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The melanin-concentrating hormone (MCH) system modulates behaviors associated with psychiatric disorders.

Chung S, Verheij MM, Hesseling P, van Vugt RW, Buell M, Belluzzi JD, Geyer MA, Martens GJ, Civelli O - PLoS ONE (2011)

Bottom Line: Using mice, we found that central administration of MCH potentiates apomorphine-induced PPI deficits.Using congenic rat lines that differ in their responses to PPI, we found that the rats that are susceptible to apomorphine (APO-SUS rats) and exhibit PPI deficits display higher MCH mRNA expression in the lateral hypothalamic region and that blocking the MCH system reverses their PPI deficits.Furthermore MCH does not affect dizocilpine-induced PPI deficit, a glutamate related response.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, University of California Irvine, Irvine, California, United States of America.

ABSTRACT
Deficits in sensorimotor gating measured by prepulse inhibition (PPI) of the startle have been known as characteristics of patients with schizophrenia and related neuropsychiatric disorders. PPI disruption is thought to rely on the activity of the mesocorticolimbic dopaminergic system and is inhibited by most antipsychotic drugs. These drugs however act also at the nigrostriatal dopaminergic pathway and exert adverse locomotor responses. Finding a way to inhibit the mesocorticolimbic- without affecting the nigrostriatal-dopaminergic pathway may thus be beneficial to antipsychotic therapies. The melanin-concentrating hormone (MCH) system has been shown to modulate dopamine-related responses. Its receptor (MCH1R) is expressed at high levels in the mesocorticolimbic and not in the nigrostriatal dopaminergic pathways. Interestingly a genomic linkage study revealed significant associations between schizophrenia and markers located in the MCH1R gene locus. We hypothesize that the MCH system can selectively modulate the behavior associated with the mesocorticolimbic dopamine pathway. Using mice, we found that central administration of MCH potentiates apomorphine-induced PPI deficits. Using congenic rat lines that differ in their responses to PPI, we found that the rats that are susceptible to apomorphine (APO-SUS rats) and exhibit PPI deficits display higher MCH mRNA expression in the lateral hypothalamic region and that blocking the MCH system reverses their PPI deficits. On the other hand, in mice and rats, activation or inactivation of the MCH system does not affect stereotyped behaviors, dopamine-related responses that depend on the activity of the nigrostriatal pathway. Furthermore MCH does not affect dizocilpine-induced PPI deficit, a glutamate related response. Thus, our data present the MCH system as a regulator of sensorimotor gating, and provide a new rationale to understand the etiologies of schizophrenia and related psychiatric disorders.

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Apomorphine-induced stereotyped behaviors upon MCH injection.A. Effect of MCH (0, 1 nmole) on apomorphine (0, 0.5, 0.75 mg/kg)-induced stereotyped behaviors in mice (***p<0.001 vs. VEH, two-way ANOVA with Bonferroni test; n = 5–10). B. Stereotypy counts in APO-UNSUS, wild type Wistar and APO-SUS rats after apomorphine (1.5 mg/kg) injections (*p<0.05 ***p<0.001 vs Wistar ###p<0.001 vs APO-UNSUS, one-way ANOVA with bonferroni's posttests; n = 10–15). C. Effect of MCH (10 nmole) and TPI 1361-17 (10 nmole) on apomorphine (1.5 mg/kg)-induced stereotyped behavior in APO-UNSUS rats (n = 10–13). D. Effect of MCH (10 nmole) and TPI 1361-17 (10 nmole) on apomorphine (1.5 mg/kg)-induced stereotyped behavior in APO-SUS rats (n = 11–13). Values (A–D) represent total stereotypy counts ± SEM.
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pone-0019286-g005: Apomorphine-induced stereotyped behaviors upon MCH injection.A. Effect of MCH (0, 1 nmole) on apomorphine (0, 0.5, 0.75 mg/kg)-induced stereotyped behaviors in mice (***p<0.001 vs. VEH, two-way ANOVA with Bonferroni test; n = 5–10). B. Stereotypy counts in APO-UNSUS, wild type Wistar and APO-SUS rats after apomorphine (1.5 mg/kg) injections (*p<0.05 ***p<0.001 vs Wistar ###p<0.001 vs APO-UNSUS, one-way ANOVA with bonferroni's posttests; n = 10–15). C. Effect of MCH (10 nmole) and TPI 1361-17 (10 nmole) on apomorphine (1.5 mg/kg)-induced stereotyped behavior in APO-UNSUS rats (n = 10–13). D. Effect of MCH (10 nmole) and TPI 1361-17 (10 nmole) on apomorphine (1.5 mg/kg)-induced stereotyped behavior in APO-SUS rats (n = 11–13). Values (A–D) represent total stereotypy counts ± SEM.

Mentions: Prism software (GraphPad, San Diego, CA) was used for statistical analysis. Data was expressed as mean ± SEM. Results were analyzed by t-test or ANOVA followed by the appropriate post hoc comparisons and p<0.05 was considered statistically significant. In PPI analysis of mice (Figure 1, 2, 4), repeated-measures two-way ANOVA with bonferroni post hoc tests was used with treatment, a between-subjects variable and prepulse intensity, a within-subjects variable. PPI values were also shown as average PPI (%) of the three prepulse intensities and analyzed using one-way ANOVA with Dunnett's test or t-test. In PPI analysis of APO-SUS/UNSUS rats (Figure 3), repeated-measures two-way ANOVA with bonferroni post hoc tests was used with treatment, a between-subjects variable and prepulse intensity, a within-subjects variable. PPI values were also shown as average PPI (%) of the three prepulse intensities and compared between genotypes. Here, two-way ANOVA with bonferroni post hoc tests was used and genotype and treatment were between-subjects variables. In stereotypy analysis of mice (Figure 5), two-way ANOVA with bonferroni post hoc tests was used with apomorphine dose and MCH dose, between-subjects variables. F values shown in the result section indicate main effect of treatment or genotype as described on the text unless indicated as genotype×treatment interaction analysis. For brevity, the main effects of prepulse intensity are not being discussed since they were always significant.


The melanin-concentrating hormone (MCH) system modulates behaviors associated with psychiatric disorders.

Chung S, Verheij MM, Hesseling P, van Vugt RW, Buell M, Belluzzi JD, Geyer MA, Martens GJ, Civelli O - PLoS ONE (2011)

Apomorphine-induced stereotyped behaviors upon MCH injection.A. Effect of MCH (0, 1 nmole) on apomorphine (0, 0.5, 0.75 mg/kg)-induced stereotyped behaviors in mice (***p<0.001 vs. VEH, two-way ANOVA with Bonferroni test; n = 5–10). B. Stereotypy counts in APO-UNSUS, wild type Wistar and APO-SUS rats after apomorphine (1.5 mg/kg) injections (*p<0.05 ***p<0.001 vs Wistar ###p<0.001 vs APO-UNSUS, one-way ANOVA with bonferroni's posttests; n = 10–15). C. Effect of MCH (10 nmole) and TPI 1361-17 (10 nmole) on apomorphine (1.5 mg/kg)-induced stereotyped behavior in APO-UNSUS rats (n = 10–13). D. Effect of MCH (10 nmole) and TPI 1361-17 (10 nmole) on apomorphine (1.5 mg/kg)-induced stereotyped behavior in APO-SUS rats (n = 11–13). Values (A–D) represent total stereotypy counts ± SEM.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3139593&req=5

pone-0019286-g005: Apomorphine-induced stereotyped behaviors upon MCH injection.A. Effect of MCH (0, 1 nmole) on apomorphine (0, 0.5, 0.75 mg/kg)-induced stereotyped behaviors in mice (***p<0.001 vs. VEH, two-way ANOVA with Bonferroni test; n = 5–10). B. Stereotypy counts in APO-UNSUS, wild type Wistar and APO-SUS rats after apomorphine (1.5 mg/kg) injections (*p<0.05 ***p<0.001 vs Wistar ###p<0.001 vs APO-UNSUS, one-way ANOVA with bonferroni's posttests; n = 10–15). C. Effect of MCH (10 nmole) and TPI 1361-17 (10 nmole) on apomorphine (1.5 mg/kg)-induced stereotyped behavior in APO-UNSUS rats (n = 10–13). D. Effect of MCH (10 nmole) and TPI 1361-17 (10 nmole) on apomorphine (1.5 mg/kg)-induced stereotyped behavior in APO-SUS rats (n = 11–13). Values (A–D) represent total stereotypy counts ± SEM.
Mentions: Prism software (GraphPad, San Diego, CA) was used for statistical analysis. Data was expressed as mean ± SEM. Results were analyzed by t-test or ANOVA followed by the appropriate post hoc comparisons and p<0.05 was considered statistically significant. In PPI analysis of mice (Figure 1, 2, 4), repeated-measures two-way ANOVA with bonferroni post hoc tests was used with treatment, a between-subjects variable and prepulse intensity, a within-subjects variable. PPI values were also shown as average PPI (%) of the three prepulse intensities and analyzed using one-way ANOVA with Dunnett's test or t-test. In PPI analysis of APO-SUS/UNSUS rats (Figure 3), repeated-measures two-way ANOVA with bonferroni post hoc tests was used with treatment, a between-subjects variable and prepulse intensity, a within-subjects variable. PPI values were also shown as average PPI (%) of the three prepulse intensities and compared between genotypes. Here, two-way ANOVA with bonferroni post hoc tests was used and genotype and treatment were between-subjects variables. In stereotypy analysis of mice (Figure 5), two-way ANOVA with bonferroni post hoc tests was used with apomorphine dose and MCH dose, between-subjects variables. F values shown in the result section indicate main effect of treatment or genotype as described on the text unless indicated as genotype×treatment interaction analysis. For brevity, the main effects of prepulse intensity are not being discussed since they were always significant.

Bottom Line: Using mice, we found that central administration of MCH potentiates apomorphine-induced PPI deficits.Using congenic rat lines that differ in their responses to PPI, we found that the rats that are susceptible to apomorphine (APO-SUS rats) and exhibit PPI deficits display higher MCH mRNA expression in the lateral hypothalamic region and that blocking the MCH system reverses their PPI deficits.Furthermore MCH does not affect dizocilpine-induced PPI deficit, a glutamate related response.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, University of California Irvine, Irvine, California, United States of America.

ABSTRACT
Deficits in sensorimotor gating measured by prepulse inhibition (PPI) of the startle have been known as characteristics of patients with schizophrenia and related neuropsychiatric disorders. PPI disruption is thought to rely on the activity of the mesocorticolimbic dopaminergic system and is inhibited by most antipsychotic drugs. These drugs however act also at the nigrostriatal dopaminergic pathway and exert adverse locomotor responses. Finding a way to inhibit the mesocorticolimbic- without affecting the nigrostriatal-dopaminergic pathway may thus be beneficial to antipsychotic therapies. The melanin-concentrating hormone (MCH) system has been shown to modulate dopamine-related responses. Its receptor (MCH1R) is expressed at high levels in the mesocorticolimbic and not in the nigrostriatal dopaminergic pathways. Interestingly a genomic linkage study revealed significant associations between schizophrenia and markers located in the MCH1R gene locus. We hypothesize that the MCH system can selectively modulate the behavior associated with the mesocorticolimbic dopamine pathway. Using mice, we found that central administration of MCH potentiates apomorphine-induced PPI deficits. Using congenic rat lines that differ in their responses to PPI, we found that the rats that are susceptible to apomorphine (APO-SUS rats) and exhibit PPI deficits display higher MCH mRNA expression in the lateral hypothalamic region and that blocking the MCH system reverses their PPI deficits. On the other hand, in mice and rats, activation or inactivation of the MCH system does not affect stereotyped behaviors, dopamine-related responses that depend on the activity of the nigrostriatal pathway. Furthermore MCH does not affect dizocilpine-induced PPI deficit, a glutamate related response. Thus, our data present the MCH system as a regulator of sensorimotor gating, and provide a new rationale to understand the etiologies of schizophrenia and related psychiatric disorders.

Show MeSH
Related in: MedlinePlus