Increased dopamine transporter function as a mechanism for dopamine hypoactivity in the adult infralimbic medial prefrontal cortex following adolescent social stress

Neuropharmacology. 2015 Oct;97:194-200. doi: 10.1016/j.neuropharm.2015.05.032. Epub 2015 Jun 6.

Abstract

Being bullied during adolescence is associated with later mental illnesses characterized by deficits in cognitive tasks mediated by prefrontal cortex (PFC) dopamine (DA). Social defeat of adolescent male rats, as a model of teenage bullying victimization, results in medial PFC (mPFC) dopamine (DA) hypofunction in adulthood that is associated with increased drug seeking and working memory deficits. Increased expression of the DA transporter (DAT) is also seen in the adult infralimbic mPFC following adolescent defeat. We propose the functional consequence of this increased DAT expression is enhanced DA clearance and subsequently decreased infralimbic mPFC DA availability. To test this, in vivo chronoamperometry was used to measure changes in accumulation of the DA signal following DAT blockade, with increased DAT-mediated clearance being reflected by lower DA signal accumulation. Previously defeated rats and controls were pre-treated with the norepinephrine transporter (NET) inhibitor desipramine (20 mg/kg, ip.) to isolate infralimbic mPFC DA clearance to DAT, then administered the selective DAT inhibitor GBR-12909 (20 or 40 mg/kg, sc.). Sole NET inhibition with desipramine produced no differences in DA signal accumulation between defeated rats and controls. However, rats exposed to adolescent social defeat demonstrated decreased DA signal accumulation compared to controls in response to both doses of GBR-12909, indicating greater DAT-mediated clearance of infralimbic mPFC DA. These results suggest that protracted increases in infralimbic mPFC DAT function represent a mechanism by which adolescent social defeat stress produces deficits in adult mPFC DA activity and corresponding behavioral and cognitive dysfunction.

Keywords: Adolescent stress; Dopamine; Dopamine transporter; Prefrontal cortex.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adrenergic Uptake Inhibitors / pharmacology
  • Animals
  • Desipramine / pharmacology
  • Disease Models, Animal
  • Dominance-Subordination
  • Dopamine / metabolism
  • Dopamine Plasma Membrane Transport Proteins / antagonists & inhibitors
  • Dopamine Plasma Membrane Transport Proteins / metabolism*
  • Dopamine Uptake Inhibitors / pharmacology
  • Dose-Response Relationship, Drug
  • Male
  • Norepinephrine Plasma Membrane Transport Proteins / antagonists & inhibitors
  • Norepinephrine Plasma Membrane Transport Proteins / metabolism
  • Piperazines / pharmacology
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / growth & development*
  • Prefrontal Cortex / metabolism*
  • Rats, Sprague-Dawley
  • Stress, Psychological / metabolism*

Substances

  • Adrenergic Uptake Inhibitors
  • Dopamine Plasma Membrane Transport Proteins
  • Dopamine Uptake Inhibitors
  • Norepinephrine Plasma Membrane Transport Proteins
  • Piperazines
  • Slc6a2 protein, rat
  • vanoxerine
  • Desipramine
  • Dopamine