Predominant D₁Receptors Involvement in the Over-expression of CART Peptides after Repeated Cocaine Administration

Abstract

The aim of this study was to investigate the involvement of dopaminergic receptors (DR) in behavioral sensitization, as measured by locomotor activity, and the over-expression of cocaine-and amphetamine-regulated transcript (CART) peptides after repeated administration of cocaine in mice. Repeated administrations of cocaine induced behavioral sensitization and CART over-expression in mice. The levels of striatal CART mRNA were significantly increased on the 3 rd day. CART peptides were over-expressed on the 5 th day in the striata of behaviorally sensitized mice. A higher proportion of CART ＋ cells in the cocaine-treated mice were present in the nucleus accumbens (NAc) shell than in the dorsolateral (DL) part of caudate putamen (CP). The concomitant administration of both D1R and D2R antagonists, SCH 23390 (D1R selective) and raclopride (D2R selective), blocked cocaine inducedbehavioral sensitization, CART over-expression, and cyclic adenosine 5'-monophosphate (cAMP)/ protein kinase A (PKA)/phospho-cAMP response element-binding protein (pCREB) signal pathways. SCH 23390 more predominantly inhibited the locomotor activity, CART over-expression, pCREB and PKA activity than raclopride. Cocaine induced-behavioral sensitization was also attenuated in the both D1R and D2R knockout (KO) mice, respectively. CART over-expression and activated cAMP/PKA/pCREB signal pathways were inhibited in the D1R-KO mice, but not in the D2R-KO mice. It is suggested that behavioral sensitization, CART over-expression and activated cAMP/PKA/pCREB signal pathways induced by repeated administration of cocaine could be more predominantly mediated by D1R.

Cocaine‐ and amphetamine‐regulated transcript peptide in the nucleus accumbens shell inhibits cocaine‐induced locomotor sensitization to transient over‐expression of α‐Ca2+/calmodulin‐dependent protein kinase II

“…Our laboratory previously observed that repeated cocaine exposure increased D1R and D2R expression, which led to the over‐expression of CART peptide (Hu et al . ). We also found reduced cocaine‐ and amphetamine‐enhanced D3R phosphorylation in the NAc after microinjection of CART peptide (Cai et al .…”

“…; Hu et al . ). Ca 2+ binds to calmodulin ( CAM ) and activates Ca 2+ /calmodulin‐dependent protein kinase II α (Ca MKII α) (White et al .…”

Nicotine regulates cocaine‐amphetamine‐Regulated Transcript (Cart) in the mesocorticolimbic system

“…Leshan et al () showed that a subclass of VTA dopaminergic neurons project to and regulate CART neurons in the CeA. Furthermore, there are studies suggesting either an up‐regulatory effect of D1, D2, and D3 receptors or a down‐regulatory effect of D3 receptor on CART expression (Beaudry et al, ; Hu et al, ; Hunter et al, ).…”

“…Dopaminergic axons terminate on accumbal CART neurons (Smith et al, ; Upadhya et al, ). Dopamine D1, D2, and D3 receptors are expressed on these neurons (Beaudry et al, ; Hubert and Kuhar, ) and striatal CART expression is regulated by dopamine receptors (Beaudry et al, ; Hu et al, ; Hunter et al, ). Also, Leshan et al () showed that some VTA neurons project to and regulate CART neurons in the AMG.…”