Innate immune signaling in the ventral tegmental area contributes to drug-primed reinstatement of cocaine seeking. 2018

Kyle T Brown, and Sophia C Levis, and Casey E O'Neill, and Alexis L Northcutt, and Timothy J Fabisiak, and Linda R Watkins, and Ryan K Bachtell
Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO 80309, United States. Electronic address: Kyle.Brown@colorado.edu.

Cocaine addiction is a chronic relapsing disorder characterized by persistent perturbations to an organism's homeostatic processes that result in maladaptive drug seeking. Although considerable attention has been directed at the consequences of neuronal changes following chronic cocaine taking, few studies have examined the role of microglia, the brain's resident immune cells, following chronic cocaine administration. Toll-Like Receptor 4 (TLR4) is a molecular pattern receptor that recognizes pathogens, danger signals, and xenobiotics and induces proinflammatory signaling in the central nervous system. TLR4 is generally considered to be expressed primarily by microglia. Here, we used a rodent model of cocaine addiction to investigate the role of TLR4 in the ventral tegmental area (VTA) in cocaine seeking. Male Sprague-Dawley rats were trained to self-administer cocaine in daily 2-h sessions for 15days. Following self-administration, rats underwent extinction training and were tested in a drug-primed reinstatement paradigm. Pharmacological antagonism of TLR4 in the VTA using lipopolysaccharide from the bacterium Rhodobacter sphaeroides (LPS-RS) significantly reduced cocaine-primed reinstatement of drug seeking but had no effect on sucrose seeking. TLR4 activation within the VTA using the TLR4 activator, lipopolysaccharide, was sufficient to moderately reinstate cocaine seeking. We also assessed changes in proinflammatory cytokine expression in the VTA following cocaine self-administration. Cocaine self-administration increased the expression of mRNA for the proinflammatory cytokine interleukin-1ß, but not tumor necrosis factor alpha, in the VTA. Pharmacological antagonism of the interleukin-1 receptor in the VTA reduced cocaine-primed drug seeking. These results are consistent with the hypothesis that chronic cocaine produces inflammatory signaling that contributes to cocaine seeking.

UI MeSH Term Description Entries
D007113 Immunity, Innate The capacity of a normal organism to remain unaffected by microorganisms and their toxins. It results from the presence of naturally occurring ANTI-INFECTIVE AGENTS, constitutional factors such as BODY TEMPERATURE and immediate acting immune cells such as NATURAL KILLER CELLS. Immunity, Native,Immunity, Natural,Immunity, Non-Specific,Resistance, Natural,Innate Immune Response,Innate Immunity,Immune Response, Innate,Immune Responses, Innate,Immunity, Non Specific,Innate Immune Responses,Native Immunity,Natural Immunity,Natural Resistance,Non-Specific Immunity
D008297 Male Males
D003042 Cocaine An alkaloid ester extracted from the leaves of plants including coca. It is a local anesthetic and vasoconstrictor and is clinically used for that purpose, particularly in the eye, ear, nose, and throat. It also has powerful central nervous system effects similar to the amphetamines and is a drug of abuse. Cocaine, like amphetamines, acts by multiple mechanisms on brain catecholaminergic neurons; the mechanism of its reinforcing effects is thought to involve inhibition of dopamine uptake. Cocaine HCl,Cocaine Hydrochloride,HCl, Cocaine,Hydrochloride, Cocaine
D003216 Conditioning, Operant Learning situations in which the sequence responses of the subject are instrumental in producing reinforcement. When the correct response occurs, which involves the selection from among a repertoire of responses, the subject is immediately reinforced. Instrumental Learning,Learning, Instrumental,Operant Conditioning,Conditionings, Operant,Instrumental Learnings,Learnings, Instrumental,Operant Conditionings
D004660 Encephalitis Inflammation of the BRAIN due to infection, autoimmune processes, toxins, and other conditions. Viral infections (see ENCEPHALITIS, VIRAL) are a relatively frequent cause of this condition. Inflammation, Brain,Rasmussen Syndrome,Brain Inflammation,Encephalitis, Rasmussen,Rasmussen Encephalitis,Rasmussen's Syndrome,Brain Inflammations
D005108 Extinction, Psychological The procedure of presenting the conditioned stimulus without REINFORCEMENT to an organism previously conditioned. It refers also to the diminution of a conditioned response resulting from this procedure. Psychological Extinction,Extinction (Psychology),Extinctions (Psychology),Extinctions, Psychological,Psychological Extinctions
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D012333 RNA, Messenger RNA sequences that serve as templates for protein synthesis. Bacterial mRNAs are generally primary transcripts in that they do not require post-transcriptional processing. Eukaryotic mRNA is synthesized in the nucleus and must be exported to the cytoplasm for translation. Most eukaryotic mRNAs have a sequence of polyadenylic acid at the 3' end, referred to as the poly(A) tail. The function of this tail is not known for certain, but it may play a role in the export of mature mRNA from the nucleus as well as in helping stabilize some mRNA molecules by retarding their degradation in the cytoplasm. Messenger RNA,Messenger RNA, Polyadenylated,Poly(A) Tail,Poly(A)+ RNA,Poly(A)+ mRNA,RNA, Messenger, Polyadenylated,RNA, Polyadenylated,mRNA,mRNA, Non-Polyadenylated,mRNA, Polyadenylated,Non-Polyadenylated mRNA,Poly(A) RNA,Polyadenylated mRNA,Non Polyadenylated mRNA,Polyadenylated Messenger RNA,Polyadenylated RNA,RNA, Polyadenylated Messenger,mRNA, Non Polyadenylated
D012646 Self Administration Administration of a drug or chemical by the individual under the direction of a physician. It includes administration clinically or experimentally, by human or animal. Administration, Self,Administrations, Self,Self Administrations
D015398 Signal Transduction The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. Cell Signaling,Receptor-Mediated Signal Transduction,Signal Pathways,Receptor Mediated Signal Transduction,Signal Transduction Pathways,Signal Transduction Systems,Pathway, Signal,Pathway, Signal Transduction,Pathways, Signal,Pathways, Signal Transduction,Receptor-Mediated Signal Transductions,Signal Pathway,Signal Transduction Pathway,Signal Transduction System,Signal Transduction, Receptor-Mediated,Signal Transductions,Signal Transductions, Receptor-Mediated,System, Signal Transduction,Systems, Signal Transduction,Transduction, Signal,Transductions, Signal

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