Limits...
The antipsychotic-like effects in rodents of the positive allosteric modulator Lu AF21934 involve 5-HT1A receptor signaling: mechanistic studies.

Wierońska JM, Sławińska A, Łasoń-Tyburkiewicz M, Gruca P, Papp M, Zorn SH, Doller D, Kłeczek N, Noworyta-Sokołowska K, Gołembiowska K, Pilc A - Psychopharmacology (Berl.) (2014)

Bottom Line: To begin elucidating the brain circuitry involved in mGlu4 receptor pharmacology and add mechanistic support to Lu AF21934-induced phenotypic responses, the potential involvement of 5-HT1A receptors in these antipsychotic-like effects was explored.The effects caused by Lu AF2193 were inhibited by administration of the selective 5-HT1A receptor antagonist WAY100635 (0.1 mg/kg).Moreover, the concomitant administration of sub-effective doses of Lu AF21934 and a sub-effective dose of the selective 5-HT1A receptor agonist tool compound (R)-(+)-8-hydroxy-DPAT hydrobromide (0.01 mg/kg) induced a clear antipsychotic-like effect in all the procedures used.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pharmacology, Polish Academy of Sciences, Smętna Str. 12, 31-343, Kraków, Poland, wierons@if-pan.krakow.pl.

ABSTRACT

Rationale: Diverse preclinical studies suggest the potential therapeutic utility of the modulation of the glutamatergic system in brain via metabotropic glutamate (mGlu) receptors. Lu AF21934, a positive allosteric modulator of the mGlu4 receptor, was previously shown to reverse behavioral phenotypes in animal models thought to mimic positive, negative, and cognitive symptoms of schizophrenia.

Objectives: To begin elucidating the brain circuitry involved in mGlu4 receptor pharmacology and add mechanistic support to Lu AF21934-induced phenotypic responses, the potential involvement of 5-HT1A receptors in these antipsychotic-like effects was explored. The tests used were the following: MK-801-induced hyperactivity and 2,5-dimethoxy-4-iodoamphetamine (DOI)-induced head twitches in mice, for positive symptoms; MK-801-induced disruptions of social interactions for negative symptoms; and novel object recognition and spatial delayed alteration test for cognitive symptoms. The microdialysis studies in which the effect of Lu AF21934 on MK-801-induced dopamine and serotonin release was investigated.

Results: The effects caused by Lu AF2193 were inhibited by administration of the selective 5-HT1A receptor antagonist WAY100635 (0.1 mg/kg). That inhibition was observed across all models used. Moreover, the concomitant administration of sub-effective doses of Lu AF21934 and a sub-effective dose of the selective 5-HT1A receptor agonist tool compound (R)-(+)-8-hydroxy-DPAT hydrobromide (0.01 mg/kg) induced a clear antipsychotic-like effect in all the procedures used. Lu AF21934 (5 mg/kg) also inhibited MK-801-induced increase in dopamine and 5-HT release.

Conclusions: The actions of Lu AF21934 are 5-HT1A receptor-dependent. Activation of the mGlu4 receptor may be a promising mechanism for the development of novel antipsychotic drugs, efficacious toward positive, negative, and cognitive symptoms.

Show MeSH

Related in: MedlinePlus

Effects on MK-801-induced hyperactivity. The combined administration of Lu AF21934 (1 mg/kg) with WAY100635 (0.1 mg/kg) (a), and the co-administration of Lu AF21934 (0.1) with 8-OH-DPAT (0.01) (b) are presented. Data are presented as means ± SEM. Doses in milligrams per kilogram are indicated in parentheses. #P < 0.01 versus control, **P < 0.01 versus MK-801-treated group, @P < 0.05 versus Lu AF21934-treated group
© Copyright Policy - OpenAccess
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4281359&req=5

Fig1: Effects on MK-801-induced hyperactivity. The combined administration of Lu AF21934 (1 mg/kg) with WAY100635 (0.1 mg/kg) (a), and the co-administration of Lu AF21934 (0.1) with 8-OH-DPAT (0.01) (b) are presented. Data are presented as means ± SEM. Doses in milligrams per kilogram are indicated in parentheses. #P < 0.01 versus control, **P < 0.01 versus MK-801-treated group, @P < 0.05 versus Lu AF21934-treated group

Mentions: Lu AF21934 administered at a dose of 1 mg/kg, s.c, induced a clear antipsychotic-like effect, reversing MK-801-induced hyperactivity (P < 0.009). WAY100635, administered at a dose of 0.1 mg/kg, i.p., did not have any effect on its own. Co-administration of WAY100635 with Lu AF21934 (1 mg/kg) resulted in the inhibition of Lu AF21934-induced effect in the hyperactivity test. The two-way ANOVA main effects analysis revealed the significant effect of Lu AF21934 × WAY100635 interaction [F(1.29) = 8.02; P < 0.008] (Fig. 1a).Fig. 1


The antipsychotic-like effects in rodents of the positive allosteric modulator Lu AF21934 involve 5-HT1A receptor signaling: mechanistic studies.

Wierońska JM, Sławińska A, Łasoń-Tyburkiewicz M, Gruca P, Papp M, Zorn SH, Doller D, Kłeczek N, Noworyta-Sokołowska K, Gołembiowska K, Pilc A - Psychopharmacology (Berl.) (2014)

Effects on MK-801-induced hyperactivity. The combined administration of Lu AF21934 (1 mg/kg) with WAY100635 (0.1 mg/kg) (a), and the co-administration of Lu AF21934 (0.1) with 8-OH-DPAT (0.01) (b) are presented. Data are presented as means ± SEM. Doses in milligrams per kilogram are indicated in parentheses. #P < 0.01 versus control, **P < 0.01 versus MK-801-treated group, @P < 0.05 versus Lu AF21934-treated group
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4281359&req=5

Fig1: Effects on MK-801-induced hyperactivity. The combined administration of Lu AF21934 (1 mg/kg) with WAY100635 (0.1 mg/kg) (a), and the co-administration of Lu AF21934 (0.1) with 8-OH-DPAT (0.01) (b) are presented. Data are presented as means ± SEM. Doses in milligrams per kilogram are indicated in parentheses. #P < 0.01 versus control, **P < 0.01 versus MK-801-treated group, @P < 0.05 versus Lu AF21934-treated group
Mentions: Lu AF21934 administered at a dose of 1 mg/kg, s.c, induced a clear antipsychotic-like effect, reversing MK-801-induced hyperactivity (P < 0.009). WAY100635, administered at a dose of 0.1 mg/kg, i.p., did not have any effect on its own. Co-administration of WAY100635 with Lu AF21934 (1 mg/kg) resulted in the inhibition of Lu AF21934-induced effect in the hyperactivity test. The two-way ANOVA main effects analysis revealed the significant effect of Lu AF21934 × WAY100635 interaction [F(1.29) = 8.02; P < 0.008] (Fig. 1a).Fig. 1

Bottom Line: To begin elucidating the brain circuitry involved in mGlu4 receptor pharmacology and add mechanistic support to Lu AF21934-induced phenotypic responses, the potential involvement of 5-HT1A receptors in these antipsychotic-like effects was explored.The effects caused by Lu AF2193 were inhibited by administration of the selective 5-HT1A receptor antagonist WAY100635 (0.1 mg/kg).Moreover, the concomitant administration of sub-effective doses of Lu AF21934 and a sub-effective dose of the selective 5-HT1A receptor agonist tool compound (R)-(+)-8-hydroxy-DPAT hydrobromide (0.01 mg/kg) induced a clear antipsychotic-like effect in all the procedures used.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pharmacology, Polish Academy of Sciences, Smętna Str. 12, 31-343, Kraków, Poland, wierons@if-pan.krakow.pl.

ABSTRACT

Rationale: Diverse preclinical studies suggest the potential therapeutic utility of the modulation of the glutamatergic system in brain via metabotropic glutamate (mGlu) receptors. Lu AF21934, a positive allosteric modulator of the mGlu4 receptor, was previously shown to reverse behavioral phenotypes in animal models thought to mimic positive, negative, and cognitive symptoms of schizophrenia.

Objectives: To begin elucidating the brain circuitry involved in mGlu4 receptor pharmacology and add mechanistic support to Lu AF21934-induced phenotypic responses, the potential involvement of 5-HT1A receptors in these antipsychotic-like effects was explored. The tests used were the following: MK-801-induced hyperactivity and 2,5-dimethoxy-4-iodoamphetamine (DOI)-induced head twitches in mice, for positive symptoms; MK-801-induced disruptions of social interactions for negative symptoms; and novel object recognition and spatial delayed alteration test for cognitive symptoms. The microdialysis studies in which the effect of Lu AF21934 on MK-801-induced dopamine and serotonin release was investigated.

Results: The effects caused by Lu AF2193 were inhibited by administration of the selective 5-HT1A receptor antagonist WAY100635 (0.1 mg/kg). That inhibition was observed across all models used. Moreover, the concomitant administration of sub-effective doses of Lu AF21934 and a sub-effective dose of the selective 5-HT1A receptor agonist tool compound (R)-(+)-8-hydroxy-DPAT hydrobromide (0.01 mg/kg) induced a clear antipsychotic-like effect in all the procedures used. Lu AF21934 (5 mg/kg) also inhibited MK-801-induced increase in dopamine and 5-HT release.

Conclusions: The actions of Lu AF21934 are 5-HT1A receptor-dependent. Activation of the mGlu4 receptor may be a promising mechanism for the development of novel antipsychotic drugs, efficacious toward positive, negative, and cognitive symptoms.

Show MeSH
Related in: MedlinePlus