addiction-like behaviors.

Enhancement of the GluN2B subunit of glutamatergic NMDA receptors in rat brain areas after cocaine abstinence

2021 ◽  
pp. 026988112110482
Author(s):  
Irena Smaga ◽  
Karolina Wydra ◽  
Agata Suder ◽  
Marek Sanak ◽  
Lucia Caffino ◽  
...  
Keyword(s):  
Nmda Receptors ◽  
Dorsal Hippocampus ◽  
Brain Structures ◽  
Enriched Environment ◽  
Self Administration ◽  
Cocaine Use ◽  
Cocaine Seeking ◽  
Subunit Expression ◽  
Seeking Behavior ◽  
History Of

Background: Cocaine use disorder is associated with compulsive drug-seeking and drug-taking, whereas relapse may be induced by several factors, including stress, drug-related places, people, and cues. Recent observations strongly support the involvement of the N-methyl-D-aspartate (NMDA) receptors in cocaine use disorders and abstinence, whereas withdrawal in different environments may affect the intensification of relapse. Methods: The aim of this study was to examine the GluN2B subunit expression and its association with the postsynaptic density protein 95 (PSD95) in several brain structures in rats with a history of cocaine self-administration and housed either in an enriched environment or in an isolated condition. Furthermore, a selective antagonist of the GluN2B subunit—CP 101,606 (10 and 20 mg/kg) administered during exposure to cocaine or a drug-associated conditional stimulus (a cue) was used to evaluate seeking behavior in rats. Results: In rats previously self-administering cocaine, we observed an increase in the GluN2B expression in the total homogenate from the dorsal hippocampus under both enriched environment and isolation. Cocaine abstinence under isolation conditions increased the GluN2B and GluN2B/PSD95 complex levels in the PSD fraction of the prelimbic cortex in rats previously self-administering cocaine. Administration of CP 101,606 attenuated cue-induced cocaine-seeking behavior only in isolation-housed rats. Conclusion: In summary, in this study we showed region-specific changes in both the expression of GluN2B subunit and NMDA receptor trafficking during cocaine abstinence under different housing conditions. Furthermore, we showed that the pharmacological blockade of the GluN2B subunit may be useful in attenuating cocaine-seeking behavior.

scholarly journals Dopaminylation of histone H3 in ventral tegmental area regulates cocaine seeking

Science ◽  
2020 ◽  
Vol 368 (6487) ◽  
pp. 197-201 ◽  
Author(s):  
Ashley E. Lepack ◽  
Craig T. Werner ◽  
Andrew F. Stewart ◽  
Sasha L. Fulton ◽  
Ping Zhong ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ventral Tegmental Area ◽  
Critical Role ◽  
Histone H3 ◽  
Dopamine Neurons ◽  
Cocaine Seeking ◽  
Seeking Behavior ◽  
Ventral Tegmental ◽  
Midbrain Dopamine ◽  
Transcriptional Plasticity

Vulnerability to relapse during periods of attempted abstinence from cocaine use is hypothesized to result from the rewiring of brain reward circuitries, particularly ventral tegmental area (VTA) dopamine neurons. How cocaine exposures act on midbrain dopamine neurons to precipitate addiction-relevant changes in gene expression is unclear. We found that histone H3 glutamine 5 dopaminylation (H3Q5dop) plays a critical role in cocaine-induced transcriptional plasticity in the midbrain. Rats undergoing withdrawal from cocaine showed an accumulation of H3Q5dop in the VTA. By reducing H3Q5dop in the VTA during withdrawal, we reversed cocaine-mediated gene expression changes, attenuated dopamine release in the nucleus accumbens, and reduced cocaine-seeking behavior. These findings establish a neurotransmission-independent role for nuclear dopamine in relapse-related transcriptional plasticity in the VTA.

Impulsivity and Drug Addiction: A Neurobiological Perspective

2012 ◽  
Author(s):  
Trevor Robbins
Keyword(s):  
Drug Addiction ◽  
Conceptual Analysis ◽  
Animal Studies ◽  
Reaction Time Task ◽  
Compulsive Behavior ◽  
Self Administration ◽  
Detailed Characterization ◽  
Cocaine Seeking ◽  
Serial Reaction

A conceptual analysis of the impulsivity construct in behavioral and neurobiological terms is followed by an analysis of its causal role in certain forms of drug addiction in both human and animal studies. The main focus of this chapter is on a rat model of impulsivity based on premature responding in the five-choice serial reaction time task and a more detailed characterization of this phenotype in neurobehavioral, neurochemical, and genetic terms. Evidence is surveyed that high impulsivity on this task is associated with the escalation subsequently of cocaine self-administration behavior and also with a tendency toward compulsive cocaine seeking. Novelty reactivity, by contrast, is associated with the enhanced acquisition of self-administration, but not with the escalation of intravenous self-administration of cocaine or the development of compulsive behavior associated with cocaine seeking. These results indicate that the vulnerability to stimulant addiction may depend on different factors, as expressed through distinct presumed endophenotypes. These observations help us further to dissociate various aspects of the impulsivity construct in neural as well as behavioral terms.

scholarly journals Low Basal CB2R in Dopamine Neurons and Microglia Influences Cannabinoid Tetrad Effects

2020 ◽  
Vol 21 (24) ◽  
pp. 9763
Author(s):  
Qing-Rong Liu ◽  
Ana Canseco-Alba ◽  
Ying Liang ◽  
Hiroki Ishiguro ◽  
Emmanuel S. Onaivi
Keyword(s):  
Cortical Neurons ◽  
Cannabinoid Receptors ◽  
Dynamic Range ◽  
Conditional Knockout ◽  
Dopamine Neurons ◽  
In Vivo Studies ◽  
Mouse Strains ◽  
Genotypic Differences ◽  
Mrna Levels ◽  
Selective Agonist

There are two well-characterized cannabinoid receptors (CB1R and CB2R and other candidates): the central nervous system (CNS) enriched CB1R and peripheral tissue enriched CB2R with a wide dynamic range of expression levels in different cell types of human tissues. Hepatocytes and neurons express low baseline CB1R and CB2R, respectively, and their cell-type-specific functions are not well defined. Here we report inducible expression of CB1R in the liver by high-fat and high sugar diet and CB2R in cortical neurons by methamphetamine. While there is less controversy about hepatocyte CB1R, the presence of functional neuronal CB2R is still debated to date. We found that neuron CB2R basal expression was higher than that of hepatocyte CB1R by measuring mRNA levels of specific isoform CB2A in neurons isolated by fluorescence-activated cell sorting (FACS) and CB1A in hepatocytes isolated by collagenase perfusion of liver. For in vivo studies, we generated hepatocyte, dopaminergic neuron, and microglia-specific conditional knockout mice (Abl-Cnr1Δ, Dat-Cnr2Δ, and Cx3cr1-Cnr2Δ) of CB1R and CB2R by crossing Cnr1f/f and Cnr2f/f strains to Abl-Cre, Dat-Cre, and Cx3cr1-Cre deleter mouse strains, respectively. Our data reveals that neuron and microglia CB2Rs are involved in the “tetrad” effects of the mixed agonist WIN 55212-2, CB1R selective agonist arachidonyl-2′-chloroethylamide (ACEA), and CB2R selective agonist JWH133. Dat-Cnr2Δ and Cx3cr1-Cnr2Δ mice showed genotypic differences in hypomobility, hypothermia, analgesia, and catalepsy induced by the synthetic cannabinoids. Alcohol conditioned place preference was abolished in DAT-Cnr2Δ mice and remained intact in Cx3cr1-Cnr2Δ mice in comparison to WT mice. These Cre-loxP recombinant mouse lines provide unique approaches in cannabinoid research for dissecting the complex endocannabinoid system that is implicated in many chronic disorders.

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