HT and the Five Choice Serial Reaction Time Task 5CSRTT

The 5CSRTT is an animal test widely used with rodents providing substantial validity as a direct measure of different components of attention (for details see Boulougouris and Tsaltas 2008; Carli et al. 1983). In brief, animals are trained to detect the location of a brief visual stimulus presented pseudorandomly in one of the five apertures over a large number of trials. The performance measures include choice accuracy, omissions, premature responses (responses made before the target stimulus), perseverative responses (additional nose pokes made postpresentation of the stimulus in any nose-poke aperture), perseverative panel pushes (additional responses made at the food magazine before or after food retrieval), correct response latency, and food collection latency.

Optimal performance on this apparently simple task requires the integration of several cognitive processes. Sustained attention to the goal area for the duration of the intertrial interval (ITI) is necessary in order not to miss the target, while divided attention across all five exposed holes is essential in order to scan the entire visual array. Other processes measured by this task include sensor, motor or motivational processes, decision making, and inhibitory control (for details see Boulougouris and Tsaltas 2008). Apart from aspects of attention and impulse control, the task is also capable of dissociating performance elements which usually covary, although they probably rely on processes that are under control of different neural mechanisms.

Neurochemically speaking, apart from the involvement of the dopaminergic system in the modulation of the 5CSRTT (discussed in Boulougouris and Tsaltas 2008), the serotonergic system is also heavily implicated. The 5CSRTT is demonstrably sensitive to serotonergic manipulations: Global, 5,7-dihydroxytryptamine (5,7-DHT) lesion-induced 5-HT depletion consistently appears to spare response accuracy, while it increases impulsivity as reflected by increased premature responding and decreased omissions as well as correct response latency (Harrison et al. 1997; Winstanley et al. 2003a, 2004; Koskinen et al. 2000). However, systemic administration of the 5-HT receptor agonist 8-hydroxy-2-(di-«-propylamino)tetraline

(8-OH-DPAT), which also decreases 5-HT release (Bonvento et al. 1992; Hajos et al. 1999; Celada et al. 2001), does not affect impulsive responding and improves attentional performance (Winstanley et al. 2003a). At higher doses, the selective 5-HT1A receptor agonist 8-OH-DPAT reportedly increased impulsivity, possibly by activating presynaptic 5-HT1A receptors (Carli and Samanin 2000). There is an incongruence, then, between the effects of chronic lesion-induced global 5-HT decreases and the effects of acute global decreases such as those affected by systemic administration of a 5-HT1A receptor agonist.

The apparent inconsistency is compounded by the observation that systemic and intra-cerebral administration of the 5-HT2A receptor antagonist M100907 in the prefrontal cortex (PFC) decrease impulsive responding (Winstanley et al. 2003a). Moreover, infusions of M100907 in the medial prefrontal cortex (mPFC) counteracted the loss of executive control [impulsivity induced by the competitive N-methyl-d-aspartate (NMDA) receptor antagonist 3-(R)-2-carboxypiperazin-4-propyl-1-phosphonic acid (CPP)], while 8-OH-DPAT decreased compulsive perseveration (Carli et al. 2006). Thus, an antagonist of the 5-HT system effectively produces effects opposite of those of global decrease in 5-HT transmission. This paradox, along with the observation that 2,5-dimethoxy-4-iodoamphetamine (DOI), a 5-HT2A/2C agonist does increase premature responding, probably through activation of the 5-HT2A receptor (Koskinen et al. 2000), suggests dissociable behavioral contribution of 5-HT receptor subtypes in the 5CSRTT.

Indeed, evidence suggests that the 5-HT2A and 5-HT2C receptors have opposing neurochemical effects. 5-HT2C receptor activation inhibits dopamine release, whereas 5-HT2A activation enhances dopamine release (Di Matteo et al. 2000, 2001; Millan et al. 1998). Antagonism of 5-HT2C and 5-HT2A receptors has opposite effects on some behavioral effects of cocaine (Fletcher et al. 2002). Furthermore, it has been demonstrated that 5-HT2C and 5-HT2A receptors also have contrasting and dissociable behavioral contribution on impulsivity in the 5CSRTT. The selective 5-HT2C antagonist SB 242084 increases premature responding and decreases correct response latency (Winstanley et al. 2004; Higgins et al. 2003) (Fig. 23.1a). This premature responding increase has recently been shown to be mediated by the nucleus accumbens (NAc) (Robinson et al. 2008) (Fig. 23.1c). When the antagonist was administered systemically to 5,7-DHT-lesioned animals, the increase in premature responding emerged over and above the similar effects of the 5,7-DHT lesion (Winstanley et al. 2004). In contrast, the selective 5-HT2A antagonist M100907 had no effect on response latency and actually reduced premature responding, an effect mediated by the NAc (Robinson et al. 2008). The effect of M100907 (administered systemically) was abolished by 5,7-DHT lesions (Winstanley et al. 2004). This dissociation challenges the hypothesis that general decreases in 5-HT neurotransmission increase impulsivity. Furthermore, the fact that antagonism of the 5-HT2C receptor produces a behavioral profile closer to 5,7-DHT lesions than any other receptor so far tested including the 5-HT2A receptor suggests that the 5-HT2C receptor is central in the serotonergic regulation of behavioral inhibition.

Compulsivity, another form of inhibition deficit, is also accessible by the 5CSRTT via the measure of repeated responding at the holes (perseverative responding), offering a putative index of compulsivity. Winstanley et al. (2004) demonstrated that 5,7-DHT lesions increased perseverative as well as impulsive responding, a finding consistent with increased perseverative errors during reversal in the marmoset after localized 5-HT depletion within the PFC (Clarke et al. 2004) and after orbitofrontal cortex (OFC) damage (Jones and Mishkin 1972; Rogers et al. 1999; Schoenbaum et al. 2002; Chudasama and Robbins 2003; Chudasama et al. 2003). Neither 5-HT2A antagonism (M100907) nor 5-HT2C antagonism (SB 242084) appears to affect perseverative responses (Winstanley et al. 2003a, 2004; Higgins et al. 2003; Chudasama and Robbins 2003; Chudasama et al. 2003). These data suggest that different kinds of motor disinhibition differ in their neurobiologi-cal bases, as impulsivity and compulsivity appear to be differentially regulated by the 5-HT system.

Fig. 23.1 (a) Effects of systemic administration of the 5-HT2C receptor antagonist SB 242084 on the percentage of premature responses performed during the 5CSRTT in ICV 5,7-DHT-lesioned animals and sham-operated controls (Reproduced from Winstanley et al. 2004. With permission). (b) Effects of systemic administration of SB 242084 on incorrect responses during spatial reversal learning (Adapted from Boulougouris et al. 2008. With permission). (c) Effects of intra-NAc infusions of SB 242084 on the percent correct, omissions, and premature responses during the 5CSRTT (Reproduced from Robinson et al. 2008. With permission). (d) Effects of intra-OFC infusions of SB 242084 on incorrect responses during spatial reversal learning (Adapted from Boulougouris and Robbins 2010. With permission)

Fig. 23.1 (a) Effects of systemic administration of the 5-HT2C receptor antagonist SB 242084 on the percentage of premature responses performed during the 5CSRTT in ICV 5,7-DHT-lesioned animals and sham-operated controls (Reproduced from Winstanley et al. 2004. With permission). (b) Effects of systemic administration of SB 242084 on incorrect responses during spatial reversal learning (Adapted from Boulougouris et al. 2008. With permission). (c) Effects of intra-NAc infusions of SB 242084 on the percent correct, omissions, and premature responses during the 5CSRTT (Reproduced from Robinson et al. 2008. With permission). (d) Effects of intra-OFC infusions of SB 242084 on incorrect responses during spatial reversal learning (Adapted from Boulougouris and Robbins 2010. With permission)

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