Pre-treatment with the mGlu23 receptor agonist LY379268 attenuates DOI-induced impulsive responding and regional c-Fos protein expression.
Overactivation of serotonin (5-hydroxytryptamine, 5-HT)(2A) receptors causes impulsivity and attentional deficits. Since 5-HT(2A) receptors are known to entertain antagonistic interactions with metabotropic glutamate (mGlu)23 receptors, this interaction may provide an alternative target for a novel class of antipsychotics. The study characterizes interactions between 5-HT(2A) and mGlu23 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-HT(2A2C) receptor agonist (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropan hydrochloride (DOI, 0.1 mgkg) and the mGlu23 receptor agonist LY379268 (1 mgkg). 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. 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 (GAD(67)-positive) cells lacking the calcium-binding protein parvalbumin while LY379268 increased Fos IR in GABAergic and non-GABAergic cells. Our results suggest that impulsivity is possibly due to a primary increase in Glu transmission mediated via 5-HT(2A) receptor activation. Thus, mGlu23 receptor agonists might have some potential for treating motor impulsivity-related impairments while their cognitive enhancing effects were not confirmed in this study.