Skip to Main content Skip to Navigation
Journal articles

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 tegmen-tal 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.
Complete list of metadatas

Cited literature [4 references]  Display  Hide  Download

https://www.hal.inserm.fr/inserm-02472228
Contributor : Maxim Cazorla <>
Submitted on : Monday, February 10, 2020 - 9:56:03 AM
Last modification on : Tuesday, February 11, 2020 - 1:06:37 AM

File

Contet C (2016, JNS).pdf
Publisher files allowed on an open archive

Identifiers

Collections

UGA

Citation

Michel Verheij, Leandro Vendruscolo, Lucia Caffino, Giuseppe Giannotti, Maxime Cazorla, et al.. Systemic Delivery of a Brain-Penetrant TrkB Antagonist Reduces Cocaine Self-Administration and Normalizes TrkB Signaling in the Nucleus Accumbens and Prefrontal Cortex. Journal of Neuroscience, Society for Neuroscience, 2016, 3 (36), pp.8149-8159. ⟨10.1523/JNEUROSCI.2711-14.2016⟩. ⟨inserm-02472228⟩

Share

Metrics

Record views

48

Files downloads

50