Corticostriatal Afferents Modulate Responsiveness to Psychostimulant Drugs and Drug-Associated Stimuli

Neuropsychopharmacology. 2016 Mar;41(4):1128-37. doi: 10.1038/npp.2015.253. Epub 2015 Aug 20.


The medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) are both integral components of the corticobasal ganglia-thalamic circuitry that regulates addiction-related behaviors. However, the role of afferent inputs from mPFC to NAc in these behaviors is unclear. To address this, we used a Cre-recombinase-dependent viral vector approach to express G(i/o)-coupled DREADDs (designer receptors exclusively activated by designer drugs) selectively in mPFC neurons projecting to the NAc and examined the consequences of attenuating activity of these neurons on the induction of amphetamine sensitization and on drug taking and drug seeking during cocaine self-administration. Surprisingly, decreasing mPFC afferent activity to the NAc only transiently reduced locomotor sensitization and had no effect on drug taking during cocaine self-administration. However, inhibiting corticostriatal afferent activity during sensitization subsequently enhanced conditioned responding. In addition, this manipulation during drug self-administration resulted in slower rates of extinction and increased responding during drug prime-induced reinstatement-an effect that was normalized by inhibiting these corticostriatal afferents immediately before the drug prime. These results suggest that dampening cortical control over the NAc during drug exposure may lead to long-term changes in the ability of drugs and associated stimuli to drive behavior that has important implications for guiding treatments to prevent relapse.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amphetamine / administration & dosage*
  • Animals
  • Central Nervous System Stimulants / administration & dosage*
  • Cocaine / administration & dosage*
  • Cues
  • Drug-Seeking Behavior / physiology*
  • Extinction, Psychological / drug effects
  • Extinction, Psychological / physiology
  • Genetic Vectors
  • Male
  • Motor Activity / drug effects
  • Neural Pathways / drug effects
  • Neural Pathways / physiology
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / physiology*
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / physiology*
  • Rats, Long-Evans
  • Rats, Sprague-Dawley
  • Receptor, Muscarinic M4 / genetics
  • Receptor, Muscarinic M4 / physiology
  • Self Administration


  • Central Nervous System Stimulants
  • Receptor, Muscarinic M4
  • Amphetamine
  • Cocaine