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 3rd day. CART peptides were over-expressed on the 5th 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 induced-behavioral 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 (CART) Peptide Plays Critical Role in Psychostimulant-Induced Depression

“…Previous studies indicated that injection of GABA B R agonist baclofen or GABA B R positive allosteric modulators can attenuate self-administration and drug craving in ethanol-dependent rats and human alcoholics ( Addolorato et al ., 2006 ; Knapp et al ., 2007 ). Recently, we have shown the modulatory effect of intra-accumbally injected CART peptide on methamphetamine-induced depression of GABA B R-GIRK signaling and concomitant internalization and reduction of membrane GABA B R and GIRK receptors in the VTA and mPFC neurons ( Hu et al ., 2015 ), which suggests the regulatory targets of CART peptide are similar to those of the positive allosteric modulator GABA B R on GABA B1 R and GABA B2 R in the context of rescue from drug-depressed GABA B R-GIRK signaling ( Fig. 2 ).…”

“…Recently, CART peptide has been suggested to positively and allosterically modulate γ-aminobutyric acid B receptors (GABA B R), based on the observation that it inhibited drug-depressed GABA B R-G-protein-coupled inwardly rectifying K + -channel (GIRK) signaling. Thus, it has been suggested CART peptide modulates psychostimulant-induced hyperlo-comotion through DR-related calcium signaling and GABA-R-associated pathways ( Moffett et al ., 2011 ; Upadhya et al ., 2012 ; Cai et al ., 2014 ; Hu et al ., 2015 ; Fu et al ., 2016 ; Xiong et al ., 2018 ). However, our understanding of CART pathways in neuronal circuits is lacking.…”

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

“…Dopaminergic axons terminate on accumbal CART neurons (Smith et al, 1999;Upadhya et al, 2012). Dopamine D1, D2, and D3 receptors are expressed on these neurons (Beaudry et al, 2004;Hubert and Kuhar, 2006) and striatal CART expression is regulated by dopamine receptors (Beaudry et al, 2004;Hu et al, 2015;Hunter et al, 2006). Also, Leshan et al (2010) showed that some VTA neurons project to and regulate CART neurons in the AMG.…”

“…Leshan et al (2010) 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, 2004;Hu et al, 2015;Hunter et al, 2006).…”

Decreased Caffeine-Induced Locomotor Activity via Microinjection of CART Peptide into the Nucleus Accumbens Is Linked to Inhibition of the pCaMKIIa-D3R Interaction

“…In turn, CART peptides can regulate locomotor activity via dopamine receptor and cAMP/PKA/pCREB signaling pathway activities. Our previous report showed that cocaine- and caffeine-induced sensitization was expressed on the 5 th day of administration and that CREB phosphorylation and CART peptide expression peaked on the 5 th day [ 28 , 29 ]. In the present study, we examined the effects of CART peptides on locomotor activity and CREB phosphorylation on the 5 th day of caffeine administration.…”