Dopamine D1 receptors, regulation of gene expression in the brain, and neurodegeneration

Abstract

Dopamine (DA), the most abundant catecholamine in the basal ganglia, participates in the regulation of motor functions and of cognitive processes such as learning and memory. Abnormalities in dopaminergic systems are thought to be the bases for some neuropsychiatric disorders including addiction, Parkinson's disease, and Schizophrenia. DA exerts its arrays of functions via stimulation of D1-like (D1 and D5) and D2-like (D2, D3, and D4) DA receptors which are located in various regions of the brain. The DA D1 and D2 receptors are very abundant in the basal ganglia where they exert their functions within separate neuronal cell types. The present paper focuses on a review of the effects of stimulation of DA D1 receptors on diverse signal transduction pathways and gene expression patterns in the brain. We also discuss the possible involvement of the DA D1 receptors in DA-mediated toxic effects observed both in vitro and in vivo. Future studies using more selective agonist and antagonist agents and the use of genetically modified animals should help to further clarify the role of these receptors in the normal physiology and in pathological events that involve DA.

Fig. 1. Quantitative PCR analyses of SCH23390-mediated inhibition of METH-induced expression of AP1 transcription factors

The levels of mRNA were measured by real-time quantitative PCR; mRNA levels were normalized to 18s RNA. Data represent means ± SEM of fold changes relative to the controls (n = 6 rats per group). Statistical significance was determined by ANOVA followed by protected least-squares difference (PLSD). $ = p <0.05, M vs. C; # = p < 0.05, M vs. M + S. Abbreviations are C, control; S, SCH23390; M, methamphetamine, and M + S, methamphetamine plus SCH23390.

Fig. 2. Quantitative PCR analyses of the effects of METH and SCH23390 on the expression of Egr family of transcription factors

The levels of mRNA were measured by real-time quantitative PCR; mRNA levels were normalized to 18s RNA. Data represent means ± SEM of fold changes relative to the controls (n = 6 rats per group). Statistical significance was determined by ANOVA followed by protected least-squares difference (PLSD). $ = p <0.05, M vs. C; # = p < 0.05, M vs. M + S. Abbreviations are C, control; S, SCH23390; M, methamphetamine, and M + S, methamphetamine plus SCH23390.

Fig. 3. Quantitative PCR analyses of the effects of METH and SCH23390 on the expression of Nr4a family of transcription factors

The levels of mRNA were measured by real-time quantitative PCR; mRNA levels were normalized to 18s RNA. Data represent means ± SEM of fold changes relative to the controls (n = 6 rats per group). Statistical significance was determined by ANOVA followed by protected least-squares difference (PLSD). $ = p <0.05, M vs. C; # = p < 0.05, M vs. M + S. Abbreviations are C, control; S, SCH23390; M, methamphetamine, and M + S, methamphetamine plus SCH23390.

Fig. 4. Quantitative PCR analyses of the effects of METH and SCH23390 on the expression of Arc, Icer, and Nab2

The levels of mRNA were measured by real-time quantitative PCR; mRNA levels were normalized to 18s RNA. Data represent means ± SEM of fold changes relative to the controls (n = 6 rats per group). Statistical significance was determined by ANOVA followed by protected least-squares difference (PLSD). $ = p <0.05, M vs. C; # = p < 0.05, M vs. M + S. Abbreviations are C, control; S, SCH23390; M, methamphetamine, and M + S, methamphetamine plus SCH23390.