Antipsychotic-induced DRD2 up-regulation and its prevention by alpha-lipoic acid in SH-SY5Y neuroblastoma cells.

Deslauriers J, LefranÃ§ois M, Larouche A, Sarret P, Grignon S

Antipsychotic-induced DRD2 up-regulation and its prevention by alpha-lipoic acid in SH-SY5Y neuroblastoma cells.

Synapse. 2010 Aug 20;

Authors: Deslauriers J, LefranÃ§ois M, Larouche A, Sarret P, Grignon S

Most antipsychotic drugs are dopamine D2 receptor (DRD2) antagonists and remain the main pharmacological treatment of schizophrenia. Long-term antipsychotic use can give rise to tardive dyskinesia. It has been reported that chronic treatment with antipsychotics induces DRD2 up-regulation and oxidative stress, which have been associated with tardive dyskinesia. We showed previously that H(2)O(2)-induced oxidative stress increased DRD2 expression in human SH-SY5Y neuroblastoma cells. We report here the effects of antipsychotic drugs on DRD2 expression levels in the same cell line and the effects of the inhibition of oxidative phenomena by (+/-)-alpha-Lipoic acid treatment. Haloperidol, a first-generation antipsychotic, induced an increase in DRD2 protein and mRNA levels, while amisulpride, a second-generation antipsychotic, had no significant effect. (+/-)-alpha-Lipoic acid pre-treatment reversed the haloperidol-induced DRD2 up-regulation in mRNA and protein levels. Furthermore, haloperidol induced a larger increase of oxidative stress biomarkers (protein carbonylation, lipid peroxidation and superoxide anion production) than amisulpride. (+/-)-alpha-Lipoic acid also attenuated antipsychotic-induced oxidative stress. Inhibition of catecholamine synthesis by alpha-methyl-DL-tyrosine (AMPT) increased DRD2 expression and prevented further increase by antipsychotics. Our results suggest that haloperidol-induced DRD2 up-regulation is linked to oxidative stress and provide potential mechanisms by which (+/-)-alpha-Lipoic acid can be considered as a therapeutic agent to prevent and treat side effects related to the use of first-generation antipsychotics. (c) 2010 Wiley-Liss, Inc.

PMID: 20730801 [PubMed - as supplied by publisher]

Acute and long-term response of dopamine nigrostriatal synapses to a single low dose episode of 3-nitropropionic acid-mediated chemical hypoxia.

Acute and long-term response of dopamine nigrostriatal synapses to a single low dose episode of 3-nitropropionic acid-mediated chemical hypoxia.

Synapse. 2010 Aug 20;

Authors: Crawford CA, Akopian G, Ring J, Jakowec MW, Petzinger GM, Andersen JK, Vittozzi-Wong P, Wang K, Farley CM, Charntikov S, Mitroi D, Beal MF, Chow R, Walsh JP

The goal of the present investigation was to determine the persistence of striatal dopaminergic dysfunction after a mild chemically-induced hypoxic event in Fisher 344 rats. To this end, we gave a single injection of the mitochondrial complex II inhibitor 3-nitropropionic acid (3-NP; 16.5 mg/kg, i.p.) to 2 month old male F344 rats and measured various indices of striatal dopaminergic functioning and lipid peroxidation over a 3 month span. Separate groups of rats were used to measure rod walking, evoked dopamine (DA) release, DA content, MDA accumulation, DA receptor binding, and tyrosine hydroxylase activity. The results showed that 3-NP exposure reduced most measures of DA functioning including motoric ability, DA release, and D(2) receptor densities for 1 to 3 months post drug administration. Interestingly, DA content was reduced 1 week after 3-NP exposure, but rose to 147% of control values 1 month after 3-NP treatment. MDA accumulation, a measure of lipid peroxidation activity, was increased 24 hr and 1 month after 3-NP treatment. 3-NP did not affect tyrosine hydroxylase activity, suggesting that alterations in DA functioning were not the result of nigrostriatal terminal loss. These data demonstrate that a brief mild hypoxic episode caused by 3-NP exposure has long-term detrimental effects on the functioning of the nigrostriatal DA system. Synapse, 2010. (c) 2010 Wiley-Liss, Inc.

PMID: 20730800 [PubMed - as supplied by publisher]

Lipid peroxidation & Synapse Research News

Antipsychotic-induced DRD2 up-regulation and its prevention by alpha-lipoic acid in SH-SY5Y neuroblastoma cells.

Acute and long-term response of dopamine nigrostriatal synapses to a single low dose episode of 3-nitropropionic acid-mediated chemical hypoxia.