Impulsive behaviour in rats induced by intracortical DOI infusions is antagonized by co-administration of an mGlu2/3 receptor agonist

Abstract

The orbitofrontal cortex (OFC) and the medial prefrontal cortex (mPFC) modulate impulsive behaviours. Serotonin [5-hydroxytryptamine (5-HT)] 2A receptors have also been implicated in impulsivity and govern antagonistic interactions with metabotropic glutamate (mGlu)2/3 receptors. This study examined the interactions between 5-HT2A and mGlu2/3 receptors in the OFC and mPFC with relevance to impulsive choice and impulsive action. Impulsive choice was assessed in Lister Hooded rats, trained in a delay-discounting T-maze task, after bilateral intra-OFC infusions of the 5-HT2A/C receptor agonist DOI [(+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropan hydrochloride; 5 μg/0.5 μl] and the mGlu2/3 receptor agonist LY379268 (1 μg/0.5 μl). Impulsive action was assessed in a second group of rats trained in a five-choice serial reaction time task (5-CSRTT) and receiving bilateral intra-mPFC infusions of DOI (5 μg/0.5 μl) and LY379268 (1 μg/0.5 μl). Intra-OFC DOI increased impulsive choice, which was not seen when DOI was co-administered with LY379268. LY379268 itself had no effect on choice behaviour. Intra-mPFC DOI caused impulsive over-responding in the 5-CSRTT that was attenuated when DOI and LY379268 were co-injected. Local mPFC-infusions of LY379268 had no effect on 5-CSRTT performance. This study suggests a differential involvement of OFC and mPFC 5-HT2A receptors in impulsive choice and impulsive action. Moreover, compounds acting at mGlu2/3 receptors might have the potential to improve impulsivity-related impairments.

Individual Differences in Impulsive Action Reflect Variation in the Cortical Serotonin 5-HT2A Receptor System

“…We discovered that HI rats exhibited higher sensitivity to the effects of the preferential 5-HT 2A R agonist DOI (5-HT 2A R-mediated head-twitches) and to the effects of the selective 5-HT 2A R antagonist M100907 (suppression of premature responses). Our finding that HI action tracks with high cortical 5-HT 2A R density, particularly within the mPFC, is consistent with microinfusion studies that validate the importance of the 5-HT 2A R in the mPFC for both generating the head-twitch response (Willins and Meltzer, 1997) and mediating impulsive action Winstanley et al, 2003;Wischhof et al, 2011; but see Robinson et al, 2008). Furthermore, the higher level of 5-HT 2A R/PSD95 association in the mPFC of HI rats relative to LI rats suggests that factors that control the functional status of the 5-HT 2A R in mPFC may drive in part the predisposition to inherent impulsive action.…”

“…The quantity of tissue required to conduct receptor binding assays necessitated the use of the whole frontal cortex that comprises not only the mPFC, but also cortical subregions that putatively could have limited or opposing functional involvement in inhibitory control. Thus, 5-HT 2A R density determined in whole frontal cortex may underestimate differences between impulsive action phenotypes within functionally relevant frontal cortical subregions such as the mPFC that mediates DOI-induced head-twitches (Willins and Meltzer, 1997) and motor impulsivity Winstanley et al, 2003;Wischhof et al, 2011). Interestingly, we found that HI rats expressed higher 5-HT 2A R protein expression assessed by immunodetection methods in the whole frontal cortex as well as the mPFC.…”

“…The mPFC is a subregion of the frontal cortex known to modulate impulsive action (Dalley et al, 2004), and microinfusion of the 5-HT 2A R agonist DOI into the mPFC is sufficient to increase impulsive action and elicit the head-twitch response (Willins and Meltzer, 1997;Wischhof et al, 2011). Thus, we next sought to determine whether the 5-HT 2A R protein expression level was higher in HI relative to LI rats, specifically within the mPFC subregion of the frontal cortex.…”

“…Specifically, systemically administered preferential 5-HT 2A R agonists increase whereas selective 5-HT 2A R antagonists reduce impulsive action (Anastasio et al, 2011;Cunningham et al, 2013;Fletcher et al, 2007;Koskinen et al, 2000b;Robinson et al, 2008;Winstanley et al, 2004b), effects that are recapitulated by intra-mPFC infusion Winstanley et al, 2003;Wischhof et al, 2011). The 5-HT 2A R in corticostriatal circuits may also drive individual differences in impulsive action given that 5-HT 2A R binding density is elevated in frontal cortical regions of the selectively bred Roman high-avoidance rat .…”

Psychedelics

“…Their findings suggest that in frontal cortex mGlu2/3 receptors negatively regulate the G q phospholipase C3 pathway that is activated by 5-HT 2A receptors. Wischhof et al (2011) examined interactions between 5-HT 2A and mGlu2/3 receptors in the orbitofrontal cortex (OFC) and mPFC with respect to impulsive choice and impulsive action in Lister Hooded rats. Impulsive choice was assessed in rats trained in a delay-discounting T-maze task, after bilateral infra-OFC infusions of DOI or the mGlu2/3 agonist LY379268.…”