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Chronic loss of noradrenergic tone produces β‐arrestin2‐mediated cocaine hypersensitivity and alters cellular D 2 responses in the nucleus accumbens
Author(s) -
GavalCruz Meriem,
Goertz Richard B.,
Puttick Daniel J.,
Bowles Dawn E.,
Meyer Rebecca C.,
Hall Randy A.,
Ko Daijin,
Paladini Carlos A.,
Weinshenker David
Publication year - 2016
Publication title -
addiction biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.445
H-Index - 78
eISSN - 1369-1600
pISSN - 1355-6215
DOI - 10.1111/adb.12174
Subject(s) - quinpirole , nucleus accumbens , dopamine , agonist , chemistry , pharmacology , autoreceptor , endocrinology , medicine , medium spiny neuron , monoamine neurotransmitter , neuroscience , serotonin , dopamine receptor d2 , biology , receptor , striatum
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 .