Dorsal–striatal 5-HT2A and 5-HT2C receptors control impulsivity and perseverative responding in the 5-choice serial reaction Time Task
Prefrontal cortex (PFC) and dorsal striatum are part of the neural circuit critical for executive attention. The relationship between 5-HT and aspects of attention and executive control is complex depending on experimental conditions and the level of activation of different 5-HT receptors within the nuclei of corticostriatal circuitry.
The present study investigated which 5-HT2A and 5-HT2C receptors in the dorsomedial-striatum (dm-STR) contribute to executive attention deficit induced by blockade of NMDA receptors in the PFC.
Materials and results
Executive attention was assessed by the five-choice serial reaction time task (5-CSRTT), which provides indices of attention (accuracy) and those of executive control over performance such as premature (an index of impulsivity) and perseverative responding. The effects of targeted infusion in dm-STR of 100 and 300 ng/μl doses of the selective 5-HT2A antagonist M100907 and 1 and 3 μg/μl doses of 5-HT2C agonist Ro60-0175 was examined in animals injected with 50 ng/μl dose of a competitive NMDA receptor antagonist 3-(R)-2-carboxypiperazin-4-phosphonic acid (CPP) in the mPFC. Blockade of NMDA receptors impaired accuracy as well as executive control as shown by increased premature and perseverative responding. The CPP-induced premature and perseverative over-responding were dose-dependently prevented by both M100907 and Ro60-0175. Both drugs partially removed the CPP-induced accuracy deficit but only at the highest dose tested.
It is suggested that in the dorsal striatum, 5-HT by an action on 5-HT2A and 5-HT2C receptors may integrate the glutamate corticostriatal inputs critical for different aspects of the 5-CSRT task performance.
Keywords5-HT2A receptor 5-HT2C receptor Dorsal striatum Prefrontal cortex NMDA receptor Attention Rat
- Agnoli L (2011) Modulation of cortical cognitive functions by dopamine and serotonin receptors in the dorsal striatum. Life Science. Open University, Milton Keynes, p 300Google Scholar
- Agnoli L, Carli M (2009) Dopamine D1 and D2 receptors in the dorsal striatum control different aspects of attentional performance in the 5-CSRT task. Behav Pharmacol 20(special Issue1):S92Google Scholar
- Carli M, Robbins TW, Evenden JL, Everitt BJ (1983) Effects of lesions to ascending noradrenergic neurones on performance of a 5-choice serial reaction task in rats; implications for theories of dorsal noradrenergic bundle function based on selective attention and arousal. Behav Brain Res 9:361–380PubMedCrossRefGoogle Scholar
- Carli M, Baviera M, Invernizzi RW, Balducci C (2006) Dissociable contribution of 5-HT1A and 5-HT2A receptors in the medial prefrontal cortex to different aspects of executive control such as impulsivity and compulsive perseveration in rats. Neuropsychopharmacology 31:757–767PubMedCrossRefGoogle Scholar
- Fletcher PJ, Grottick AJ, Higgins GA (2002) Differential effects of the 5-HT(2A) receptor antagonist M100907 and the 5-HT(2 C) receptor antagonist SB242084 on cocaine-induced locomotor activity, cocaine self-administration and cocaine-induced reinstatement of responding. Neuropsychopharmacology 27:576–586PubMedGoogle Scholar
- Gobert A, Rivet JM, Lejeune F, Newman-Tancredi A, Adhumeau-Auclair A, Nicolas JP, Cistarelli L, Melon C, Millan MJ (2000) Serotonin(2 C) receptors tonically suppress the activity of mesocortical dopaminergic and adrenergic, but not serotonergic, pathways: a combined dialysis and electrophysiological analysis in the rat. Synapse 36:205–221PubMedCrossRefGoogle Scholar
- Kehne JH, Baron BM, Carr AA, Chaney SF, Elands J, Feldman DJ, Frank RA, van Giersbergen PL, McCloskey TC, Johnson MP, McCarty DR, Poirot M, Senyah Y, Siegel BW, Widmaier C (1996) Preclinical characterization of the potential of the putative atypical antipsychotic MDL 100,907 as a potent 5-HT2A antagonist with a favorable CNS safety profile. J Pharmacol Exp Ther 277:968–981PubMedGoogle Scholar
- Lucas G, De Deurwaerdere P, Caccia S, Umberto S (2000) The effect of serotonergic agents on haloperidol-induced striatal dopamine release in vivo: opposite role of 5-HT(2A) and 5-HT(2 C) receptor subtypes and significance of the haloperidol dose used. Neuropharmacology 39:1053–1063PubMedCrossRefGoogle Scholar
- Passetti F, Dalley JW, Robbins TW (2003) Double dissociation of serotonergic and dopaminergic mechanisms on attentional performance using a rodent five-choice reaction time task. Psychopharmacology (Berl) 165:136–145Google Scholar
- Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates. Academic Press, London UKGoogle Scholar
- Porras G, Di Matteo V, Fracasso C, Lucas G, De Deurwaerdere P, Caccia S, Esposito E, Spampinato U (2002) 5-HT2A and 5-HT2C/2B receptor subtypes modulate dopamine release induced in vivo by amphetamine and morphine in both the rat nucleus accumbens and striatum. Neuropsychopharmacology 26:311–324PubMedCrossRefGoogle Scholar
- Roberts AC, De Salvia MA, Wilkinson LS, Collins P, Muir JL, Everitt BJ, Robbins TW (1994) 6-Hydroxydopamine lesions of the prefrontal cortex in monkeys enhance performance on an analog of the Wisconsin Card Sort Test: possible interactions with subcortical dopamine. J Neurosci 14:2531–2544PubMedGoogle Scholar
- Steinbusch HWM (1984) Serotonin-immunoreactive neurons and their projections in the CNS. In: Bjorklund A, Hokfelt T, Kuhar MJ (eds) Handbook of chemical neuroanatomy. Elsevier, Amsterdam, pp 68–125Google Scholar
- Wilkinson LS, Dias R, Thomas KL, Augood SJ, Everitt BJ, Robbins TW, Roberts AC (1997) Contrasting effects of excitotoxic lesions of the prefrontal cortex on the behavioural response to D-amphetamine and presynaptic and postsynaptic measures of striatal dopamine function in monkeys. Neuroscience 80:717–730PubMedCrossRefGoogle Scholar
- Winstanley CA, Chudasama Y, Dalley JW, Theobald DE, Glennon JC, Robbins TW (2003) Intra-prefrontal 8-OH-DPAT and M100907 improve visuospatial attention and decrease impulsivity on the five-choice serial reaction time task in rats. Psychopharmacology (Berl) 167:304–314Google Scholar