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.”

“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).”

“…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).”

“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).”

“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].”