Cocaine-Induced Reinstatement of Cocaine Seeking Provokes Changes in the Endocannabinoid and N-Acylethanolamine Levels in Rat Brain Structures

Bystrowska, Beata; Frankowska, Małgorzata; Smaga, Irena; Niedzielska-Andres, Ewa; Pomierny-Chamioło, Lucyna; Filip, Małgorzata

doi:10.3390/molecules24061125

Cited by 24 publications

(12 citation statements)

References 33 publications

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“…Endocannabinoid levels in the limbic forebrain are regulated following cocaine-SA with 2-AG unchanged [49], or decreased [48], the latter specifically in the NAc of short access rats [75]. Interestingly, both 2-AG and AEA were increased in the HPC only in cocaine-SA rats, matching previous results using a reinstatement paradigm [74]. Similar increases in 2-AG were observed in rats receiving passive cocaine injections (yoked), whereas both AEA and 2-AG were reduced following extinction of cocaine-SA.…”

Section: Endocannabinoid Regulation In the Hpc Following Cocaine-sasupporting

confidence: 84%

“…Pharmacological blockade of either CB1Rs or CB2Rs prevented both cocaine-induced conditioned locomotion and cocaine-induced reduction of cell proliferation in the HPC of adult male rats [86]. Common regulation of both receptors in the PFC was described with a decreased expression in a cocaine-SA paradigm [46], and an increased expression in a cocaine-SA reinstatement paradigm [74]. Nevertheless, as in our study, some findings support opposite regulations and opposing roles for the two receptors.…”

Section: Opposite Role Of Cb1rs and Cb2rs In Cocaine Adaptationssupporting

confidence: 74%

“…As Crip1A enhances CB1R signaling in the HPC [73], this protein could participate in the regulation of CB1R signaling. Few studies have examined CB1R changes in the HPC following cocaine-SA and no changes could be detected at the protein level, using immunohistochemistry [74]. On the contrary, CB1R were increased in a cocaine sensitization paradigm in mice [43], possibly reflecting a compensatory mechanism as this modification was coupled with decreased gene/protein expression of the endocannabinoid-synthesis enzymes NAPE-PLD and DAGLα [43].…”

Section: Endocannabinoid Regulation In the Hpc Following Cocaine-samentioning

confidence: 99%

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Hippocampal Cannabinoid 1 Receptors Are Modulated Following Cocaine Self-administration in Male Rats

et al. 2022

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Cocaine addiction is a complex pathology inducing long-term neuroplastic changes that, in. turn, contribute to maladaptive behaviors. This behavioral dysregulation is associated with transcriptional reprogramming in brain reward circuitry, although the mechanisms underlying this modulation remain poorly understood. The endogenous cannabinoid system may play a role in this process in that cannabinoid mechanisms modulate drug reward and contribute to cocaine-induced neural adaptations. In this study, we investigated whether cocaine selfadministration induces long-term adaptations, including transcriptional modifications and associated epigenetic processes. We first examined endocannabinoid gene expression in reward-related brain regions of the rat following self-administered (0.33mg/kg intravenous, FR1, 10 days) cocaine injections. Interestingly, we found increased Cnr1 expression in several structures, including prefrontal cortex, nucleus accumbens, dorsal striatum, hippocampus, habenula, amygdala, lateral hypothalamus, ventral tegmental area and rostromedial tegmental nucleus, with most pronounced effects in the hippocampus.Endocannabinoid levels, measured by mass spectrometry, were also altered in this structure.Chromatin immunoprecipitation followed by qPCR in the hippocampus revealed that two activating histone marks, H3K4Me3 and H3K27Ac, were enriched at specific endocannabinoid genes following cocaine intake. Targeting CB1 receptors using chromosome conformation capture, we highlighted spatial chromatin re-organization in the hippocampus, as well as in the nucleus accumbens, suggesting that destabilization of the chromatin may contribute to neuronal responses to cocaine. Overall, our results highlight a key role for the hippocampus in cocaine-induced plasticity and broaden the understanding of neuronal alterations associated with endocannabinoid signaling. The latter suggests that epigenetic modifications contribute to maladaptive behaviors associated with chronic drug use.

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Section: Endocannabinoid Regulation In the Hpc Following Cocaine-sasupporting

confidence: 84%

Section: Opposite Role Of Cb1rs and Cb2rs In Cocaine Adaptationssupporting

confidence: 74%

Section: Endocannabinoid Regulation In the Hpc Following Cocaine-samentioning

confidence: 99%

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Hippocampal Cannabinoid 1 Receptors Are Modulated Following Cocaine Self-administration in Male Rats

et al. 2022

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“…; Biowet, Puławy, Poland) and xylazine (5 mg/kg, i.m. ; Biowet, Puławy, Poland) and implanted with a silastic catheter to the external right jugular vein as described previously (Bystrowska et al, 2019)]. In the first 3 days after surgery, meloxicam (5 mg/kg, s.c. ; Metacam, Boehringer IIngelheim, Ingelheim, Germany) was used to reduce post-operative pain.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2021

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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.

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“…Particular nicotinic (CHRNA6, CHRNB2) and muscarinic acetylcholine subunit genes (CHRM1, CHRM4) we found to be associated with CUD have previously been implicated in rodent cocaine research (Carrigan and Dykstra, 2007;Dencker et al, 2012;Sanjakdar et al, 2015) and might govern selective attention and promote incentive salience to drugs/ drug-related cues (Williams and Adinoff, 2008). Cocaine has also been found to alter the expression of endocannabanoid genes/receptors in the mouse PFC (Bystrowska et al, 2019), which could facilitate the strength of connections between PFC neurons (Kasanetz et al, 2013). Overall our study utilized human brain data that corroborated specific genes and pathways studied in animal models of cocaine use and other relevant molecular endophenotypes.…”

Section: Discussionmentioning

confidence: 79%

Genetic Architecture and Molecular Neuropathology of Human Cocaine Addiction

Huggett

Stallings

2020

J. Neurosci.

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We integrated genomic and bioinformatic analyses, using data from the largest genome-wide association study of cocaine dependence (CD; n = 6546; 82.37% with CD; 57.39% male) and the largest postmortem gene-expression sample of individuals with cocaine use disorder (CUD; n = 36; 51.35% with CUD; 100% male). Our genome-wide analyses identified one novel gene (NDUFB9) associated with the genetic predisposition to CD in African-Americans. The genetic architecture of CD was similar across ancestries. Individual genes associated with CD demonstrated modest overlap across European-Americans and African-Americans, but the genetic liability for CD converged on many similar tissue types (brain, heart, blood, liver) across ancestries. In a separate sample, we investigated the neuronal gene expression associated with CUD by using RNA sequencing of dorsal-lateral prefrontal cortex neurons. We identified 133 genes differentially expressed between CUD case patients and cocaine-free control subjects, including previously implicated candidates for cocaine use/addiction (FOSB, ARC, KCNJ9/GIRK3, NR4A2, JUNB, and MECP2). Differential expression analyses significantly correlated across European-Americans and African-Americans. While genes significantly associated with CD via genome-wide methods were not differentially expressed, two of these genes (NDUFB9 and C1qL2) were part of a robust gene coexpression network associated with CUD involved in neurotransmission (GABA, acetylcholine, serotonin, and dopamine) and drug addiction. We then used a "guilt-by-association" approach to unravel the biological relevance of NDUFB9 and C1qL2 in the context of CD. In sum, our study furthers the understanding of the genetic architecture and molecular neuropathology of human cocaine addiction and provides a framework for translating biological meaning into otherwise obscure genome-wide associations.

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Cocaine-Induced Reinstatement of Cocaine Seeking Provokes Changes in the Endocannabinoid and N-Acylethanolamine Levels in Rat Brain Structures

Cited by 24 publications

References 33 publications

Hippocampal Cannabinoid 1 Receptors Are Modulated Following Cocaine Self-administration in Male Rats

Hippocampal Cannabinoid 1 Receptors Are Modulated Following Cocaine Self-administration in Male Rats

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

Genetic Architecture and Molecular Neuropathology of Human Cocaine Addiction

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