CREB-Binding Protein Regulates Cocaine- and Amphetamine-Regulated Transcript Peptide Expression in the Lateral Hypothalamus: Implication in Reward and Reinforcement

Abstract

Neuropeptide cocaine- and amphetamine-regulated transcript peptide (CARTp) is known to play an important role in reward processing. The rats conditioned to intra-cranial self-stimulation (ICSS) showed massive upregulation of CART protein and mRNA in the vicinity of the electrode implanted to deliver the electric current directly at the lateral hypothalamus (LH)-medial forebrain bundle (MFB) area. However, the underlying mechanisms leading to the upregulation of CART in ICSS animals remain elusive. We tested the putative role of CREB-binding protein (CBP), an epigenetic enzyme with intrinsic histone acetyltransferase (HAT) activity, in regulating CART expression during ICSS. An electrode was implanted in LH-MFB and the rats were conditioned to self-stimulation in an operant chamber. CBP siRNA was delivered ipsilaterally in the LH-MFB to knock-down CBP and the effects on lever press activity were monitored. While ICSS-conditioned rats showed distinct increase in CART, CBP and pCREB levels, enhanced CBP binding and histone acetylation (H3K9ac) were noticed on the CART promoter in chromatin immunoprecipitation assay. Direct infusion of CBP siRNA in the LH-MFB lowered lever press activity, CBP levels, histone acetylation at the CART promoter, and CART mRNA and peptide expression. Co-infusion of CARTp in LH-MFB rescued the waning effects of CBP siRNA on self-stimulation. We suggest that CBP-mediated histone acetylation may play a causal role in CART expression in LH, which in turn may drive the positive reinforcement of lever press activity.