Chronic treatment with certain antipsychotic drugs preserves upregulation of regulator of G-protein signalling 2 mRNA in rat striatum as opposed to c-fos mRNA

doi:10.1016/S0304-3940(01)01923-1

Neuroscience Letters

Volume 307, Issue 1, 6 July 2001, Pages 45-48

https://doi.org/10.1016/S0304-3940(01)01923-1 Get rights and content

Abstract

Quantitative in situ hybridization on rat coronal brain sections with radiolabelled oligonucleotide probes was performed to investigate the effects of antipsychotic drugs on mRNA levels of regulator of G-protein signalling (RGS) 2 and c-fos. This study demonstrated a similar increase of RGS2 mRNA level in the striatum upon both a single and a 21-day treatment with either haloperidol (2 mg/kg) or risperidone (7.5 mg/kg) in contrast to clozapine (20 mg/kg). Otherwise, the acute c-fos mRNA induction in the striatum was abolished by 74 to 89% upon chronic treatment with either haloperidol or risperidone. In conclusion, the induction of RGS2 mRNA in the striatum, in contrast to the immediate early gene c-fos mRNA, is preserved upon chronic treatment with haloperidol and risperidone.

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Regulator of G-protein signaling (RGS) proteins interact with α subunits of heterotrimeric G-proteins via the RGS domain and attenuate their activity by accelerating GTPase activity. RGS2, a member of the RGS family, regulates synaptic development via hereto unknown mechanism. In this study, we found that RGS2 directly interacted with tubulin via a short region at the N-terminus: amino acids 41–60. RGS2 enhanced microtubule polymerization in vitro, and the tubulin binding region was necessary and sufficient for this activity. In Vero cells, polymerization of microtubule was stimulated when peptides containing the tubulin binding region were microinjected. Immunocytochemical analysis showed that endogenous RGS2 was localized at the termini of neurites in differentiated PC12 cells. Over-expression of RGS2 enhanced the nerve growth factor-induced neurite outgrowth in PC12 cells, while specific knock-down of endogenous RGS2 suppressed the neurite outgrowth. These findings demonstrate that RGS2 contributes to the neuronal cell differentiation via regulation of microtubule dynamics.
Dopamine-D1 and -D2 receptors differentially regulate synapsin II expression in the rat brain
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We previously demonstrated that chronic treatment with the dopamine-D2 receptor antagonist, haloperidol, increases mRNA and protein content of the phosphoprotein, synapsin II, in the rat striatum. Since dopamine-D2 receptor antagonism and dopamine-D1 receptor blockade can have opposing effects on gene expression, the present investigation compared the effects of haloperidol with those of the dopamine-D1 receptor antagonist, R-[+]-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH23390), on the expression of synapsin II protein. Haloperidol and SCH23390 respectively elevated and reduced concentrations of the molecule in mouse primary midbrain cell cultures. Additional experiments revealed that the dopamine-D1 receptor agonist, R-[+]-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzapezine-7,8-diol (SKF38393), upregulated the phosphoprotein in these cells. Furthermore, in vivo rat studies demonstrated that chronic haloperidol treatment increases synapsin II protein expression in the medial prefrontal cortex and nucleus accumbens, as was observed in the striatum. In contrast, chronic SCH23390 administration reduced concentrations of this protein in all of these regions, although the reductions seen in the medial prefrontal cortex were insignificant. Neither haloperidol nor the dopamine-D1 receptor antagonist affected synapsin I protein expression in any of the studied brain areas. Based on these findings, we propose dopamine receptors may specifically regulate synapsin II expression through a cyclic AMP-dependent pathway. Since synapsin II is involved in neurotransmitter release and synaptogenesis, and changes in synaptic efficacy and structure are suggested in schizophrenia as well as in haloperidol treatment, our findings offer insight into the mechanistic actions of the antipsychotic agent at the synaptic level.
Altered expression of regulators of G-protein signaling (RGS) mRNAs in the striatum of rats undergoing dopamine depletion
2003, Biochemical Pharmacology
Citation Excerpt :
While some of them—mainly RGS2—are now well characterized for their acute regulation by a variety of drugs (including dopamine receptor antagonists, amphetamine and opioids) [16–23], their modulation after long-term injury or chronic pharmacological treatments remains poorly described. Recent papers, particularly concerning the central dopamine system, suggest a potential role of RGS proteins in long-term adaptation processes observed in response to pharmacological treatment [24,25] or occurring during the development of neurodegenerative diseases [26]. In the present study we have used in situ hybridization to measure the mRNA levels of several RGS proteins in the striatum of rats after either 6-hydroxydopamine-mediated denervation of the nigrostriatal pathway or reserpine-induced monoamine depletion.
Quantitative in situ hybridization was used to investigate the effect of prolonged striatal dopamine or monoamine depletion on the mRNA density of regulators of G-protein signaling (RGS) 2–12 proteins. Two types of treatments were studied: a 6-hydroxydopamine-induced unilateral lesion of the nigrostriatal pathway and a 5-day reserpine treatment. The results clearly show a selective increase in the mRNA levels of RGS2, 5 and 8 and a decrease in RGS4 and 9 mRNA levels following nigrostriatal denervation. In this model, we observed no change in the mRNA levels of RGS10 and other RGS proteins that are weakly expressed in the striatum (RGS3, 6, 7, 11 and 12). On the other hand, the mRNA levels RGS2, 4, 5, 8, 9 and 10 were found to be significantly decreased after prolonged reserpine treatment. In contrast, the densities of these transcripts (in particular, RGS2, 4 and 10) tend to increase after an acute administration of reserpine, used as control. These results provide further evidence for the influence of dopamine and/or other monoamines in the regulation of RGS protein expression in the striatum. In connection with the previously documented acute regulation of RGS proteins after modulation of the dopaminergic transmission [Geurts et al., Neurosci Lett 2002;333:146–50], the present study demonstrates that alteration in their genetic expression can be long-lasting and this could reflect the adaptation processes that occur in certain pathological states, such as Parkinson’s disease.
Opposite modulation of regulators of G protein signalling-2 (RGS2) and RGS4 expression by dopamine receptors in the rat striatum
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The role of dopaminergic transmission on striatal mRNA levels of regulators of G protein signalling proteins (RGS 2–12) was evaluated by quantitative in situ hybridisation. A single injection of l-dopa (50 mg/kg i.p.) significantly increased the RGS2 mRNA level (by 25%), an effect that was specifically abolished by the D1 dopamine receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (R(+)-SCH23390), but not changed by S(−)-eticlopride. Interestingly, the administration of this D2 dopamine receptor antagonist alone markedly enhanced the expression of RGS2 (by 71%), which suggests a constitutive inhibition of RGS2 expression by D2 dopamine receptors. Opposite results were obtained concerning the regulation of RGS4 since l-dopa alone was without effect whereas co-administration of l-dopa and R(+)-SCH23390 significantly enhanced the RGS4 mRNA levels (by 38%). In conclusion, D1 and D2 dopamine receptors appear to mediate opposite regulatory effects on RGS2 and RGS4 expression in the striatum.
Canonical and Non-Canonical Antipsychotics’ Dopamine-Related Mechanisms of Present and Next Generation Molecules: A Systematic Review on Translational Highlights for Treatment Response and Treatment-Resistant Schizophrenia
2023, International Journal of Molecular Sciences
Antipsychotics-Induced Changes in Synaptic Architecture and Functional Connectivity: Translational Implications for Treatment Response and Resistance
2022, Biomedicines

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Chronic treatment with certain antipsychotic drugs preserves upregulation of regulator of G-protein signalling 2 mRNA in rat striatum as opposed to c-fos mRNA

Abstract

Trends Pharmacol. Sci.

Brain Res. Mol. Brain Res.

Neurochem. Int.

Curr. Biol.

Regulators of G protein signaling: rapid changes in mRNA abundance in response to amphetamine

J. Neurochem.

RGS mRNA expression in rat striatum: modulation by dopamine receptors and effects of repeated amphetamine administration

J. Neurochem.

Regulators of G protein signaling: A bestiary of modular protein binding domains

J. Neurochem.

Atypical antipsychotics: an inspiring but confusing concept

Psychopharmacology (Berl.)