Systemic Delivery of a Brain-Penetrant TrkB Antagonist Reduces Cocaine Self-Administration and Normalizes TrkB Signaling in the Nucleus Accumbens and Prefrontal Cortex

摘要: Cocaine exposure alters brain-derived neurotrophic factor (BDNF) expression in the brain. BDNF signaling through TrkB receptors differentially modulates cocaine self-administration, depending on brain regions involved. In present study, we determined how brain-wide inhibition of affects intake, motivation for drug, and reinstatement drug taking after extinction. To overcome inability ligands to cross blood–brain barrier, antagonist cyclotraxin-B was fused nontoxic transduction domain tat protein from human immunodeficiency virus type 1 (tat-cyclotraxin-B). Intravenous injection tat-cyclotraxin-B dose-dependently reduced (as measured under a progressive ratio schedule reinforcement), rats allowed either short or long access self-administration. contrast, treatment did not affect operant responding highly palatable sweet solution, demonstrating that effects are specific reinforcement. self-administration increased activated downstream Akt pathway nucleus accumbens, had opposite prefrontal cortex. Pretreatment with normalized levels these two dopamine-innervated regions. also ventral tegmental area, where dopaminergic projections originate, but pretreatment alter this effect. Altogether, our data show systemic administration brain-penetrant leads region-specific may be potential pharmacological strategy addiction. SIGNIFICANCE STATEMENT Brain-derived plays well established role However, local manipulation yields divergent effects, region, thereby questioning viability targeting use disorders. Our study provides first-time evidence (tat-cyclotraxin-B) reduces several behavioral measures dependence, without altering motor performance reinforcement by solution. addition, although produced accumbens cortex, cocaine-induced changes both