RATIONALE: It has been shown that antagonism of the glutamatergic N-methyl-D-aspartate (NMDA) receptor with subanesthetic doses of ketamine perturbs the perception of elapsed time. Anticipatory eye movements are based on an internal representation of elapsed time. Therefore, the occurrence of anticipatory saccades could be a particularly sensitive indicator of abnormal time perception due to NMDA receptors blockade. OBJECTIVES: To determine whether the occurrence of anticipatory saccades could be selectively altered by a subanesthetic dose of ketamine. METHODS: Three Rhesus monkeys were trained in a simple visually-guided saccadic task with a variable delay. Monkeys were rewarded for making a visually-guided saccade at the end of the delay. Premature anticipatory saccades to the future position of the eccentric target initiated before the end of the delay were not rewarded. A sub-anesthetic dose of ketamine (0.25 mg/kg) or a saline solution of the same volume was injected i.m. during the task. RESULTS: We found that the injected dose of ketamine did not induce sedation or abnormal behavior. However, in ~4 minutes, ketamine induced a strong reduction of the occurrence of anticipatory saccades but did not reduce the occurrence of visually-guided saccades. CONCLUSION: This unexpected reduction of anticipatory saccade occurrence could be interpreted as resulting from an altered use of the perception of elapsed time during the delay period induced by NMDA receptors antagonism.
Abi-Saab W., D'Souza D., Moghaddam B., Krystal J., The NMDA Antagonist Model for Schizophrenia: Promise and Pitfalls, 10.1055/s-2007-979354
Ameqrane Ilhame, Pouget Pierre, Wattiez Nicolas, Carpenter Roger, Missal Marcus, Implicit and Explicit Timing in Oculomotor Control, 10.1371/journal.pone.0093958
Arnsten A. F. T., The Neurobiology of Thought: The Groundbreaking Discoveries of Patricia Goldman-Rakic 1937-2003, 10.1093/cercor/bht195
Avila Matthew T., Weiler Martin A., Lahti Adrienne C., Tamminga Carol A., Thaker Gunvant K., Effects of Ketamine on Leading Saccades During Smooth-Pursuit Eye Movements May Implicate Cerebellar Dysfunction in Schizophrenia, 10.1176/appi.ajp.159.9.1490
Association of ketamine-induced psychosis with focal activation of the prefrontal cortex in healthy volunteers, 10.1176/ajp.154.6.805
Buhusi Catalin V., Meck Warren H., What makes us tick? Functional and neural mechanisms of interval timing, 10.1038/nrn1764
Carlsson A, Hansson LO, Waters N, Carlsson ML (1999) A glutamatergic deficiency model of schizophrenia. Br J Psychiatry Suppl 37:2–6
Carroll Christine A., Boggs Jennifer, O’Donnell Brian F., Shekhar Anantha, Hetrick William P., Temporal processing dysfunction in schizophrenia, 10.1016/j.bandc.2007.12.005
Carroll Christine A., O’Donnell Brian F., Shekhar Anantha, Hetrick William P., Timing dysfunctions in schizophrenia span from millisecond to several-second durations, 10.1016/j.bandc.2009.02.001
Carroll Christine A., O’Donnell Brian F., Shekhar Anantha, Hetrick William P., Timing dysfunctions in schizophrenia as measured by a repetitive finger tapping task, 10.1016/j.bandc.2009.06.009
Condy Carine, Wattiez Nicolas, Rivaud-Péchoux Sophie, Gaymard Bertrand, Ketamine-induced distractibility: An oculomotor study in monkeys, 10.1016/j.biopsych.2004.10.036
Corlett P.R., Honey G.D., Fletcher P.C., From prediction error to psychosis: ketamine as a pharmacological model of delusions, 10.1177/0269881107077716
Coull Jennifer T., Getting the Timing Right: Experimental Protocols for Investigating Time with Functional Neuroimaging and Psychopharmacology, Advances in Experimental Medicine and Biology (2014) ISBN:9781493917815 p.237-264, 10.1007/978-1-4939-1782-2_13
Coull Jennifer T, Morgan Hannah, Cambridge Victoria C, Moore James W, Giorlando Francesco, Adapa Ram, Corlett Philip R., Fletcher Paul C, Ketamine perturbs perception of the flow of time in healthy volunteers, 10.1007/s00213-011-2346-9
Davalos Deana B., Kisley Michael A., Ross Randal G., Effects of interval duration on temporal processing in schizophrenia, 10.1016/s0278-2626(03)00157-x
de Hemptinne C., Nozaradan S., Duvivier Q., Lefevre P., Missal M., How Do Primates Anticipate Uncertain Future Events?, 10.1523/jneurosci.0388-07.2007
Funahashi Shintaro, Functions of delay-period activity in the prefrontal cortex and mnemonic scotomas revisited, 10.3389/fnsys.2015.00002
Gråwe R. W., Levander S., Smooth pursuit eye movements and neuropsychological impairments in schizophrenia, 10.1111/j.1600-0447.1995.tb09552.x
Smooth pursuit ocular motor dysfunction in schizophrenia: evidence for a major gene, 10.1176/ajp.149.10.1362
Guillermain Y, N-methyl-?-aspartate receptors and information processing: human choice reaction time under a subanaesthetic dose of ketamine, 10.1016/s0304-3940(01)01695-0
Hartvig Per, Valtysson Johann, Lindner Karl-Johan, Kristensen Jens, Karlsten Rolf, Gustafsson Lars L., Persson Jan, Svensson Jan O., Øye Ivar, Antoni Gunnar, Westerberg Göran, Långström Bengt, Central nervous system effects of subdissociative doses of (S)-ketamine are related to plasma and brain concentrations measured with positron emission tomography in healthy volunteers*, 10.1016/0009-9236(95)90194-9
Heinen S. J., Badler J. B., Ting W., Timing and velocity randomization similarly affect anticipatory pursuit, 10.1167/5.6.1
Higgins G.A., Ballard T.M., Huwyler J., Kemp J.A., Gill R., Evaluation of the NR2B-selective NMDA receptor antagonist Ro 63-1908 on rodent behaviour: evidence for an involvement of NR2B NMDA receptors in response inhibition, 10.1016/s0028-3908(02)00402-1
Higgins Guy A., Ballard Theresa M., Enderlin Michel, Haman Marie, Kemp John A., Evidence for improved performance in cognitive tasks following selective NR2B NMDA receptor antagonist pre-treatment in the rat, 10.1007/s00213-005-2203-9
Homayoun H., Moghaddam B., NMDA Receptor Hypofunction Produces Opposite Effects on Prefrontal Cortex Interneurons and Pyramidal Neurons, 10.1523/jneurosci.2213-07.2007
Janssen Peter, Shadlen Michael N, A representation of the hazard rate of elapsed time in macaque area LIP, 10.1038/nn1386
Krystal John H., Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans : Psychotomimetic, Perceptual, Cognitive, and Neuroendocrine Responses, 10.1001/archpsyc.1994.03950030035004
Krystal John H., Karper Laurence P., Bennett Alexandre, D'Souza D. Cyril, Abi-Dargham Anissa, Morrissey Kristen, Abi-Saab Danielle, Bremner J. Douglas, Bowers Jr. M. B., Suckow Raymond F., Stetson Philip, Heninger George R., Charney Dennis S., Interactive effects of subanesthetic ketamine and subhypnotic lorazepam in humans, 10.1007/s002130050503
Malhotra A, NMDA Receptor Function and Human Cognition: The Effects of Ketamine in Healthy Volunteers, 10.1016/0893-133x(95)00137-3
Malhotra, M.D. A, Ketamine-Induced Exacerbation of Psychotic Symptoms and Cognitive Impairment in Neuroleptic-Free Schizophrenics, 10.1016/s0893-133x(97)00036-5
Functional and Neural Mechanisms of Interval Timing, ISBN:9780849311093, 10.1201/9780203009574
Mettens P, Cheron G, Godaux E (1994) NMDA receptors are involved in temporal integration in the oculomotor system of the cat. Neuroreport 5(11):1333–1336
Micallef Joëlle, Guillermain Yves, Tardieu Sophie, Hasbroucq Thierry, Possamaï Camille, Jouve Elisabeth, Blin Olivier, Effects of Subanesthetic Doses of Ketamine on Sensorimotor Information Processing in Healthy Subjects : , 10.1097/00002826-200203000-00008
Morgan CJ, Mofeez A, Brandner B, Bromley L, Curran HV (2004) Ketamine impairs response inhibition and is positively reinforcing in healthy volunteers: a dose–response study. Psychopharmacology (Berl) 172:298–308
Oye N, Paulsen O, Maurset A (1992) Effects of ketamine on sensory preception: evidence for a role of N-methyl-d-asparate receptors. J Pharmacol Exp Ther 260:1209–1213
Pomarol-Clotet E., Honey G. D., Murray G. K., Corlett P. R., Absalom A. R., Lee M., McKenna P. J., Bullmore E. T., Fletcher P. C., Psychological effects of ketamine in healthy volunteers: Phenomenological study, 10.1192/bjp.bp.105.015263
Radant A, Does Ketamine-Mediated N-methyl-D-aspartate Receptor Antagonism Cause Schizophrenia-like Oculomotor Abnormalities?, 10.1016/s0893-133x(98)00030-x
Rammsayer Thomas H., Effects of pharmacologically induced changes in NMDA receptor activity on human timing and sensorimotor performance, 10.1016/j.brainres.2005.12.019
Reilly James L., Lencer Rebekka, Bishop Jeffrey R., Keedy Sarah, Sweeney John A., Pharmacological treatment effects on eye movement control, 10.1016/j.bandc.2008.08.026
Reutimann Jan, Fusi Stefano, Senn Walter, Yakovlev Volodya, Zohary Ehud, A model of expectation effects in inferior temporal cortex, 10.1016/s0925-2312(01)00551-3
Reutimann J., Climbing Neuronal Activity as an Event-Based Cortical Representation of Time, 10.1523/jneurosci.4098-03.2004
Roberts Brooke M., Seymour Patricia A., Schmidt Christopher J., Williams Graham V., Castner Stacy A., Amelioration of ketamine-induced working memory deficits by dopamine D1 receptor agonists, 10.1007/s00213-010-1840-9
Schmechtig A, Lees J, Perkins A, Altavilla A, Craig K J, Dawson G R, William Deakin J F, Dourish C T, Evans L H, Koychev I, Weaver K, Smallman R, Walters J, Wilkinson L S, Morris R, Williams S C R, Ettinger U, The effects of ketamine and risperidone on eye movement control in healthy volunteers, 10.1038/tp.2013.109
Shen K., Kalwarowsky S., Clarence W., Brunamonti E., Pare M., Beneficial Effects of the NMDA Antagonist Ketamine on Decision Processes in Visual Search, 10.1523/jneurosci.6317-09.2010
Skoblenick K., Everling S., NMDA Antagonist Ketamine Reduces Task Selectivity in Macaque Dorsolateral Prefrontal Neurons and Impairs Performance of Randomly Interleaved Prosaccades and Antisaccades, 10.1523/jneurosci.1510-12.2012
Skoblenick Kevin, Everling Stefan, N-methyl-d-aspartate Receptor Antagonist Ketamine Impairs Action-monitoring Activity in the Prefrontal Cortex, 10.1162/jocn_a_00519
Wang Min, Yang Yang, Wang Ching-Jung, Gamo Nao J., Jin Lu E., Mazer James A., Morrison John H., Wang Xiao-Jing, Arnsten Amy F.T., NMDA Receptors Subserve Persistent Neuronal Firing during Working Memory in Dorsolateral Prefrontal Cortex, 10.1016/j.neuron.2012.12.032
Ameqrane, Ilhame ; Wattiez, Nicolas ; Pouget, Pierre ; Missal, Marcus ; et. al. A subanesthetic dose of ketamine in the Rhesus monkey reduces the occurrence of anticipatory saccades. In: Psychopharmacology, Vol. 232, no. 19, p. 3563-3572 (2015)