Chronic loss of noradrenergic tone produces β‐arrestin2‐mediated cocaine hypersensitivity and alters cellular D 2 responses in the nucleus accumbens

Cocaine blocks plasma membrane monoamine transporters and increases extracellular levels of dopamine ( DA ), norepinephrine ( NE ) and serotonin (5‐ HT ). The addictive properties of cocaine are mediated primarily by DA , while NE and 5‐ HT play modulatory roles. Chronic inhibition of dopamine β‐hydroxylase ( DBH ), which converts DA to NE , increases the aversive effects of cocaine and reduces cocaine use in humans, and produces behavioral hypersensitivity to cocaine and D 2 agonism in rodents, but the underlying mechanism is unknown. We found a decrease in β‐arrestin2 (β A rr2) in the nucleus accumbens ( NAc ) following chronic genetic or pharmacological DBH inhibition, and overexpression of β A rr2 in the NAc normalized cocaine‐induced locomotion in DBH knockout ( D bh − / −) mice. The D 2/3 agonist quinpirole decreased excitability in NAc medium spiny neurons ( MSNs ) from control, but not D bh − / − animals, where instead there was a trend for an excitatory effect. The G α i inhibitor NF 023 abolished the quinpirole‐induced decrease in excitability in control MSNs , but had no effect in D bh − / − MSNs , whereas the G α s inhibitor NF 449 restored the ability of quinpirole to decrease excitability in D bh − / − MSNs , but had no effect in control MSNs . These results suggest that chronic loss of noradrenergic tone alters behavioral responses to cocaine via decreases in β A rr2 and cellular responses to D 2/ D 3 activation, potentially via changes in D 2‐like receptor G ‐protein coupling in NAc MSNs .