The blocking of kappa-opioid receptor reverses the changes in dorsolateral striatum dopamine dynamics during the amphetamine sensitization

Abstract

Kappa-opioid receptors (KOR) control dopamine (DA) levels in the striatum and contribute significantly to the progression of drug addiction. Repeated exposure to psychostimulants has been associated with up-regulated KOR activity and increased DA levels in dorsal striatum. However, it has not been tested if both processes are linked. In this work, we studied if a mechanism mediated by KOR is contributing to the increase in DA levels in the dorsolateral striatum (DLS) after amphetamine (AMPH) sensitization. The AMPH sensitization was assessed after single or repeated once-a-day AMPH injections (1 mg/kg). Only repeated AMPH exposure produced a significant locomotor sensitization. No-net flux microdialysis was used to assess basal DA dialysate, DA extracellular concentration (C_ext ), and DA uptake in DLS of anesthetized rats. The role of KOR on DA dynamics in DLS was evaluated by local perfusion (250 μM) and systemic administration (10 mg/kg) of the KOR antagonist nor-binaltorphimine. A significant decrease in DA C_ext is observed in the DLS after an AMPH challenge in rats exposed to a single dose of AMPH. The decrease in DA C_ext was associated with both a decreased basal DA dialysate and an increased DA uptake. Conversely, the expression of AMPH sensitization was accompanied by a significant increase in DA C_ext associated with an increased basal DA dialysate and an attenuation in DA uptake. Both local and systemic administration of nor-binaltorphimine reversed changes in DLS after AMPH pre-treatment. These findings indicate that endogenous KOR system tunes DLS DA dynamics during the progression to AMPH sensitization.

Keywords: amphetamine sensitization; dopamine; dorsolateral striatum; kappa-opioid receptor; no-net flux microdialysis.