Chemokine CCR5 and cocaine interactions in the brain: Cocaine enhances mesolimbic CCR5 mRNA levels and produces place preference and locomotor activation that are reduced by a CCR5 antagonist

Nayak, Sunil U.; Cicalese, Stephanie; Tallarida, Chris; Oliver, Chicora F.; Rawls, Scott M.

doi:10.1016/j.bbi.2019.09.017

Cited by 29 publications

(17 citation statements)

References 27 publications

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“…Although we did not extend our findings to additional dopaminergic mesocorticolimbic regions that regulate psychostimulant addiction-like behaviors, there is an emerging body of literature that implicates other dopaminergic region alterations in chemokine activity and relates this to psychostimulant exposure related rodent behaviors [ 37 , 77 , 117 – 120 ]. For example, exogenous CXCL12 administration prior to cocaine injection into the nucleus accumbens shell has inhibitory effects on rat activity [ 120 ].…”

Section: Discussionmentioning

confidence: 69%

“…As chemokines become better elucidated in the literature, there is an emerging body of evidence that highlights the role of chemokine signaling in neuronal communication and thus, could be necessary for the development and expression of responses to psychostimulant drugs. For example, human in vitro models [ 76 ] implicate CC Chemokine Receptor 5 (CCR5) mechanisms in the cellular response to methamphetamine, while silencing genes for and blocking CC Chemokine Receptor 2 (CCR2) and CCR5 elicit an attenuation in conditioned place preference and locomotor behavior to methamphetamine or cocaine in rodent in vivo models [ 77 – 79 ]. We have likewise demonstrated that systemic CXCR4 antagonism attenuates AMPH-induced hyperlocomotion in adolescent male Long Evans rats.…”

Section: Discussionmentioning

confidence: 99%

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CXCR4 inhibition with AMD3100 attenuates amphetamine induced locomotor activity in adolescent Long Evans male rats

et al. 2021

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Adolescent psychostimulant abuse has been on the rise over the past decade. This trend has demonstrable ramifications on adolescent behavior and brain morphology, increasing risk for development of addiction during adolescence and in later adulthood. Neuroimmune substrates are implicated in the etiology of substance use disorders. To add to this body of work, the current study was developed to explore the role of a chemokine receptor, CXC Chemokine Receptor 4 (CXCR4), in the development of amphetamine (AMPH) sensitization. We targeted CXCR4 as it is implicated in developmental processes, dopaminergic transmission, neuroimmune responses, and the potentiation of psychostimulant abuse pathology. To evaluate the role of CXCR4 activity on the development of AMPH sensitization, a CXCR4 antagonist (Plerixafor; AMD3100) was administered to rats as a pretreatment variable. Specifically, adolescent Long Evans male rats (N = 37) were divided into four groups: (1) AMD3100 (IP, 4.0 mg/kg) + AMPH (IP, 4.0 mg/kg), (2) saline (SAL; 0.9% NaCl) + AMPH, (3) AMD3100 + SAL, and (4) SAL + SAL. Animals were first habituated to locomotor activity (LMA) chambers, then injected with a pretreatment drug (AMD3100 or SAL) followed by AMPH or SAL every other for four days. After a one-week withdrawal period, all animals were administered a low challenge dose of AMPH (IP, 1.0 mg/kg). AMPH-injected rats displayed significantly more locomotor activity compared to controls across all testing days. CXCR4 antagonism significantly attenuated AMPH-induced locomotor activity. On challenge day, AMD3100 pre-treated animals exhibited diminutive AMPH-induced locomotor activity compared to SAL pre-treated animals. Postmortem analyses of brain tissue revealed elevated CXCR4 protein levels in the striatum of all experimental groups. Our results implicate CXCR4 signaling in the development of AMPH sensitization and may represent an important therapeutic target for future research in psychostimulant abuse.

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Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 99%

CXCR4 inhibition with AMD3100 attenuates amphetamine induced locomotor activity in adolescent Long Evans male rats

et al. 2021

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“…maraviroc), chemokine ligands, and monoclonal antibodies (Fantuzzi et al, 2019). The use of CCR5 antagonists is well established for the treatment of HIV infection and is currently being tested for the treatment of many other diseases, such as cancer (Pervaiz et al, 2019;Huang et al, 2020a), stroke (Joy et al, 2019), and cocaine addictionrelated disorders (Hall et al, 2020;Nayak et al, 2020).…”

Section: Ccr5 Gene Editing and Ccr5 Modulation: What Would Be The Effmentioning

confidence: 99%

Beyond HIV infection: Neglected and varied impacts of CCR5 and CCR5Δ32 on viral diseases

et al. 2020

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The interactions between chemokine receptors and their ligands may affect susceptibility to infectious diseases as well as their clinical manifestations. These interactions mediate both the traffic of inflammatory cells and virus-associated immune responses. In the context of viral infections, the human CC chemokine receptor type 5 (CCR5) receives great attention from the scientific community due to its role as an HIV-1 co-receptor. The genetic variant CCR5Δ32 (32 base-pair deletion in CCR5 gene) impairs CCR5 expression on the cell surface and is associated with protection against HIV infection in homozygous individuals. Also, the genetic variant CCR5Δ32 modifies the CCR5-mediated inflammatory responses in various conditions, such as inflammatory and infectious diseases. CCR5 antagonists mimic, at least in part, the natural effects of the CCR5Δ32 in humans, which explains the growing interest in the potential benefits of using CCR5 modulators for the treatment of different diseases. Nevertheless, beyond HIV infection, understanding the effects of the CCR5Δ32 variant in multiple viral infections is essential to shed light on the potential effects of the CCR5 modulators from a broader perspective. In this context, this review discusses the involvement of CCR5 and the effects of the CCR5Δ32 in human infections caused by the following pathogens: West Nile virus, Influenza virus, Human papillomavirus, Hepatitis B virus, Hepatitis C virus, Poliovirus, Dengue virus, Human cytomegalovirus, Crimean-Congo hemorrhagic fever virus, Enterovirus, Japanese encephalitis virus, and Hantavirus. Subsequently, this review addresses the impacts of CCR5 gene editing and CCR5 modulation on health and viral diseases. Also, this article connects recent findings regarding extracellular vesicles (e.g., exosomes), viruses, and CCR5. Neglected and emerging topics in "CCR5 research" are briefly described, with focus on Rocio virus, Zika virus, Epstein-Barr virus, and Rhinovirus. Finally, the potential influence of CCR5 on the immune responses to coronaviruses is discussed.

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“…This chemokine receptor generally mediates the entry of HIV virions into myeloid cells such as macrophages or microglia ( 66 , 67 ), and our prior data show that the impact of dopamine on HIV infection requires CCR5 ( 55 ). In addition, both methamphetamine and cocaine increase CCR5 expression in non-human primate ( 68 , 69 ) and rodent models of substance abuse ( 70 ). Cocaine also produces place preference and locomotor activation that are reduced by the ART drug maraviroc (MVC), a CCR5 inhibitor ( 70 ).…”

Section: Introductionmentioning

confidence: 99%

“…In addition, both methamphetamine and cocaine increase CCR5 expression in non-human primate ( 68 , 69 ) and rodent models of substance abuse ( 70 ). Cocaine also produces place preference and locomotor activation that are reduced by the ART drug maraviroc (MVC), a CCR5 inhibitor ( 70 ). The promoter region of CCR5 has binding sites specific to dopamine-responsive transcription factors ( 71 ) and CCR5 deficiency in mice induces both a loss of dopaminergic neurons and microglial activation ( 72 ).…”

Section: Introductionmentioning

confidence: 99%

Dopamine Levels Induced by Substance Abuse Alter Efficacy of Maraviroc and Expression of CCR5 Conformations on Myeloid Cells: Implications for NeuroHIV

et al. 2021

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Despite widespread use of antiretroviral therapy (ART), HIV remains a major public health issue. Even with effective ART many infected individuals still suffer from the constellation of neurological symptoms now known as neuroHIV. These symptoms can be exacerbated by substance abuse, a common comorbidity among HIV-infected individuals. The mechanism(s) by which different types of drugs impact neuroHIV remains unclear, but all drugs of abuse increase central nervous system (CNS) dopamine and elevated dopamine increases HIV infection and inflammation in human myeloid cells including macrophages and microglia, the primary targets for HIV in the brain. Thus, drug-induced increases in CNS dopamine may be a common mechanism by which distinct addictive substances alter neuroHIV. Myeloid cells are generally infected by HIV strains that use the chemokine receptor CCR5 as a co-receptor, and our data indicate that in a subset of individuals, drug-induced levels of dopamine could interfere with the effectiveness of the CCR5 inhibitor Maraviroc. CCR5 can adopt distinct conformations that differentially regulate the efficiency of HIV entry and subsequent replication and using qPCR, flow cytometry, Western blotting and high content fluorescent imaging, we show that dopamine alters the expression of specific CCR5 conformations of CCR5 on the surface of human macrophages. These changes are not affected by association with lipid rafts, but do correlate with dopamine receptor gene expression levels, specifically higher levels of D1-like dopamine receptors. These data also demonstrate that dopamine increases HIV replication and alters CCR5 conformations in human microglia similarly to macrophages. These data support the importance of dopamine in the development of neuroHIV and indicate that dopamine signaling pathways should be examined as a target in antiretroviral therapies specifically tailored to HIV-infected drug abusers. Further, these studies show the potential immunomodulatory role of dopamine, suggesting changes in this neurotransmitter may also affect the progression of other diseases.

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Chemokine CCR5 and cocaine interactions in the brain: Cocaine enhances mesolimbic CCR5 mRNA levels and produces place preference and locomotor activation that are reduced by a CCR5 antagonist

Cited by 29 publications

References 27 publications

CXCR4 inhibition with AMD3100 attenuates amphetamine induced locomotor activity in adolescent Long Evans male rats

CXCR4 inhibition with AMD3100 attenuates amphetamine induced locomotor activity in adolescent Long Evans male rats

Beyond HIV infection: Neglected and varied impacts of CCR5 and CCR5Δ32 on viral diseases

Dopamine Levels Induced by Substance Abuse Alter Efficacy of Maraviroc and Expression of CCR5 Conformations on Myeloid Cells: Implications for NeuroHIV

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