HT and Reversal Learning

Tests such as the WCST, which index cognitive flexibility, in fact address several similar yet distinct forms of attentional shifts. For example, if we consider discrimination learning based on compound stimuli involving two perceptual dimensions (e.g., shapes and lines), where exemplars of these dimensions occur in combination with one another on successive trials, one exemplar of one particular dimension being correct (e.g., vertical but not skewed line correct), then (1) when the relevant stimulus dimension (i.e., lines) stays constant but novel stimuli are used (e.g., straight but not curly line correct), this is an intradimensional (ID) shift; (2) when an exemplar from the previously irrelevant dimension (shapes) becomes correct (square but not triangle), then an extradimensional (ED) shift is demanded; finally (3) when the stimuli remain the same, but the previously correct exemplar is now incorrect (triangle but not square), then we refer to reversal learning, a shift which can occur either at the compound discrimination learning stage or after the ID or ED shift.

Different tests of attentional flexibility involving ID or ED shifts and reversal are used translationally. Such procedures by necessity engage other processes besides switching attention (e.g., ability to utilize feedback denoting that a shift is necessary, ability to overcome "learned irrelevance" of a previously nonoperative perceptual dimension). However, the precise nature of any failure to make a required shift can be further analyzed (see, e.g., Owen et al. 1993).

Accumulating evidence implicated the serotonergic system in reversal learning but not in attentional shifting. Selective 5-HT depletion in the marmoset had no effect on ED or serial ID shifting, but it produced a large deficit in reversal learning due to perseverative responding to the previously rewarded object (Clarke et al. 2004, 2008, 2005, 2007).

In human volunteers, transient depletion of central 5-HT by the tryptophan depletion technique produced effects on discrimination learning that were especially evident in reversal learning (Park et al. 1994). Another study (Rogers et al. 1999) also reported that tryptophan depletion led to relatively selective effects on human reversal learning (but see also reference Talbot et al. 2006) with no effect on ED shifting. Evers et al. (2005) showed that behavioral reversal was accompanied by significant signal change in the right ventrolateral and dorsome-dial PFC of healthy volunteers performing a probabilistic reversal task. Tryptophan depletion enhanced reversal-related signal change in the dorsomedial PFC only, affecting the blood oxygen level-dependent (BOLD) signal specifically associated with negative feedback. These data indicate that the 5-HT system has a modula-tory role in reversal learning specifically.

On the receptor level, recent evidence suggests that different 5-HT receptor subtypes have distinct roles in the modulation of reversal learning. Boulougouris et al. (2008) established a double dissociation in the role of 5-HT2C and 5-HT2A receptor subtypes in serial spatial reversal learning. Specifically, systemic administration of the 5-HT2C receptor antagonist SB 242084 facilitated spatial reversal learning in a dose-dependent manner (Fig. 23.1b). Selective infusions into the orbitofrontal cortex (OFC) of SB 242084 also promoted reversal learning, whereas infusions in the mPFC or nucleus accumbens did not. The facilitation of reversal learning therefore appears to be mediated by 5-HT2C receptors within the OFC (Boulougouris and Robbins 2010) (Fig. 23.1d). In contrast, systemic treatment with the 5-HT2A receptor antagonist M100907 dose-dependently impaired reversal learning, on the first reversal of the series in particular. This deficit emerged as increased perseveration of the previously correct response, reproducing the effects observed after selective orbitofrontal 5,7-DHT lesions (Clarke et al. 2004, 2005, 2007) as well as orbitofrontal cortical lesions in rats and nonhuman primates (Chudasama and Robbins 2003; Dias et al. 1996; Boulougouris et al. 2007).

The finding that the enhancement of spatial reversal learning via 5-HT2C receptor blockade is actually mediated by the OFC is apparently at odds with the above-mentioned lesion studies. This is not the only instance where contrasting effects between 5-HT depletion and 5-HT receptor antagonism have been reported. For example, recent studies showed no effect of 5-HT depletion on the delayed discounting task (Winstanley et al. 2003b), while the 5-HT1A receptor agonist 8-OH-DPAT (shown to turn off 5-HT release at autoreceptors) produces impulsive choice (Winstanley et al. 2005). Therefore, although the discrepancy could be attributed to task differences between lesion and antagonist studies (e.g., differences in the modalities of the reversal learning task used here and by Roberts and colleagues: object versus spatial response reversal), such explanations would appear rather superficial. A more interesting hypothesis is that the discrepancy between the lesion and antagonist studies may reflect incomplete 5-HT depletion from OFC resulting in 5-HT2C receptor supersensitivity (as may occur in OCD) (Graf et al. 2003; Yamauchi et al. 2004). This possibility could perhaps be investigated through infusions of 5-HT2C and 5-HT2A receptor antagonists on 5-HT depleted animals.

These findings are of considerable theoretical and clinical importance. At a theoretical level, the opposing effects of 5-HT2A and 5-HT2C antagonism on perseverative responding in spatial reversal learning task (increase and decrease, respectively) contrast with the also reverse effects of these agents on impulsive responding in the 5CSRTT (see Sect. 23.3 on 5CSRTT). Specifically, intra-PFC 5-HT2A antagonism decreases impulsive responding (Winstanley et al. 2003a; Higgins et al. 2003), whereas 5-HT2C antagonism increases it (Winstanley et al. 2004). These observations are relevant to the concept of an impulsivity-compulsivity spectrum in obsessive-compulsive spectrum disorders (Hollander and Rosen 2000). At a clinical level, these data also bear on the issue of whether 5-HT2C receptor antagonists might be expected to be useful in the treatment of human obsessive-compulsive disorder (OCD).

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