Intra-prefrontal 8-OH-DPAT and M100907 improve visuospatial attention and decrease impulsivity on the five-choice serial reaction time task in rats
- 674 Downloads
The central serotonergic systems are a major target for drugs used to treat neuropsychiatric disorders such as depression and schizophrenia in which disruption of frontal cortex function has been implicated. However, it is not known precisely how serotonin (5-HT) modulates the medial prefrontal cortex (mPFC) to affect cognitive function and behaviour.
To investigate the roles of 5-HT1A and 5-HT2A receptors in mPFC on performance of the five-choice serial reaction time task (5CSRT), which assesses visuospatial attention, impulsivity and motivational processes.
Following training on the 5CSRT, rats were implanted with bilateral guide cannulae aimed at the mPFC. Rats received intra-mPFC infusions of either 8-OH-DPAT (10, 30 and 100 ng) or M100907 (30, 100 and 300 ng) according to a Latin square design.
Both 8-OH-DPAT and M100907 selectively enhanced accuracy of target detection. When the stimulus duration was shortened, infusions of 8-OH-DPAT continued to improve accuracy, whereas M100907 decreased premature responding and omissions, thus partly dissociating the effects of these two compounds. Similar effects were obtained following systemic administration of M100907 and 8-OH-DPAT. The effects of 8-OH-DPAT were blocked by the 5-HT1A antagonist WAY 100635, at a dose that itself had no significant effects on behaviour.
These results indicate that modulation of 5-HT function within the mPFC via distinct receptors can enhance performance on the 5CSRT. These findings suggest a mechanism by which serotonergic agents improve cognitive function, which may be relevant to their therapeutic benefit in the treatment of neuropsychiatric disorders.
Keywords5-HT1A receptor 5-HT2A receptor Prefrontal cortex Attention Impulsivity Schizophrenia
This work was supported by a Wellcome Trust programme grant and completed within the MRC Centre for Behavioural and Clinical Neuroscience. C.A.W. was supported by an MRC studentship.
- Aghajanian GK, Marek GJ (1999b) Serotonin-glutamate interactions: a new target for antipsychotic drugs. Neuropsychopharmacology 21:S122–S133Google Scholar
- Araneda R, Andrade R (1991) 5-hydroxytryptamine2 and 5-hydroxytryptamine1A receptors mediate opposing responses on membrane excitability in rat- association cortex. Neuroscience 40:399–412Google Scholar
- Ashby CR, Edwards E, Wang RY (1994) Electrophysiological evidence for a functional interaction between 5-HT1A and 5-HT2A receptors in the rat medial prefrontal cortex—an iontophoretic study. Synapse 17:173–181Google 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 task in rats—implications for theories of dorsal noradrenergic bundle function based on selective attention and arousal. Behav Brain Res 9:361–380PubMedGoogle Scholar
- Dalley JW, McGaughy J, O'Connell MT, Cardinal RN, Levita L, Robbins TW (2001) Distinct changes in cortical acetylcholine and noradrenaline efflux during contingent and noncontingent performance of a visual attentional task. J Neurosci 21:4908–4914Google Scholar
- Evenden JL (1999a) The pharmacology of impulsive behaviour in rats. VII. The effects of serotonergic agonists and antagonists on responding under a discrimination task using unreliable visual stimuli. Psychopharmacology 146:422–431Google Scholar
- Fletcher PJ, Grottick AJ, Higgins GA (2002) Differential effects of the 5-HT2A receptor antagonist M100,907 and the 5-HT2C receptor antagonist SB242,084 on cocaine-induced locomotor activity, cocaine self-administration and cocaine-induced reinstatement of responding. Neuropsychopharmacology 27:576–586PubMedGoogle 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 84:413–429Google Scholar
- Hajos M, Richards CD, Szekely AD, Sharp T (1998) An electrophysiological and neuroanatomical study of the medial prefrontal cortical projection to the midbrain raphe nuclei in the rat. Neuroscience 87:95–108Google Scholar
- Harel-Dupas C, Cloez I, Fillion G (1991) The inhibitory effect of trifluoromethylphenylpiperazine on [3H]acetylcholine-release in guinea-pig hippocampal synaptosomes is mediated by a 5-hydroxytryptamine1 receptor distinct from 1A-subtype, 1B-subtype, and 1C-subtype. J Neurochem 56:221–227PubMedGoogle Scholar
- Ichikawa J, Meltzer HY (1999) Relationship between dopaminergic and serotonergic neuronal activity in the frontal cortex and the action of typical and atypical antipsychotic drugs. Eur Arch Psych Clin Neurosci 249:90–98Google 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 277:968–981Google Scholar
- Leysen JE, Janssen PMF, Schotte A, Luyten W, Megens A (1993) Interaction of antipsychotic-drugs with neurotransmitter receptor-sites in-vitro and in-vivo in relation to pharmacological and clinical effects—role of 5HT2 receptors. Psychopharmacology 112:S40–S54Google Scholar
- McGaughy J, Dalley JW, Morrison CH, Everitt BJ, Robbins TW (2002) Selective behavioral and neurochemical effects of cholinergic lesions produced by intrabasalis infusions of 192 IgG-saporin on attentional performance in a five-choice serial reaction time task. J Neurosci 22:1905–1913PubMedGoogle Scholar
- Paxinos G, Watson C (1998) The rat brain in stereotaxic co-ordinates, 4th edn. Academic Press, New YorkGoogle Scholar
- Samanin R, Quattrone A, Consolo S, Ladinsky H, Algen S (1978) Biochemical and pharmacological evidence of the interaction of serotonin with other aminergic systems in the brain. In: Garattini S, Pujol JF, Samanin R (eds) Interactions between putative neurotransmitters in the brain. Ravens Press, New York, pp 383–399Google Scholar
- Sorensen SM, Kehne JH, Fadayel GM, Humphreys TM, Ketteler HJ, Sullivan CK, Taylor VL, Schmidt CJ (1993) Characterization of the 5-HT2 receptor antagonist MDL 100907 as a putative atypical antipsychotic—behavioral, electrophysiological and neurochemical studies. J Pharmacol Exp Ther 266:684–691Google Scholar
- Soubrié P (1986) Reconciling the role of central serotonin neurons in human and animal behavior. Behav Brain Sci 9:319–364Google Scholar
- Tandon R (1999) Cholinergic aspects of schizophrenia. Br J Psychiatry 174:7–11Google Scholar
- Zilles K, Wree A (1995) Cortex: areal and laminar structure. In: Paxinos G (ed) The rat nervous system. Academic Press, London, pp 649–685Google Scholar