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.”

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

“(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.”

“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).”

“…between lesion and antagonist studies (e.g., differences in the modalities of the reversal learning task used here and in Roberts and colleagues (Walker et al., 2006; Clarke et al., 2004, 2005, 2007, 2008): object vs spatial response reversal), such explanations would appear rather superficial.”

“, 2008), rat (Schoenbaum et al., 2002; McAlonan and Brown, 2003; Boulougouris et al., 2007)].”

“…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, 1972; Dias et al., 1996; Clarke et al., 2008), rat (Schoenbaum et al.,…”

“The striatum is also implicated in reversal learning: electrolytic lesions of the ventrolateral head of the caudate nucleus in macaques (Divac et al., 1967), excitotoxic lesions of the medial striatum in marmosets (Clarke et al.”

“…OCD, since abnormally reduced activation of the lateral OFC was recently reported during reversal learning in OCD patients and their clinically unaffected close relatives, supporting the existence of an underlying previously undiscovered endophenotype for this disorder (Chamberlain et al., 2008).”

“…between lesion and antagonist studies (e.g., differences in the modalities of the reversal learning task used here and in Roberts and colleagues (Walker et al., 2006; Clarke et al., 2004, 2005, 2007, 2008): object vs spatial response reversal), such explanations would appear rather superficial.”

“For example, recent studies showed no effect of 5-HT depletion on the delayed discounting task (Winstanley et al., 2003), whereas the 5-HT1A receptor agonist 8-OH-DPAT (shown to turn off 5-HT release at autoreceptors) produces impulsive choice (Winstanley et al., 2005).”

“Specifically, it has been shown previously that it is the 5-HT2A receptor antagonist that reduces impulsive responding in the 5CSRTT, whereas the 5-HT2C receptor antagonist exacerbates it (Winstanley et al., 2004).”

“, 2008), rat (Schoenbaum et al., 2002; McAlonan and Brown, 2003; Boulougouris et al., 2007)].”

“Rats were trained on the instrumental two-lever spatial discrimination and serial reversal learning task as described and illustrated previously (Boulougouris et al., 2007, 2008, 2009) (see Fig.”

“, 1967), excitotoxic lesions of the medial striatum in marmosets (Clarke et al., 2008), and nucleus accumbens (NAc) lesions in monkeys (Stern and Passingham, 1995) have been shown to produce reversal impairments.”

“For example, recent studies showed no effect of 5-HT depletion on the delayed discounting task (Winstanley et al., 2003), whereas the 5-HT1A receptor agonist 8-OH-DPAT (shown to turn off 5-HT release at autoreceptors) produces impulsive choice (Winstanley et al.”

“They also show impairments on laboratory tests of frontal lobe function involving response shifting and inhibitory processing that correlate with the severity of their symptoms (Veale et al., 1996; Rosenberg et al., 1997; Schmidtke et al., 1998; Hollander and Rosen, 2000).”

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

“Local blockade of the 5-HT2C receptors in the OFC produced dose-dependent effects similar to those of systemic administration (Boulougouris et al., 2008).”

“Another possibility worth considering arises from the finding that 5-HT2C antagonists enhance neuronal activity in the dorsal raphé, although this has so far been demonstrated to depend on the descending influence of the habenula rather than the OFC (Sharp et al., 2007).”

“…in opposing changes in extracellular glutamate induced by the NMDA antagonist CPP [3-(2-carboxypiperazin-4-yl)propyl1-phosphonic acid] and attentional performance deficits in the 5CSRTT, indicating that 5-HT2A receptors of the mPFC are mainly involved (Ceglia et al., 2004; Carli et al., 2006).”

“Finally, although amygdala lesions do not seem to disrupt reversal learning (Izquierdo and Murray, 2007; Clarke et al., 2008), a recent study demonstrated that basolateral amygdala lesions abolished OFC-induced reversal learning impairments (Stalnaker et al., 2007).”

“They also show impairments on laboratory tests of frontal lobe function involving response shifting and inhibitory processing that correlate with the severity of their symptoms (Veale et al., 1996; Rosenberg et al., 1997; Schmidtke et al., 1998; Hollander and Rosen, 2000).”

“Although OCD patients are not markedly impaired on simple reversal learning that has been associated in animal studies with damage to the OFC and to 5-HT-modulated mechanisms there, they have impairments in other tasks sensitive to OFC function such as alternation learning, a task related to reversal learning (Freedma…”

“As mentioned above, Liu et al. (2007) showed that these receptors definitely occur in certain parts of the rat PFC and have characteristic neuronal locations: this may suggest a similar pattern in the OFC and remains an issue to be addressed in future.”

“These opposing effects on impulsivity have been shown to be mediated in the NAc, but not in the OFC, prelimbic cortex, or infralimbic cortex (Robinson et al., 2008).”

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

“However, a recent study assessing the effects of chronic SSRI administration in rodents has suggested that the anticompulsive effects of the SSRIs is mediated by enhanced 5-HT release in the OFC that activated normosensitive postsynaptic 5-HT2 receptors (El Mansari and Blier, 2006).”

“, NAc (Schoenbaum and Setlow, 2003) vs ventral or medial striatum (Ferry et al.”

“Moreover, it has been reported that NMDA and cholinergic receptor blockade in the dorsomedial striatum also disrupts reversal learning (Palencia and Ragozzino, 2004; Ragozzino et al., 2009).”

“Finally, although amygdala lesions do not seem to disrupt reversal learning (Izquierdo and Murray, 2007; Clarke et al., 2008), a recent study demonstrated that basolateral amygdala lesions abolished OFC-induced reversal learning impairments (Stalnaker et al., 2007).”

“…possibility might be that the 1.0 g dose of the 5-HT2C receptor antagonist SB 242084 has been reported to offer decreased pharmacological specificity, or a preferential activation of a subpopulation of 5-HT2C receptors in different cellular compartments and/or phenotypes (Marek et al., 2005).”

“One possibility is an involvement of 5-HT6 receptors, as it has been shown that 5-HT6 receptor antagonists also enhance reversal learning, although they appear to do so by affecting monoamines and acetylcholine release in the cortex (Hatcher et al., 2005).”

“…serotonergic system is heavily implicated in OCD, for example, via the therapeutic effects of the selective serotonin reuptake inhibitors (SSRIs) (Baumgarten and Grozdanovic, 1998; El Mansari and Blier, 2006) and the 5-HT2 receptor families in the pathophysiology of OCD as well as in the…”

“, discrimination go/no-go (Ferry et al., 2000) vs rule reversal (Block et al.”

“Rats were trained on the instrumental two-lever spatial discrimination and serial reversal learning task as described and illustrated previously (Boulougouris et al., 2007, 2008, 2009) (see Fig.”

“Additionally, OFC 5-HT depletion has also been shown to produce stimulus-bound responding on other tests assessing flexible behavior such as conditioned reinforcement and discrimination extinction (Walker et al., 2009).”

“…in opposing changes in extracellular glutamate induced by the NMDA antagonist CPP [3-(2-carboxypiperazin-4-yl)propyl1-phosphonic acid] and attentional performance deficits in the 5CSRTT, indicating that 5-HT2A receptors of the mPFC are mainly involved (Ceglia et al., 2004; Carli et al., 2006).”

“Moreover, it has been reported that NMDA and cholinergic receptor blockade in the dorsomedial striatum also disrupts reversal learning (Palencia and Ragozzino, 2004; Ragozzino et al., 2009).”

“In neurochemical terms, preclinical and clinical research suggest that a dysregulation of serotonergic systems (5-HT) is involved in behavioral flexibility and response inhibition (for review, see Boulougouris and Tsaltas, 2008).”

“…lesions of the ventrolateral head of the caudate nucleus in macaques (Divac et al., 1967), excitotoxic lesions of the medial striatum in marmosets (Clarke et al., 2008), and nucleus accumbens (NAc) lesions in monkeys (Stern and Passingham, 1995) have been shown to produce reversal impairments.”

“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).”

“…between lesion and antagonist studies (e.g., differences in the modalities of the reversal learning task used here and in Roberts and colleagues (Walker et al., 2006; Clarke et al., 2004, 2005, 2007, 2008): object vs spatial response reversal), such explanations would appear rather superficial.”

“In that study intra-OFC infusions of the 5-HT2C receptor antagonist RS 102221 decreased “surplus” lever pressing in the signal attenuation model, whereas a 5-HT2A receptor antagonist did not produce any significant effects (Flaisher-Grinberg et al., 2008).”

“However, they are in line with the findings of another study that assessed the effects of intra-OFC infusions of a 5-HT2C receptor antagonist in an animal model of OCD.”

“A more interesting hypothesis could be that incomplete 5-HT depletion from OFC may result in 5-HT2C receptor supersensitivity [as may occur in OCD (Graf et al., 2003; Yamauchi et al., 2004)], a possibility that could perhaps be investigated through infusions of 5-HT2C and 5-HT2A receptor antagonists in 5-HT-depleted a…”

“An important new study by Calcagno et al. (2009) showed that there is a balance of 5-HT2A and 5-HT2C receptor activity in this region, which regulates the impulsivity response to glutamate manipulations, presumably via opposite effects on pyramidal cells.”

“…OFC might alleviate obsessivecompulsive symptomatology is in accordance with the hypersensitivity of the 5-HT2C receptors noted in OCD patients (de Leeuw and Westenberg, 2008) and the exacerbation of their symptoms after activation of the same receptors (for discussion, see Boulougouris 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).”