Persistent changes in motivation to self-administer cocaine following modulation of cyclic AMP-dependent protein kinase A (PKA) activity in the nucleus accumbens.
Drug-induced neuroadaptations within the nucleus accumbens, including activation of cAMP-dependent protein kinase A (PKA), may contribute to the synaptic plasticity and behavioural changes that underlie drug addiction. As a direct test of this hypothesis, we examined the effects in rats of PKA activation (Sp-cAMPS infusions of 10 and 20 nmol/side) and inhibition (Rp-cAMPS infusions of 10 and 20 nmol/side) in the nucleus accumbens on motivation to obtain cocaine as measured by responding under the progressive-ratio schedule. Bilateral infusions of Sp-cAMPS (20 nmol/side) resulted in an increase in progressive-ratio responding for cocaine and this effect persisted for several days. In contrast, Rp-cAMPS (20 nmol/side) produced persistent decreases in progressive-ratio responding for cocaine beginning on the day of administration and lasting for several days. These data suggest that alternations in PKA activity within the nucleus accumbens as a consequence of repeated cocaine exposure may contribute to addiction by producing persistent increases in motivation to obtain cocaine.
Lynch
W J
WJ
Department of Psychiatry, Yale University School of Medicine, CMHC, Abraham Ribicoff Research Facilities, 34 Park Street, New Haven, CT 06508, USA. wendy.lynch@yale.edu
Taylor
J R
JR
D000779:Anesthetics, Local / Q000008:administration & dosage*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003042:Cocaine / Q000008:administration & dosage*; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004789:Enzyme Activation / Q000187:drug effects; D008297:Male; D009042:Motivation; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012646:Self Administration; D013997:Time Factors
D000779:Anesthetics, Local; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D003042:Cocaine