Cocaine-seeking is associated with PKC-dependent reduction of excitatory signaling in accumbens shell D2 dopamine receptor-expressing neurons.
Stimulation of D1-like dopamine receptors (D1DRs) or D2-like dopamine receptors (D2DRs) in the nucleus accumbens (NAc) shell reinstates cocaine seeking in rats, an animal model of relapse. D2DRs and D1DRs activate protein kinase C (PKC) and recent studies indicate that activation of PKC in the NAc plays an important role in the reinstatement of drug seeking induced by a systemic cocaine priming injection. In the present study, pharmacological inhibition of PKC in the NAc shell attenuated cocaine seeking induced by intra-accumbens shell microinjection of a D2DR agonist, but not a D1DR agonist. D1DRs and D2DRs are primarily expressed on different accumbens medium spiny (MSN) neurons. Neuronal signaling and activity were assessed in these two populations of NAc neurons with transgenic mice expressing fluorescent labels under the control of D1DR and D2DR promoters. Following the extinction of cocaine self-administration, bath application of a PKC inhibitor produced similar effects on single evoked excitatory and inhibitory post-synaptic currents in D1DR- and D2DR-positive MSNs in the NAc shell. However, inhibition of PKC preferentially improved the ability of excitatory, but not inhibitory, synapses to sustain responding to brief train of stimuli specifically in D2DR-positive MSNs. This effect did not appear to involve modulation of presynaptic release mechanisms. Taken together, these findings indicate that the reinstatement of cocaine seeking is at least partially due to D2DR-dependent increases in PKC signaling in the NAc shell, which reduce excitatory synaptic efficacy in D2DR-expressing MSNs.
['Ortinski|Pavel I|PI|', 'Briand|Lisa A|LA|', 'Pierce|R Christopher|RC|', 'Schmidt|Heath D|HD|']
D000200:Action Potentials D000818:Animals D053119:Benzophenanthridines D003042:Cocaine D003216:Conditioning, Operant D015259:Dopamine Agents D018765:Dopamine Uptake Inhibitors D058999:Drug-Seeking Behavior D004791:Enzyme Inhibitors D005108:Extinction, Psychological D049452:Green Fluorescent Proteins D007211:Indoles D008297:Male D051379:Mice D008822:Mice, Transgenic D009474:Neurons D009714:Nucleus Accumbens D011493:Protein Kinase C D051381:Rats D017207:Rats, Sprague-Dawley D017448:Receptors, Dopamine D2 D055366:Synaptic Potentials
Dopamine Relapse Self-administration Addiction EPSCs Electrophysiology IPSCs Striatum