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5-HT2A and 5-HT2C receptor antagonists have opposing effects on a measure of impulsivity: interactions with global 5-HT depletion

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Abstract

Rationale

Global serotonin (5-HT) depletion increases the number of premature responses made on the five-choice serial reaction time task (5CSRT) in rats. In contrast, the 5-HT2A receptor antagonist M100907 decreases this measure of impulsivity. Mounting evidence suggests that 5-HT2A and 5-HT2C receptors have opposing effects on behaviour, and that the 5-HT2C receptor antagonist SB 242084 produces a pattern of behaviour similar to 5-HT depletion.

Objectives

To assess the effects of 5-HT2A and 5-HT2C receptor antagonists on performance of the 5CSRT, to directly compare the effects of these drugs with those of ICV 5,7-dihydroxytryptamine (5,7-DHT) lesions and to investigate whether 5-HT depletion affects the action of these agents.

Methods

The effects of M100907 (0, 0.01, 0.03, 0.1 mg/kg IP) and SB 242084 (0, 0.1, 0.25, 0.5 mg/kg IP) were investigated on performance of the 5CSRT in both ICV 5,7-DHT-lesioned and sham-operated rats.

Results

ICV 5,7-DHT lesions, which significantly decreased forebrain levels of 5-HT by around 90%, increased levels of premature responding, decreased omissions and the latency to respond correctly, yet did not affect performance accuracy. M100907 decreased premature responding in sham-operated controls but not in 5-HT-depleted rats. In contrast, SB 242084 increased premature responding in all animals, and also decreased the latency to make a correct response in sham-operated controls.

Conclusions

These data support the view that serotonergic regulation of impulsive behaviour through different members of the 5-HT2 receptor family is functionally heterogeneous. Although both 5-HT2A and 5-HT2C receptors participate in controlling this form of impulsive action, their relative contribution may depend on the endogenous state of the 5-HT system.

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References

  • Arborelius L, Nomikos GG, Hacksell U, Svensson TH (1993) (R)-8-OH-DPAT preferentially increases dopamine release in rat medial prefrontal cortex. Acta Physiol Scand 148:465–466

    CAS  PubMed  Google Scholar 

  • Barnes NM, Sharp T (1999) A review of central 5-HT receptors and their function. Neuropharmacology 38:1083–1152

    Article  CAS  PubMed  Google Scholar 

  • Barker EL, Westphal RS, Schmidt D, Sanders-Bush E (1994) Constitutively active 5-Hydroxytryptamine2C receptors reveal novel inverse agonist activity of receptor ligands. J Biol Chem 269:11687–11690

    CAS  PubMed  Google Scholar 

  • Bjorkland A, Baumgarten HD, Rensch A (1975) 5,7-Dihydroxytryptamine: improvement of its selectivity for serotonin neurons in the CNS by treatment with desipramine. J Neurochem 24:833–835

    PubMed  Google Scholar 

  • Bonvento G, Scatton B, Claustre Y, Rouquier L (1992) Effect of local injection of 8-OH-DPAT into the dorsal or median raphe nuclei on extracellular levels of serotonin in serotonergic projection areas in the rat brain. Neurosci Lett 137:101–104

    Article  CAS  PubMed  Google Scholar 

  • Carli M, Robbins TW, Evenden JL, Everitt BJ (1983) Effects of lesions to ascending noradrenergic neurons on performance of a 5-choice serial reaction time task in rats-implications for theories of dorsal noradrenergic bundle function based on selective attention and arousal. Behav Brain Res 9:361–380

    Article  CAS  PubMed  Google Scholar 

  • Carli M, Samanin R (2000) The 5-HT1A receptor agonist 8-OH-DPAT reduces rats’ accuracy of attentional performance and enhances impulsive responding in a five-choice serial reaction time task: role of presynaptic 5-HT1A receptors. Psychopharmacology 149:259–268

    Article  CAS  PubMed  Google Scholar 

  • Celada P, Puig MV, Casanovas JM, Guillazo G, Artigas F (2001) Control of dorsal raphe serotonergic neurons by the medial prefrontal cortex: involvement of serotonin-1A, GABA(A), and glutamate receptors. J Neurosci 21:9917–9929

    CAS  PubMed  Google Scholar 

  • Chudasama Y, Robbins TW (2003) Dissociable contributions of the orbitofrontal and infralimbic cortex to pavlovian autoshaping and discrimination reversal learning: further evidence for the functional heterogeneity of the rodent frontal cortex. J Neurosci 23:8771–8780

    CAS  PubMed  Google Scholar 

  • Chudasama Y, Passetti F, Rhodes SEV, Lopian D, Desai A, Robbins TW (2003) Dissociable aspects of performance on the 5 choice serial reaction time task following lesions of the dorsal anterior cingulate, infralimbic and orbitofrontal cortex in the rat: differential effects on selectivity, impulsivity and compulsivity. Behav Brain Res 146:105–119

    Article  CAS  PubMed  Google Scholar 

  • Clarke H, Crofts HS, Dalley JW, Robbins TW, Roberts AC (2003) Serial reversal learning and the effects of prefrontal serotonin depletion. Program No. 722.10. 2003 Abstract Viewer/Itinerary Planner. Society for Neuroscience, Washington, DC, 2003. On-line

  • Cole BJ, Robbins TW (1987) Amphetamine impairs the discriminative performance of rats with dorsal noradrenergic bundle lesions on a 5-choice serial reaction time task: new evidence for central dopaminergic-noradrenergic interactions. Psychopharmacology 91:458–466

    CAS  PubMed  Google Scholar 

  • Cole BJ, Robbins TW (1989) Effects of 6-hydroxydopamine lesions of the nucleus accumbens septi on performance of a 5-choice serial reaction-time task in rats-implications for theories of selective attention and arousal. Behav Brain Res 33:165–179

    CAS  PubMed  Google Scholar 

  • Compan V, Segu L, Buhot M-C, Daszuta A (1998) Differential effects of serotonin (5-HT) lesions and synthesis blockade on neuropeptide-Y immunoreactivity and 5-HT1A, 5-HT1B/1D and 5-HT2A/2C receptor binding sites in the rat cerebral cortex. Brain Res 795:264–276

    Article  CAS  PubMed  Google Scholar 

  • Dalley JW, Theobald DE, Eagle DM, Passetti F, Robbins TW (2002) Deficits in impulse control associated with tonically-elevated serotonergic function in rat prefrontal cortex. Neuropsychopharmacology 26:716–728

    Article  CAS  PubMed  Google Scholar 

  • Di Matteo V, Di Giovanni G, Di Mascio M, Esposito E (2000) Biochemical and electrophysiological evidence that RO 60-0175 inhibits mesolimbic dopaminergic function through serotonin2C receptors. Brain Res 865:85–90

    Article  PubMed  Google Scholar 

  • Di Matteo V, De Blasi A, Di Giulio C, Esposito E (2001) Role of 5-HT2C receptors in the control of central dopamine function. Trends Pharmacol Sci 22:229–232

    Article  PubMed  Google Scholar 

  • Fletcher PJ (1995) Effects of combined or separate 5,7-dihydroxytryptamine lesions of the dorsal and median raphe nuclei on responding maintained by a DRL 20s schedule of food reinforcement. Brain Res 675:45–54

    Article  CAS  PubMed  Google Scholar 

  • Fletcher PJ, Grottick AJ, Higgins GA (2002) Differential effects of the 5-HT2A receptor antagonist M100,907 and the 5-HT2C receptor antagonist SB 242,084 on cocaine-induced locomotor activity, cocaine self-administration and cocaine-induced reinstatement of responding. Neuropsychopharmacology 272:576–586

    Google Scholar 

  • Gobert A, Millan MJ (1999) Serotonin (5-HT)2A receptor activation enhances dialysate levels of dopamine and noradrenaline, but not 5-HT, in the frontal cortex of freely-moving rats. Neuropharmacology 38:315–317

    Article  CAS  PubMed  Google Scholar 

  • Gobert A, Rivet JM, Audinot V, Newman-Tancredi A, Cistarelli L, Millan MJ (1998) Simultaneous quantification of serotonin, dopamine and noradrenaline levels in single frontal cortex dialysates of freely-moving rats reveals a complex pattern of reciprocal auto- and heteroreceptor-mediated control of release. Neuroscience 84:413–429

    Article  CAS  PubMed  Google Scholar 

  • Gobert A, Rivet JM, Lejeune F, Newman-Tancredi A, Adhumeau-Auclair A, Nicolas JP, Cistarelli L, Melon C, Millan MJ (2000) Serotonin2C receptors tonically suppress the activity of mesocortical dopaminergic and adrenergic, but not serotonergic, pathways: a combined dialysis and electrophysiological analysis in the rat. Synapse 36:205–221

    Article  CAS  PubMed  Google Scholar 

  • Granon S, Passetti F, Thomas KL, Dalley JW, Everitt BJ, Robbins TW (2000) Enhanced and impaired attentional performance after infusion of D1 dopaminergic receptor agents into rat prefrontal cortex. J Neurosci 20:1208–1215

    CAS  PubMed  Google Scholar 

  • Hajos M, Hajos-Korcsok E, Sharp T (1999) Role of the medial prefrontal cortex in 5-HT1A receptor-induced inhibition of 5-HT neuronal activity in the rat. Br J Pharmacol 126:1741–1750

    CAS  PubMed  Google Scholar 

  • Hall FS, Devries AC, Fong GW, Huang S, Pert A (1999) Effects of 5,7-dihydroxytryptamine depletion of tissue serotonin levels on extracellular serotonin in the striatum assessed with in vivo microdialysis: relationship to behavior. Synapse 33:16–25

    Article  CAS  PubMed  Google Scholar 

  • Harrison AA, Everitt BJ, Robbins TW (1997) Central 5-HT depletion enhances impulsive responding without affecting the accuracy of attentional performance: interactions with dopaminergic mechanisms. Psychopharmacology 133:329–342

    Article  CAS  PubMed  Google Scholar 

  • Harrison AA, Everitt BJ, Robbins TW (1999) Central serotonin depletion impairs both the acquisition and performance of a symmetrically reinforced go/no-go conditional visual discrimination. Behav Brain Res 100:99–112

    Article  CAS  PubMed  Google Scholar 

  • Herrick-Davis K, Grinde W, Teitler M (2000) Inverse agonist activity of atypical antipsychotic drugs at human 5-Hydroxytryptamine2C receptors. J Pharmacol Exp Ther 295:226–232

    CAS  PubMed  Google Scholar 

  • Higgins GA, Enderlin M, Haman M, Fletcher PJ (2003) The 5-HT2A receptor antagonist M100,907 attenuates motor and “impulsive-like” behaviours produced by NMDA receptor antagonism. Psychopharmacology 170:309–319

    Article  CAS  PubMed  Google Scholar 

  • Hollander E, Rosen J (2000) Impulsivity. J Psychopharmacol 14 S1:s39–s44

    Google Scholar 

  • Jones B, Mishkin M (1972) Limbic lesions and the problem of stimulus-reinforcement associations. Exp Neurol 36:362–377

    Article  CAS  PubMed  Google Scholar 

  • Kehne JH, Baron BM, Carr AA, Chaney SF, Elands J, Feldman DJ, Frank RA, VanGiersbergen PLM, 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 277:968–981

    CAS  PubMed  Google Scholar 

  • Kennett G, Wood MD, Bright F, Trail B, Riley G, Holland V, Avenell KY, Stean T, Upton N, Bromidge S, Forbes IT, Brown AM, Middlemiss DN, Blackburn TP (1997) SB 242084, a selective and brain penetrant 5-HT2C receptor antagonist. Neuropharmacology 36:609–620

    Article  CAS  PubMed  Google Scholar 

  • Kirby LG, Kreiss DS, Singh A, Lucki I (1995) Effect of destruction of serotonin neurons on basal and fenfluramine-induced serotonin release in striatum. Synapse 20:99–105

    CAS  PubMed  Google Scholar 

  • Koskinen T, Ruotsalainen S, Puumala T, Lappalainen R, Koivisto E, Mannisto PT, Sirvio J (2000) Activation of 5-HT2A receptors impairs response control of rats in a five-choice serial reaction time task. Neuropharmacology 39:471–481

    Article  CAS  PubMed  Google Scholar 

  • Linnoila M, Virkkunen M, Scheinin M, Nuutila A, Rimon R, Goodwin FK (1983) Low cerebrospinal-fluid 5-Hydroxyindoleacetic acid concentration differentiates impulsive from nonimpulsive violent behavior. Life Sci 33:2609–2614

    Article  CAS  PubMed  Google Scholar 

  • Martin P, Waters N, Schmidt CJ, Carlsson A, Carlsson ML (1998). Rodent data and general hypothesis: antipsychotic action exerted through 5-HT2A receptor antagonism is dependent on increased serotonergic tone. J Neural Transm 105:365–396

    Article  CAS  PubMed  Google Scholar 

  • Matthews K, Dalley JW, Matthews C, Tsai T-H, Robbins TW (2001) Periodic maternal separation of neonatal rats produces regional and gender-specific effects on biogenic amine content in post-mortem adult brain. Synapse 40:1–10

    Article  CAS  PubMed  Google Scholar 

  • McDonald J, Schleifer L, Richards JB, de Wit H (2003). Effects of THC on behavioral measures of impulsivity in humans. Neuropsychopharmacology 28:1356–1365

    Article  CAS  PubMed  Google Scholar 

  • Millan MJ, Dekeyne A, Gobert A (1998) Serotonin (5-HT)2C receptors tonically inhibit dopamine (DA) and noradrenaline (NA), but not 5-HT, release in the frontal cortex in vivo. Neuropharmacology 37:953–955

    Article  CAS  PubMed  Google Scholar 

  • Palkovits M (1973) Isolated removal of hypothalamic or other brain nuclei of the rat. Brain Res 59:449–450

    Article  CAS  PubMed  Google Scholar 

  • Paxinos G, Watson C. (1998) The rat brain in stereotaxic co-ordinates, 4th edn. Academic, Sydney

  • Rogers RD, Everitt BJ, Baldacchino A, Blackshaw AJ, Swainson R, Wynne K, Baker NB, Hunter J, Carthy T, Booker E, London M, Deakin JFW, Sahakian BJ, Robbins TW (1999) Dissociable deficits in the decision-making cognition of chronic amphetamine abusers, opiate abusers, patients with focal damage to prefrontal cortex, and tryptophan-depleted normal volunteers: Evidence for monoaminergic mechanisms. Neuropsychopharmacology 20:322–339

    Article  CAS  PubMed  Google Scholar 

  • Schmidt CJ, Sullivan CK, Fadayel GM (1994) Blockade of striatal 5-hydroxytryptamine2 receptors reduces the increase in extracellular concentrations of dopamine produced by the amphetamine analogue 3,4-methylenedioxymethamphetamine. J Neurochem 62:1382–1389

    CAS  PubMed  Google Scholar 

  • Schoenbaum G, Nugent S, Saddoris MP, Setlow B (2002) Orbitofrontal lesions in rats impair reversal but not acquisition of go/no-go odor discriminations. Neuroreport 13:885–890

    Article  PubMed  Google Scholar 

  • Soubrié P (1986) Reconciling the role of central serotonin neurons in human and animal behavior. Behav Brain Sci 9:319–364

    Google Scholar 

  • Van Oekelen D, Luyten WHML, Leysen JE (2003) 5-HT2A and 5-HT2C receptors and their atypical regulation properties. Life Sci 72:2429–2449

    Article  PubMed  Google Scholar 

  • Winstanley CA, Chudasama Y, Dalley JW, Theobald DE, Glennon JC, Robbins TW (2003a) Intra-prefrontal 8-OH-DPAT and M100907 improve visuospatial attention and decrease impulsivity on the five-choice serial reaction time task in rats. Psychopharmacology 167:304–314

    CAS  PubMed  Google Scholar 

  • Winstanley CA, Theobald DE, Dalley JW, Robbins TW (2003b) Global 5-HT depletion attenuates the ability of amphetamine to decrease impulsive choice in rats. Psychopharmacology 170:320–331

    Article  CAS  PubMed  Google Scholar 

  • Winstanley CA, Theobald DE, Dalley JW, Robbins TW (2004) Fractionating impulsivity: contrasting effects of central 5-HT depletion on different measures of impulsive behavior. Neuropsychopharmacology: http://www.acnp.org/citations/NPP02090403391/default.pdf

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Authors and Affiliations

  1. Department of Experimental Psychology, University of Cambridge, Downing Street, Cambridge, CB2 3EB, UK

    Catharine A. Winstanley, David E. H. Theobald, Jeffrey W. Dalley & Trevor W. Robbins

  2. Department of Biological Lead Optimisation, Solvay Pharmaceuticals, Weesp, 1380 DA, The Netherlands

    Jeffrey C. Glennon

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  1. Catharine A. Winstanley
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  2. David E. H. Theobald
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  3. Jeffrey W. Dalley
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  4. Jeffrey C. Glennon
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  5. Trevor W. Robbins
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Correspondence to Catharine A. Winstanley.

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Winstanley, C.A., Theobald, D.E.H., Dalley, J.W. et al. 5-HT2A and 5-HT2C receptor antagonists have opposing effects on a measure of impulsivity: interactions with global 5-HT depletion. Psychopharmacology 176, 376–385 (2004). https://doi.org/10.1007/s00213-004-1884-9

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  • DOI: https://doi.org/10.1007/s00213-004-1884-9

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