title: Systemic Delivery of a Brain-Penetrant TrkB Antagonist Reduces Cocaine Self-Administration and Normalizes TrkB Signaling in the Nucleus Accumbens and Prefrontal Cortex.
abstract: Cocaine exposure alters brain-derived neurotrophic factor (BDNF) expression in the brain. BDNF signaling through TrkB receptors differentially modulates cocaine self-administration, depending on the brain regions involved. In the present study, we determined how brain-wide inhibition of TrkB signaling affects cocaine intake, the motivation for the drug, and reinstatement of drug taking after extinction. To overcome the inability of TrkB ligands to cross the blood-brain barrier, the TrkB antagonist cyclotraxin-B was fused to the nontoxic transduction domain of the tat protein from human immunodeficiency virus type 1 (tat-cyclotraxin-B). Intravenous injection of tat-cyclotraxin-B dose-dependently reduced cocaine intake, motivation for cocaine (as measured under a progressive ratio schedule of reinforcement), and reinstatement of cocaine taking in rats allowed either short or long access to cocaine self-administration. In contrast, the treatment did not affect operant responding for a highly palatable sweet solution, demonstrating that the effects of tat-cyclotraxin-B are specific for cocaine reinforcement. Cocaine self-administration increased TrkB signaling and activated the downstream Akt pathway in the nucleus accumbens, and had opposite effects in the prefrontal cortex. Pretreatment with tat-cyclotraxin-B normalized protein levels in these two dopamine-innervated brain regions. Cocaine self-administration also increased TrkB signaling in the ventral tegmental area, where the dopaminergic projections originate, but pretreatment with tat-cyclotraxin-B did not alter this effect. Altogether, our data show that systemic administration of a brain-penetrant TrkB antagonist leads to brain region-specific effects and may be a potential pharmacological strategy for the treatment of cocaine addiction.
  
  
  
  Brain-derived neurotrophic factor (BDNF) signaling through TrkB receptors plays a well established role in cocaine reinforcement. However, local manipulation of BDNF signaling yields divergent effects, depending on the brain region, thereby questioning the viability of systemic TrkB targeting for the treatment of cocaine use disorders. Our study provides first-time evidence that systemic administration of a brain-penetrant TrkB antagonist (tat-cyclotraxin-B) reduces several behavioral measures of cocaine dependence, without altering motor performance or reinforcement by a sweet palatable solution. In addition, although cocaine self-administration produced opposite effects on TrkB signaling in the nucleus accumbens and prefrontal cortex, tat-cyclotraxin-B administration normalized these cocaine-induced changes in both brain regions.
authors.affiliation: Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre, 6500 HB, Nijmegen, The Netherlands, Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California 92037, M.Verheij@cns.umcn.nl.
authors.forename: Michel M M
authors.initials: MM
authors.lastname: Verheij
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California 92037, Neurobiology of Addiction Section, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224.
authors.forename: Leandro F
authors.identifier: 0000-0002-8829-8627
authors.initials: LF
authors.lastname: Vendruscolo
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, University of Milan, 20133 Milan, Italy, Collaborative Center of Department of Antidrug Policies, Presidency of the Council of Ministers, 00187 Rome, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Caffino
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, University of Milan, 20133 Milan, Italy, Collaborative Center of Department of Antidrug Policies, Presidency of the Council of Ministers, 00187 Rome, Italy.
authors.forename: Giuseppe
authors.identifier: 0000-0003-0629-4882
authors.initials: G
authors.lastname: Giannotti
authors.affiliation: University Grenoble Alpes, Grenoble Institute of Neuroscience, GIN F-38000 Grenoble, France, and Institut National de la Santé et de la Recherche Médicale U1216, F-38000 Grenoble, France.
authors.forename: Maxime
authors.identifier: 0000-0002-8260-1154
authors.initials: M
authors.lastname: Cazorla
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, University of Milan, 20133 Milan, Italy, Collaborative Center of Department of Antidrug Policies, Presidency of the Council of Ministers, 00187 Rome, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Fumagalli
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, University of Milan, 20133 Milan, Italy.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Riva
authors.affiliation: Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Judith R
authors.identifier: 0000-0002-7621-1010
authors.initials: JR
authors.lastname: Homberg
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California 92037, Neurobiology of Addiction Section, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224.
authors.forename: George F
authors.initials: GF
authors.lastname: Koob
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California 92037.
authors.forename: Candice
authors.initials: C
authors.lastname: Contet
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000378:metabolism; D019970:Cocaine-Related Disorders / Q000378:metabolism* / Q000517:prevention & control*; D007275:Injections, Intravenous; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000008:administration & dosage* / Q000493:pharmacokinetics; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020813:Receptor, trkB; D012646:Self Administration / Q000379:methods; D016896:Treatment Outcome
chemical_list: D008562:Membrane Glycoproteins; D010456:Peptides, Cyclic; C554840:cyclotraxin-B; D011505:Protein-Tyrosine Kinases; D020813:Receptor, trkB; C000591259:tropomyosin-related kinase-B, human
keywords: BDNF; TrkB signaling; brain-derived neurotrophic factor; cocaine; cyclotraxin-B; dopamine system