Experimental treatment of antipsychotic-induced movement disorders

Abstract

Antipsychotic drugs are extensively prescribed for the treatment of schizophrenia and other related psychiatric disorders. These drugs produced their action by blocking dopamine (DA) receptors, and these receptors are widely present throughout the brain. Therefore, extended antipsychotic use also leads to severe extrapyramidal side effects. The short-term effects include parkinsonism and the later appearing tardive dyskinesia. Currently available treatments for these disorders are mostly symptomatic and insufficient, and are often linked with a number of detrimental side effects. Antipsychotic-drug-induced tardive dyskinesia prompted researchers to explore novel drugs with fewer undesirable extrapyramidal side effects. Preclinical studies suggest a role of 5-hydroxytryptamine (serotonin)-1A and 2A/2C receptors in the modulation of dopaminergic neurotransmission and motivating a search for better therapeutic strategies for schizophrenia and related disorders. In addition, adjunctive treatment with antioxidants such as vitamin E, red rice bran oil, and curcumin in the early phases of illness may prevent additional oxidative injury, and thus improve and prevent further possible worsening of related neurological and behavioral deficits in schizophrenia. This review explains the role of serotonergic receptors and oxidative stress, with the aim of providing principles for prospect development of compounds to improve therapeutic effects of antischizophrenic drugs.

Keywords: antipsychotic drugs; movement disorders; parkinsonian-like symptoms; tardive dyskinesia.

Figure 1

Cataleptic effects of haloperidol (1 mg/kg) in saline, 8-OH-DPAT (0.25 mg/kg), or buspirone (1 mg/kg) pre-injected rats. Notes: Values are mean ± SD (n=6), 30 minutes after the administration of haloperidol. Significant differences by Newman–Keuls test: *P<0.01 in 8-OH-DPAT or buspirone-injected animals as compared with respective saline-injected (first injection) controls. ⁺P<0.01 in haloperidol-injected animals as compared with respective saline, 8-OH-DPAT or buspirone-injected animals following the two-way ANOVA. Abbreviations: ANOVA, analysis of variance; 8-OH-DPAT, 8-hydroxy-2-(di-n-propylamino) tetralin; SD, standard deviation.

Figure 2

Effects of mianserin (2.5 and 5.0 mg/kg) on haloperidol-induced deficits of exploratory activity (in an open field [A]) and motor coordination (B) on Rota-Rod in rats. Notes: Values are mean ± SD (n=6), 30 minutes after the administration of haloperidol. Significant differences by Newman–Keuls test. *P<0.01 from respective saline-injected controls, ⁺P<0.01 from saline- plus haloperidol-injected animals, #P<0.01 from mianserin- plus haloperidol-injected animals. Abbreviation: SD, standard deviation.

Figure 3

Effects of mesulergine (1.0 and 3.0 mg/kg) on haloperidol-induced deficits of exploratory activity (in an open field [A]) and motor coordination (B) on Rota-Rod in rats. Notes: Values are mean ± SD (n=6), 30 minutes after the administration of haloperidol. Significant differences by Newman–Keuls test. *P<0.01 from respective saline-injected controls, ⁺P<0.01 from saline- plus haloperidol-injected animals, #P<0.01 from mesulergine- plus haloperidol-injected animals. Abbreviation: SD, standard deviation.

Figure 4

Role of 5-HT receptors in the modulation of haloperidol-induced EPSE. Abbreviations: DA, dopamine; EPSE, extrapyramidal side effects; 5-HT, 5-hydroxytryptamine; 8-OH-DPAT, 8-hydroxy-2-(di-n-propylamino) tetralin.

Figure 5

Proposed pathophysiological mechanisms of antipsychotic-induced TD. Abbreviations: DA, dopamine; GABA, gamma amino butyric acid; TD, tardive dyskinesia; GSH, glutathione; SOD, superoxide dismutase.

Figure 6

Time course effect of RRBO on haloperidol-induced deficits of vacuous chewing movements. Notes: Values are mean ± SD (n=12). Significant differences by Newman–Keuls test. **P<0.01 from values of similarly treated animals, ⁺⁺P<0.01 from respective week values of W-treated animals, and ^##P<0.01 from respective week values of WS and haloperidol- plus saline-treated animals. Abbreviations: RRBO, red rice bran oil; SD, standard deviation; VCMs, vacuous chewing movements; W, water; S, saline; H, haloperidol.