Enhancement of Spatial Reversal Learning by 5-HT2CReceptor Antagonism Is Neuroanatomically Specific

“The coordinates used were as follows (Paxinos and Watson, 1998): OFC: anteroposterior (AP), 3.”

“Without this top-down cognitive control, behavior controlled by other cortical and subcortical regions is more likely to be inflexible, dependent on simple sensory motor associations or habits (Miller and Cohen, 2001).”

“The medial region of the PFC (mPFC) has been shown to mediate behavioral flexibility in attentional set-shifting tasks, requiring the updating of attentional biases or rules (Owen et al., 1991; Dias et al., 1996; Birrell and Brown, 2000; Ragozzino and Kesner, 2001).”

“The medial region of the PFC (mPFC) has been shown to mediate behavioral flexibility in attentional set-shifting tasks, requiring the updating of attentional biases or rules (Owen et al., 1991; Dias et al., 1996; Birrell and Brown, 2000; Ragozzino and Kesner, 2001).”

“Neuroanatomically speaking, converging evidence from a plethora of studies has implicated the orbitofrontal cortex (OFC) in efficient reversal learning, as damage to this region produces selective reversal deficits [human (Rolls et al., 1994; Hornak et al., 2004), monkey (Iversen and Mishkin, 1970; Jones and Mishkin,…”

“If this regulation also results from descending influences from mPFC (Amat et al., 2005), then this may imply a descending modulation of the dorsal raphé by OFC 5-HT2C receptors.”

“(Robbins, 2000; Chudasama and Robbins, 2004; Winstanley et al., 2006).”

“, 2004), monkey (Iversen and Mishkin, 1970; Jones and Mishkin, 1972; Dias et al., 1996; Clarke et al., 2008), rat (Schoenbaum et al.”

“, 2004), monkey (Iversen and Mishkin, 1970; Jones and Mishkin, 1972; Dias et al., 1996; Clarke et al., 2008), rat (Schoenbaum et al.”

“For instance, in rats antagonism of 5-HT2A (via MDL 100-907) impairs reversal performance, while 5-HT2C antagonism (with SB 242084) facilitates performance (Boulougouris et al., 2008; Boulougouris and Robbins, 2010; Nilsson et al., 2012; Furr et al., 2012b), though there is also a report of an overall impairment after…”

“In contrast, the deficit found after systemic blockade of 5HT2A receptors could not be reproduced by direct injection into either OFC, medial PFC, or nucleus accumbens (49).”

“Drugs targeting serotonin receptors, particularly 5-HT1A and 5-HT2A, have shown promise for increasing social interaction or decreasing cognitive rigidity (File et al., 1996, Edwards et al., 2006, Boulougouris and Robbins, 2010, Gould et al., 2011, Amodeo et al., 2014).”

“Thus, as is the case for DA, 5-HT might have distinct effects in the ventral striatum, the amygdala, and the OFC (Clarke et al, 2008; Boulougouris and Robbins, 2010), or on functions associated with ventral versus dorsal frontostriatal circuitry (Tanaka et al, 2007).”

“In animal models, 5-HT2C blockade alone has been found to enhance [30, 38] or have no impact cognitive flexibility [34].”

“…Nonkes et al. (2011) Response: magazine approach 5HT2A/C receptor antagonists Stimuli: spatial 5HT2A antagonists impair, while 5HT2C antagonists improve, reversal learning; 5HT2C antagonist effects mediated in OFC Boulougouris et al. (2008b), Boulougouris and Robbins (2010) Response: lever press”

“criterion (Boulougouris et al., 2008; Boulougouris and Robbins, 2010), and serotonin depletion in the orbitofrontal cortex in nonhuman primates increased the number of perseverative errors on a deterministic reversal learning task (Clarke et al.”

“Expected and unexpected uncertainty may differentially activate neuromodulatory systems (Yu and Dayan, 2005).”

“…the behavior of others Val66Met: a common single-nucleotide polymorphism (SNP) in the brain-derived neurotrophic factor (BDNF) gene that leads to a valine-(Val)to-methionine (Met) substitution at codon 66 (Val66Met) receptor agents in rats (Boulougouris et al. 2008, Boulougouris & Robbins 2010).”

“…have also been reported to show impaired reversal learning, a behavioural index of cognitive flexibility which, at the level of the OFC, is 5-HT dependent (Clarke et al., 2004; Boulougouris and Robbins, 2010), thus providing indirect evidence that OT also modulates 5-HT activity in this region.”

“However, the relevance of 5-HT2C-R for cognitive and affective processes (Heisler et al., 2007; Boulougouris and Robbins, 2010; Pennanen et al., 2013) suggests its participation in the modulation of PFCbased circuits.”

“…receptor antagonists has also been shown to increase sensitivity to aversive outcomes, at the expense of rewarding ones, leading to a reduction in the number of perseverative errors during the performance of a reversal learning paradigm (Boulougouris et al., 2008, Boulougouris and Robbins, 2010).”

“In reversal learning tasks, results are mixed with 5HT2A antagonists or agonists impairing [23,26,70] or improving [71] performance, and 5HT2C antagonists having no effect or enhancing [72] performance.”

“Specifically, the OC plays a distinct role in flexible behavior, most notably in adapting behavior to reward contingencies (Amodeo et al., 2017; Boulougouris and Robbins, 2010; Boulougouris et al., 2007, 2008; Chudasama and Robbins, 2003; de Bruin et al., 1983; Flaisher-Grinberg et al., 2008;…”

“…egr-1 expression can lead to long-lasting synaptic changes that influence behaviors associated with learning and memory (Cole et al., 1989); and 5-HT2C-receptor signaling in the orbital frontal cortex plays a role in early phases of spatial reversal learning (Boulougouris and Robbins, 2010).”

“OFC 5-HT depletion decreases behavioral flexibility in monkeys (Clarke et al, 2007), which has been proposed to result from 5-HT2cR supersensitivity (Boulougouris and Robbins, 2010).”

“The observation that spatial reversal learning is facilitated by local administration of a 5-HT2C receptor antagonist in the OFC (Boulougouris and Robbins, 2010) lends further support to an involvement of orbitofrontal 5-HT mechanisms in spatial reversal performance.”

“…depends on a circuit including orbital frontal cortex and striatum with discrete roles for dopamine and serotonin (Boulougouris et al., 2007; Boulougouris and Robbins, 2010; Clarke et al., 2004; Ghods-Sharifi et al., 2008; Kehagia et al., 2010; Kim and Ragozzino, 2005; McAlonan and Brown,…”

“…effects was further investigated regarding neuroanatomical specificity within some of the brain regions implicated in cognitive flexibility (Boulougouris and Robbins, 2010), namely, the orbitofrontal cortex (OFC), medial PFC (mPFC), and NAc, by means of targeted infusions of selective…”

“…antagonist increased perseverative errors in an operant two-choice serial reversal task, whereas systemic blockade of 5-HT 2C Rs had the opposite effect, improving performance (Boulougouris et al. 2008), as did direct administration of a 5-HT 2C R antagonist into OFC (Boulougouris & Robbins, 2010).”

“SB-242084 was also found to promote spatial reversal learning in rats, an effect attributed to 5-HT2C receptors located in the orbitofrontal cortex[46].”

“Indeed, it is interesting to note that 5-HT2AR and 5-HT2CR activation produces similar actions on vigilance states and ASs whereas these two classes of 5-HTRs produce opposite effects on a plethora of other behaviors (Boulougouris and Robbins, 2010; Cunningham et al., 2013; Di Giovanni and De Deurwaerd ere, 2016; Di G…”

“Serotonergic, dopaminergic, and glutamatergic systems are also involved in reversal learning (Balschun et al., 2010; Bannerman, Deacon, Seeburg, & Rawlins, 2003; Boulougouris & Robbins, 2010; Floresco et al., 2009; Lapiz-Bluhm et al., 2009; Robbins & Roberts, 2007).”

“…intact 5-HT signalling in the orbitofrontal cortex (OFC) and dopamine signalling in the caudate nucleus (primates) or dorsomedial striatum (rodents) is critical for successful reversal learning (Clarke et al. 2004, 2011; O'Neill and Brown 2007; Boulougouris and Robbins 2010; Groman et al. 2013).”

“, 2007) and drugs that target specific 5-HT receptors infused into the rat orbitofrontal cortex enhance reversal learning (Boulougouris and Robbins, 2010).”

“Variation in central serotonin systems also associates with impulsiveness, and pharmacological manipulation of cortical serotonin transmission signaling alters reversal learning performance (35, 36).”

“For xample, in operant tasks, early or perseverative errors have been ndexed by repetitive bouts of responding towards the previous S+ (Boulougouris and Robbins, 2010) or incorrect responses made arly in reversal when the majority of responses are to the previous S+ (Boulougouris et al.”

“Similarly, selective 5-HT2A and 5-HT2C antagonists show dissociable effects in the five-choice serial reaction test and the serial spatial reversal learning task in rats (Boulougouris et al. 2008; Boulougouris and Robbins 2010; Robinson et al. 2008).”

“Furthermore, systemic (Boulougouris et al. 2008; Nilsson et al. 2012) or OFC-specific (Boulougouris and Robbins 2010) antagonism of the 5-HT2C receptor (5-HT2CR) through SB 242084 can improve spatial reversal-learning performance in rodents, whereas blockade of the 5-HT2A receptor, in contrast,…”

“However, previous reports have suggested no impact on reversal learning after 5HT2C receptor manipulation in the NAcC [56].”

“cognitive functions, such as recognition memory (Pitsikas and Sakellaridis, 2005) or spatial reversal learning (Boulougouris and Robbins, 2010).”

“…2007a,b, 2013, 2014; Meneses and Hong, 1997; Meneses and LiySalmeron, 2012; Meneses et al., 2003, 2008, 2009, 2011b; Roth et al., 2004; van Praag, 2008; Bockaert et al., 2008; Borg, 2008; Boulougouris and Robbins, 2010; King et al., 2008; Ögren et al., 2008; Terry et al., 2008; Elvander-Tottie…”

“…revealed important roles of 5-HT in the regulation of OFC functions such as reversal learning, response inhibition, devaluation, and aggressive behaviors (Clarke et al., 2004, 2007; De Almeida et al., 2006; Walker et al., 2006; Boulougouris and Rob- bins, 2010; Man et al., 2010; West et al., 2013).”

“However, similar to systemic treatment, infusion of SB242084 into the orbitofrontal cortex enhances spatial reversal learning [7].”

“2008) with effects of 5HT2C antagonists specific to the OFC (Boulougouris and Robbins 2010).”

“The application of 5-HT2A, 5-HT2C, 5-HT6, 5-HT7 receptor antagonists or 5-HT1A receptor agonists to the ORB improved reversal learning using various paradigms (Boulougouris et al., 2008; Boulougouris and Robbins, 2010; Hatcher et al., 2005; McLean et al., 2009).”

“However, a recent study suggests that 5-HT2A antagonism does not improve, but rather worsens, cognitive functions [62].”

“…in other aspects of response inhibition as manifest in the five-choice serial reaction time task (Robinson et al , 2008b) and reversal learning (Boulougouris and Robbins, 2010), hence it will be a priority to establish the extent to which these brain regions are involved in mediating the…”

“Indeed, administered systemically, as well as in the NAc core SB242084 increased the number of premature responses in normal rats (Higgins et al. 2003; Robinson et al. 2008; Winstanley et al. 2004a) and tended to further increase MK801-induced impulsivity (Higgins et al. 2003) ).”

“The procedure was adapted as previously described (Boulougouris and Robbins, 2010).”

“…associated with perseverative behaviors in reversal learning and in other tasks and manipulations proposed to model OCD in animals (Boulougouris et al., 2008; Boulougouris & Robbins, 2010; Flaisher-Grinberg, Klavir, & Joel, 2008; Graf, Kantor, Anheuer, Modos, & Bagdy, 2003; Papakosta et al., 2013).”

“This rescue is found in both pharmacologically induced and genetically induced impairments in behavioral flexibility (Amodeo et al., 2014; Boulougouris et al., 2008; Boulougouris and Robbins, 2010; Furr et al., 2012; Alsiö et al., 2015; Barlow et al., 2015).”

“Furthermore, errors made during the reversal stages were broken down into two types: perseverative errors (six or more consecutive errors within a session) and learning errors (all other errors) (Boulougouris and Robbins, 2010).”

“As suggested above, an important effector of (myo-)inositol signalling, 5-HT2 receptor function within the OFC crucially regulates cognitive performance in reversal learning and, presumably, other relevant cognitive operations depending on the OFC [3, 20].”

“The experiment by Boulougouris et al. (2007) did not attempt to disassociate between manipulations of perseverance and learned non-reward; however, one could speculate that the discrepancies are related to the different task designs creating different loading upon perseverance and learned…”

“…weight control (likely through blockade of hypothalamic 5-HT2C-R [Hsu et al. 2010]), the presence of 5-HT2C-R in PFC and anatomically related brain areas suggests that it may participate in cognitive and affective functions (Heisler et al. 2007; Boulougouris and Robbins 2010; Pennanen et al. 2013).”

“Consistent with neuroimaging studies in humans, reversal learning in rodents has highlighted the importance of dopamine, serotonin, and the orbitofrontal cortex.(45,46) Furthermore, lesions of the orbitofrontal cortex in rodents and nonhuman primates induce a perseverative response tendency to the previously rewarded…”

“5 μl/site) did not induce any significant effects on SIP; and also on previous studies (Alsiö et al., 2015; Boulougouris and Robbins, 2010; Wischhof et al., 2011).”

“Previously, modulation of the 5-HT2C receptor with SB242084 has been found to improve cognitive function in a rodent assay of cognitive flexibility when delivered systemically (Boulougouris, Glennon, & Robbins, 2008) or selectively to the orbitofrontal cortex (Boulougouris & Robbins, 2010).”

“Antagonism of the 5-HT2C receptor enhances reversal learning performance, while antagonism of the 5-HT2A receptor increases perseverative errors in rodents (Boulougouris et al. 2008; Boulougouris and Robbins 2010).”

“…and improve reversal learning (Boulougouris et al. 2008) with the orbitofrontal cortex (OFC) an important locus for the latter beneficial effects (Boulougouris and Robbins 2010), consistent with much previous evidence implicating the OFC in reversal learning (Boulougouris et al. 2007; Dias et…”

“Based on the cellular distribution of 5-HT2CRs in the PFC [35] and evidence that antagonism of these receptors in the OFC improves reversal learning [39], we hypothesized that drug-induced increases in the co-localization of 5HT2CRs on PV-ir interneurons could be a mechanism through which drug-induced deficits in cogn…”

“Reversal learning was facilitated by intra-OFC infusions of a 5-HT 2C - receptor antagonist (Alsio et al., 2015; Boulougouris & Robbins, 2010).”

“Moreover, selective ligand activation of 5-HT receptor subtypes within the OFC alters 49 reversal learning, a form of behavioral flexibility (Boulougouris and Robbins 2010; Furr et al., 2012), and 50 other OFC-dependent behaviors such as reinforcer devaluation and response inhibition are blocked by 51 lesions of OFC 5…”

“Serotonergic activity within the OFC, and the 2C receptor, have been implicated in cognitive flexibility by multiple previous studies (Boulougouris and Robbins, 2010; Alsiö et al., 2015, 2021; Barlow et al., 2015).”