Korean J Physiol Pharmacol.  2015 Mar;19(2):89-97. 10.4196/kjpp.2015.19.2.89.

Predominant D1 Receptors Involvement in the Over-expression of CART Peptides after Repeated Cocaine Administration

• Hu Z
• Oh EH
• Chung YB
• Hong JT
• Oh KW

• KMID: 2285559
• DOI: http://doi.org/10.4196/kjpp.2015.19.2.89

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.

Keyword

cAMP; cAMP/PKA/pCREB signal pathways; CART; Cocaine; Dopamine receptors

MeSH Terms

Adenosine
Animals
Cocaine*
Mice
Motor Activity
Nucleus Accumbens
Peptides*
Phosphotransferases
Putamen
Raclopride
Receptors, Dopamine
RNA, Messenger
Signal Transduction
Adenosine
Cocaine
Peptides
Phosphotransferases
RNA, Messenger
Raclopride
Receptors, Dopamine

Figure

• 

  Fig. 1 Effects of cocaine (5, 15 and 30 mg/kg) on the locomotor activity of mice for 7 days. The data are given as the means±SEM of at least 8 mice. ##p<0.01 and ###p<0.001, compared with that of the saline group. *p<0.05, **p<0.01 and ***p<0.001, compared with that of the cocaine group on the 1st day.

• 

  Fig. 2 Effects of cocaine on the levels of CART peptides mRNA in the striatum of mice. (A) Effects on the level of CART mRNA at different doses of cocaine (5, 15 and 30 mg/kg) on the 5th day. (B) Effects on the level of CART mRNA at different time points (3rd, 5th, 7th and 14th days) for the most effective dose of cocaine (15 mg/kg). (C) Effects on the level of CART peptides for different doses of cocaine (5, 15 and 30 mg/kg). (D) Effects on the level of CART peptides at different time points (3rd, 5th, 7th and 14th days) for the most effective dose of cocaine (15 mg/kg). A quantitative analysis was conducted by measuring the relative densitometry (OD) of the immunoreactive signal between preproCART and GAPDH. Data are given as the means±SEM of 4 mice. The total ninety six mice were used for the measurement of CART mRNA and protein levels. *p<0.05 and **p<0.01, compared with that of the control (saline) group.

• 

  Fig. 3 Effects of cocaine on the 5th day on the proportion of CART+ cells in the mouse striatum (A~D). Plot of the proportion of striatial CART+ cells through the NAc shell (A), DL part of CP (C), NAc core (B) and VL (D) part of CP immunolabeled for CART from mice treated with cocaine (15 mg/kg). Data are given as the means±SEM of 4 mice. The total eight mice were used. ***p<0.001, compared with that of the control (saline) group.

• 

  Fig. 4 Effects of SCH 23390 (0.25 mg/kg) and raclopride (0.4 mg/kg) on cocaine (15 mg/kg)-induced locomotor, CART expression, cAMP levels, PKA activity, and pCREB levels in the mice striatum. (A) Cocaine was administered in mice one time per day for 5 days. The locomotor activity was measured using the tilting-type ambulometer. (B) The cAMP levels were measured using the competition enzyme-linked immunoassay (ELISA). (C) After PKA was purified by immunoprecipitation, the PKA activity was measured using a radiometric assay. The CART levels (D), CREB phosphorylation (E), and (F) CREB levels were observed using western blotting. A quantitative analysis was conducted by measuring the relative OD of the immunoreactive signal for preproCART, pCREB, CREB, and GAPDH. Data represent the means±SEM of 4 mice. The total twenty mice were used. **p<0.01 and ***p<0.001, compared with that of the control (saline) group; ##p<0.01 and ###p<0.001, compared with that of the cocaine group; +p<0.001 and +++p<0.001, compared with that of the raclopride group.

• 

  Fig. 5 Effects in WT mice and D1R-KO mice treated with cocaine (15 mg/kg) on the 5th day on locomotor activity (A), cAMP levels (B), PKA activity (C), CART levels (D), pCREB levels (E), CREB levels (F). A quantitative analysis was conducted by measuring the relative OD of the immunoreactive signal for preproCART, pCREB, CREB, and GAPDH. Data are given as the means±SEM of 4~5 mice. The total twenty mice were used. **p<0.01 and ***p<0.001, compared with that of the control (saline) group; #p<0.05, ##p<0.01 and ###p<0.001, compared with that of the WT or KO mice group.

• 

  Fig. 6 Effects in WT mice and D2R-KO mice treated with cocaine (15 mg/kg) on the 5th day on locomotor activity (A), cAMP levels (B), PKA activity (C), CART levels (D), pCREB levels (E), CREB levels (F). Quantitative analysis was conducted by measuring the relative OD of the immunoreactive signal for prepro CART, pCREB, CREB, and GAPDH. Data represent the means±SEM of 3~4 mice. The total sixteen mice were used. *p<0.05, **p<0.01 and ***p<0.001, compared with that of the control (saline) group; #p<0.05, compared with that of the KO or WT mice.

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