Corticostriatal Afferents Modulate Responsiveness to Psychostimulant Drugs and Drug-Associated Stimuli (2015)

Neuropsychopharmacology. 2015 Aug 20. doi: 10.1038/npp.2015.253.

Kerstetter KA1, Wunsch AM1,2, Nakata KG1,2, Donckels E1, Neumaier JF2,3,4, Ferguson SM1,2,3.


The medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) are both integral components of the cortico-basal 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 Gi/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 prior to 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