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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.

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Related in: MedlinePlus

Effect of Lu AF21934 (5 mg/kg s.c) on extracellular concentration of dopamine (DA) (a) and 5-HT (b) in the rat prefrontal cortex. The figure shows time-course of the DA and 5-HT level between 20 and 180 min of the microdialysis sample collection. Values are presented as the mean ± SEM, n = 12–13 rats. *P < 0.05 and **P < 0.01 show significant differences from basal level
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Fig8: Effect of Lu AF21934 (5 mg/kg s.c) on extracellular concentration of dopamine (DA) (a) and 5-HT (b) in the rat prefrontal cortex. The figure shows time-course of the DA and 5-HT level between 20 and 180 min of the microdialysis sample collection. Values are presented as the mean ± SEM, n = 12–13 rats. *P < 0.05 and **P < 0.01 show significant differences from basal level

Mentions: MK-801 at a dose of 0.3 mg/kg significantly increased DA and 5-HT in the rat frontal cortex reaching maximal effect at 80 and 60 min after administration, respectively (Fig. 8a, b). LU AF 21934 (5 mg/kg) attenuated increase in extracellular DA level induced by MK-801 (Fig. 8a). Repeated measures ANOVA showed significant effect of treatment [F3,16 = 196, P = 0], significant effect of time [F8,128 = 27, P = 0], and interaction between both factors [F24,128 = 15, P = 0].Fig. 8


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)

Effect of Lu AF21934 (5 mg/kg s.c) on extracellular concentration of dopamine (DA) (a) and 5-HT (b) in the rat prefrontal cortex. The figure shows time-course of the DA and 5-HT level between 20 and 180 min of the microdialysis sample collection. Values are presented as the mean ± SEM, n = 12–13 rats. *P < 0.05 and **P < 0.01 show significant differences from basal level
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig8: Effect of Lu AF21934 (5 mg/kg s.c) on extracellular concentration of dopamine (DA) (a) and 5-HT (b) in the rat prefrontal cortex. The figure shows time-course of the DA and 5-HT level between 20 and 180 min of the microdialysis sample collection. Values are presented as the mean ± SEM, n = 12–13 rats. *P < 0.05 and **P < 0.01 show significant differences from basal level
Mentions: MK-801 at a dose of 0.3 mg/kg significantly increased DA and 5-HT in the rat frontal cortex reaching maximal effect at 80 and 60 min after administration, respectively (Fig. 8a, b). LU AF 21934 (5 mg/kg) attenuated increase in extracellular DA level induced by MK-801 (Fig. 8a). Repeated measures ANOVA showed significant effect of treatment [F3,16 = 196, P = 0], significant effect of time [F8,128 = 27, P = 0], and interaction between both factors [F24,128 = 15, P = 0].Fig. 8

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