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Pre-treatment with the mGlu2/3 receptor agonist LY379268 attenuates DOI-induced impulsive responding and regional c-Fos protein expression

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Abstract

Rationale

Overactivation of serotonin (5-hydroxytryptamine, 5-HT)2A receptors causes impulsivity and attentional deficits. Since 5-HT2A receptors are known to entertain antagonistic interactions with metabotropic glutamate (mGlu)2/3 receptors, this interaction may provide an alternative target for a novel class of antipsychotics.

Objectives/Methods

The study characterizes interactions between 5-HT2A and mGlu2/3 receptors implicated in impulse control. Hooded Lister rats were trained in a 5-choice serial reaction time task (5-CSRTT) and treated with the 5-HT2A/2C receptor agonist (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropan hydrochloride (DOI, 0.1 mg/kg) and the mGlu2/3 receptor agonist LY379268 (1 mg/kg). In addition, associated drug-induced changes in neuronal activity were assessed via c-Fos immunoreactivity (Fos IR), and co-localization of c-Fos and GABAergic markers was detected using double immunofluorescence labeling.

Results

Systemic DOI caused impulsive overresponding that was attenuated in animals pre-treated with LY379268. LY379268 itself had no significant effect on the rats' performance in the 5-CSRTT. DOI enhanced Fos IR within fronto-cortical and limbic brain structures, and this effect was blocked by LY379268 pre-treatment. Double immunofluorescence labeling showed a specific co-localization of DOI-elicited Fos IR with GABAergic (GAD67-positive) cells lacking the calcium-binding protein parvalbumin while LY379268 increased Fos IR in GABAergic and non-GABAergic cells.

Conclusion

Our results suggest that impulsivity is possibly due to a primary increase in Glu transmission mediated via 5-HT2A receptor activation. Thus, mGlu2/3 receptor agonists might have some potential for treating motor impulsivity-related impairments while their cognitive enhancing effects were not confirmed in this study.

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  1. Department of Neuropharmacology, Brain Research Institute, Center for Cognitive Sciences, University of Bremen, PO Box 330440, 28334, Bremen, Germany

    Lena Wischhof & Michael Koch

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  1. Lena Wischhof
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  2. Michael Koch
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Correspondence to Lena Wischhof.

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Wischhof, L., Koch, M. Pre-treatment with the mGlu2/3 receptor agonist LY379268 attenuates DOI-induced impulsive responding and regional c-Fos protein expression. Psychopharmacology 219, 387–400 (2012). https://doi.org/10.1007/s00213-011-2441-y

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