Traditionally, ketamine was considered useful as a dissociative anesthetic. More recently, ketamine has been examined for its effects as a fast-acting antidepressant, for treatment-resistant depression, and as a non-opiate treatment of chronic pain. Unfortunately, ketamine has enjoyed popularity as a recreational drug among both adolescents and young adults. While some research suggests the use of this drug during neurodevelopment is not without consequence, relatively little work has been conducted to examine the chronic effects of ketamine on the adolescent brain at different stages of neural development. Using a rodent model of development, we probed the effects of early adolescent exposure to ketamine. Between postnatal days 22 to 40, a period comprising early to mid-adolescence, rats were exposed to one of two doses of ketamine or saline. Beginning at 90 days of age and drug free for 50 days, a series of neuropsychological assessments were employed to examine general activity, spatial navigation, as well as nonspatial response learning. Contrary to prediction, except for differences in general activity levels, no spatial or nonspatial impairments were found among the drug- and saline-treated animals. The present results are considered in light of ketamine-associated effects found in a related study with older adolescent rats and the role of drug exposure during different points in adolescent brain development.
Dotson, J.W., Ackerman, D.L. and West, L.J. (1995) Ketamine Abuse. Journal of Drug Issues, 25, 751-757. https://doi.org/10.1177/002204269502500407
Domino, E.F., Domino, S.E., Smith, R.E., Domino, L.E., Goulet, J.R., Domino, K.E. and Zsigmond, E.K. (1984) Ketamine Kinetics in Unpremedicated and Diazepam-Premedicated Subjects. Clinical Pharmacology & Therapeutics, 36, 645-553. https://doi.org/10.1038/clpt.1984.235
Moghaddam, B., Adams, B., Verma, A. and Daly, D. (1997) Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex. Journal of Neuroscience, 17, 2921-2927. https://doi.org/10.1523/JNEUROSCI.17-08-02921.1997
Dahan, A., Olofsen, E., Sigtermans, M., Noppers, I., Niesters, M., Aarts, L., Bauer, M. and Sarton, E. (2011) Population Pharmacokinetic-Pharmacodynamic Modeling of Ketamine-Induced Pain Relief of Chronic Pain. European Journal of Pain, 15, 258-267. https://doi.org/10.1016/j.ejpain.2010.06.016
Mion, G. (2017) History of Anaesthesia: The Ketamine Story—Past, Present and Future. European Journal of Anaesthesiology, 34, 571-575. https://doi.org/10.1097/EJA.0000000000000638
Nejati, A., Jalili, M., Abbasi, S., Sarwari, F.T., Bidari, A., Ghajarzadeh, M. and Akhgar, A. (2019) Intranasal Ketamine Reduces Pain of Digital Nerve Block: A Double Blind Randomized Clinical Trial. American Journal of Emergency Medicine, 37, 1622-1626. https://doi.org/10.1016/j.ajem.2018.11.026
Nejati, A., Moharari, R.S., Ashraf, H., Labaf, A. and Golshani, K. (2011) Ketamine/Propofol versus Midazolam/Fentanyl for Procedural Sedation and Analgesia in the Emergency Department: A Randomized, Prospective, Double-Blind Trial. Academic Emergency Medicine, 18, 800-806. https://doi.org/10.1111/j.1553-2712.2011.01133.x
Ralph, Q., Paolino, C. and Meara, D. (2019) Subjective Changes in Mood and Chronic Pain Status-Post Intravenous Ketamine for Oral and Facial Surgery. Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology, 128, e22. https://doi.org/10.1016/j.oooo.2019.02.250
Daly, E.J., Singh, J.B., Fedgchin, M., Cooper, K., Lim, P., Shelton, R.C., Thase, M.E., Winokur, A., Van Nueten, L., Manji, H. and Drevets, W.C. (2018) Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression a Randomized Clinical Trial. JAMA Psychiatry, 75, 139-148. https://doi.org/10.1001/jamapsychiatry.2017.3739
Ramachandran, V.S. and Seckel, E.L. (2010) Using Mirror Visual Feedback and Virtual Reality to Treat Fibromyalgia. Medical Hypotheses, 75, 495-496. https://doi.org/10.1016/j.mehy.2010.07.003
Zorumski, C.F., Izumi, Y. and Mennerick, S. (2016) Ketamine: NMDA Receptors and Beyond. Journal of Neuroscience, 36, 11158-11164. https://doi.org/10.1523/JNEUROSCI.1547-16.2016
McDougall, S.A., Moran, A.E., Baum, T.J., Apodaca, M.G. and Real, V. (2017) Effects of Ketamine on the Unconditioned and Conditioned Locomotor Activity of Preadolescent and Adolescent Rats: Impact of Age, Sex, and Drug Dose. Psychopharmacology, 234, 2683-2696. https://doi.org/10.1007/s00213-017-4660-3
Aalto, S., Ihalainen, J., Hirvonen, J., Kajander, J., Scheinin, H., Tanila, H., Någren, K., Vilkman, H., Gustafsson, L.L., Syvälahti, E. and Hietala, J. (2005) Cortical Glutamate-Dopamine Interaction and Ketamine-Induced Psychotic Symptoms in Man. Psychopharmacology, 182, 375-383. https://doi.org/10.1007/s00213-005-0092-6
Amann, L.C., Halene, T.B., Ehrlichman, R.S., Luminais, S.N., Ma, N., Abel, T. and Siegel, S.J. (2009) Chronic Ketamine Impairs Fear Conditioning and Produces Long-Lasting Reductions in Auditory Evoked Potentials. Neurobiology of Disease, 35, 311-317. https://doi.org/10.1016/j.nbd.2009.05.012
Dimaggio, C., Sun, L.S. and Li, G. (2011) Early Childhood Exposure to Anesthesia and Risk of Developmental and Behavioral Disorders in a Sibling Birth Cohort. Anesthesia & Analgesia, 113, 1143-1151. https://doi.org/10.1213/ANE.0b013e3182147f42
Miech, R.A., Johnston, L.D., O’Malley, P.M., Bachman, J.G., Schulenberg, J.E. and Patrick, M.E. (2020) Monitoring the Future National Survey Results on Drug Use, 1975-2019: Volume I, Secondary School Students. Institute for Social Research, The University of Michigan, Ann Arbor. https://doi.org/10.3998/2027.42/150622 http://monitoringthefuture.org/pubs.html#monographs
Tan, S., Lam, W.P., Wai, M.S., Yu, W.H. and Yew, D.T. (2012) Chronic Ketamine Administration Modulates Midbrain Dopamine System in Mice. PLoS ONE, 7, e43947. https://doi.org/10.1371/journal.pone.0043947
Palamar, J.J., Salomone, A., Rutherford, C. and Keyes, K.M. (2020) Extensive Underreported Exposure to Ketamine among Electronic Dance Music Party Attendees. Journal of General Internal Medicine. https://doi.org/10.1007/s11606-020-05672-x
Palamar, J.J., Acosta, P., Le, A., Cleland, C.M. and Nelson, L.S. (2019) Adverse Drug-Related Effects among Electronic Dance Music Party Attendees. International Journal of Drug Policy, 73, 81-87. https://doi.org/10.1016/j.drugpo.2019.07.005
Palamar, J.J., Griffin-Tomas, M. and Ompad, D.C. (2015) Illicit Drug Use among Rave Attendees in a Nationally Representative Sample of Us High School Seniors. Drug and Alcohol Dependence, 152, 24-31. https://doi.org/10.1016/j.drugalcdep.2015.05.002
Lofwall, M.R., Griffiths, R.R. and Mitzer, M.Z. (2006) Cognitive and Subjective Acute Dose Effects of Intramuscular Ketamine in Healthy Adults. Experimental and Clinical Psychopharmacology, 14, 439-449. https://doi.org/10.1037/1064-1297.14.4.439
Morgan, C.J.A., Riccelli, M., Maitland, C.H. and Curran, H.V. (2004) Long-Term Effects of Ketamine: Evidence for a Persisting Impairment of Source Memory in Recreational Users. Drug and Alcohol Dependence, 75, 301-308. https://doi.org/10.1016/j.drugalcdep.2004.03.006
Morgan, C.J.A., Mofeez, A., Brandner, B., Bromley, L. and Curran, H.V. (2004) Acute Effects of Ketamine on Memory Systems and Psychotic Symptoms in Healthy Volunteers. Neuropsychopharmacology, 29, 208-218. https://doi.org/10.1038/sj.npp.1300342
Dillon, P., Copeland, J. and Jansen, K. (2003) Patterns of Use and Harms Associated with Non-Medical Ketamine Use. Drug and Alcohol Dependence, 69, 23-28. https://doi.org/10.1016/S0376-8716(02)00243-0
Curran, H.V. and Morgan, C. (2000) Cognitive, Dissociative and Psychotogenic Effects of Ketamine in Recreational Users on the Night of Drug Use and 3 Days Later. Addiction, 95, 575-590. https://doi.org/10.1046/j.1360-0443.2000.9545759.x
Driesen, N.R., McCarthy, G., Bhagwagar, Z., Bloch, M.H., Calhoun, V.D., D’souza, D.C., Gueorguieva, R., He, G., Leung, H.-C., Ramani, R., Anticevic, A., Suckow, R.F., Morgan, P.T. and Krystal, J.H. (2013) The Impact of NMDA Receptor Blockade on Human Working Memory-Related Prefrontal Function and Connectivity. Neuropsychopharmacology, 38, 2613. https://doi.org/10.1038/npp.2013.170
Morgan, C.J., Muetzelfeldt, L. and Curran, H.V. (2009) Ketamine Use, Cognition and Psychological Wellbeing: A Comparison of Frequent, Infrequent and Ex-Users with Polydrug and Non-Using Controls. Addiction, 104, 77-87. https://doi.org/10.1111/j.1360-0443.2008.02394.x
Morgan, C.J., Muetzelfeldt, L. and Curran, H.V. (2010) Consequences of Chronic Ketamine Self-Administration upon Neurocognitive Function and Psychological Wellbeing: A 1-Year Longitudinal Study. Addiction, 105, 121-133. https://doi.org/10.1111/j.1360-0443.2009.02761.x
Sassano-Higgins, S., Baron, D., Juarez, G., Esmaili, N. and Gold, M. (2016) A Review of Keta Mine Abuse and Diversion. Depression and Anxiety, 33, 718-727. https://doi.org/10.1002/da.22536
Tirelli, E., Laviola, G. and Adriani, W. (2003) Ontogenesis of Behavioral Sensitization and Conditioned Place Preference Induced by Psychostimulants in Laboratory Rodents. Neuroscience and Biobehavioral Reviews, 27, 163-178. https://doi.org/10.1016/S0149-7634(03)00018-6
Spear, L.P. (2000) The Adolescent Brain and Age-Related Behavioral Manifestations. Neuroscience and Biobehavioral Reviews, 24, 417-463. https://doi.org/10.1016/S0149-7634(00)00014-2
Salmanzadeh, H., Ahmadi-Soleimani, S.M., Pachenari, N., Azadi, M., Halliwell, R.F., Rubino, T. and Azizi, H. (2020) Adolescent Drug Exposure: A Review of Evidence for the Development of Persistent Changes in Brain Function. Brain Research Bulletin, 156, 105-117. https://doi.org/10.1016/j.brainresbull.2020.01.007
Spear, L.P. (2016) Consequences of Adolescent Use of Alcohol and Other Drugs: Studies Using Rodent Models. Neuroscience and Biobehavioral Reviews, 70, 228-243. https://doi.org/10.1016/j.neubiorev.2016.07.026
Andersen, S.L. (2003) Trajectories of Brain Development: Point of Vulnerability or Window of Opportunity? Neuroscience and Biobehavioral Reviews, 27, 3-18. https://doi.org/10.1016/S0149-7634(03)00005-8
Schepis, T.S., Adinoff, B. and Rao, U. (2008) Neurobiological Processes in Adolescent Addictive Disorders. American Journal of Addictions, 17, 6-23. https://doi.org/10.1080/10550490701756146
Lisdahl, K.M., Sher, K.J., Conway, K.P., Gonzalez, R., Ewing, S.W.F., Nixon, S.J., Tapert, S., Bartsch, H., Goldstein, R.Z. and Heitzeg, M. (2018) Adolescent Brain Cognitive Development (ABCD) Study: Overview of Substance Use Assessment Methods. Developmental Cognitive Neuroscience, 32, 80-96. https://doi.org/10.1016/j.dcn.2018.02.007
Compton, D.F., Wedge, T.J. and Poulton, K. (2013) A Neuropsychological Assessment of the Effects of Chronic Ketamine Exposure in a Rodent Model of Drug Abuse. International Journal of Life Science and Medical Research, 3, 179-192. https://doi.org/10.5963/LSMR0305001
Davis, J.M., Compton, D.M., Heit, M., Fravel, A. and Wood, K. (2020) Neuropsychological Assessment of Spatial and Nonspatial Learning and Memory in Rats Following Ketamine Exposure during Late Adolescence. Journal of Behavioral and Brain Research. https://doi.org/10.4236/jbbs.2020.1012036
Schwinn, T.M., Schinke, S.P. and Trent, D.N. (2010) Substance Use among Late Adolescent Urban Youths: Mental Health and Gender Influences. Addictive Behaviors, 35, 30-34. https://doi.org/10.1016/j.addbeh.2009.08.005
Hartman, R.E., Lee, J.M., Zipfel, G.J. and Wozniak, D.F. (2005) Characterizing Learning Deficits and Hippocampal Neuron Loss Following Transient Global Cerebral Ischemia in Rats. Brain Research, 1043, 48-56. https://doi.org/10.1016/j.brainres.2005.02.030
Compton, D.M., Luetzenberg, F.S. and Watkins, E. (2016) Tripping the Light Fantastic: Modelling the Consequences of Recreational Use of MDMA or 5-MeO-DIPT in Humans Using Weekend “Rave” Exposures in Rat. Psychology & Neuroscience, 9, 105-124. https://doi.org/10.1037/pne0000043
McDaniel, W.F., Via, J.D., Smith, J.S., Wells, D.L., Fu, J.J. Bishop, J.F., Ledesma, H.M., et al. (1995) Unilateral Injury of Posterior Parietal Cortex and Spatial Learning in Hooded Rats. Behavioural Brain Research, 70, 165-179. https://doi.org/10.1016/0166-4328(95)80006-9
Compton, D.M., Dietrich, K.L., Selinger, M.C. and Testa, E.K. (2011) 5-Methoxy-N,N-di(iso)propyl Tryptamine Hydrochloride (Foxy)-Induced Cognitive Deficits in Rat after Exposure in Adolescence. Physiology & Behavior, 103, 203-209. https://doi.org/10.1016/j.physbeh.2011.01.021
IBM SPSS Statistics for Windows (Version 23.0) [Computer Software]. IBM Corp., Armonk.
Compton, D.M., Selinger, M.C., Westman, E. and Otero, P. (2011) Differentiation of MDMA or 5-MeO-DIPT Induced Cognitive Deficits in Rats Following Adolescent Exposure. Psychology & Neuroscience, 4, 157-169. https://doi.org/10.3922/j.psns.2011.1.018
Spear, L.P. (2015) Adolescent Alcohol Exposure: Are There Separable Vulnerable Periods within Adolescence. Physiology & Behavior, 148, 122-130. https://doi.org/10.1016/j.physbeh.2015.01.027
Gogtay, N., Giedd, J.N., Lusk, L., Hayashi, K.M., Greenstein, D., Vaituzis, A.C., Nugent III, T.F., Herman, D.H., Clasen, L.S., Toga, A.W., Rapoport, J.L. and Thompson, P.M. (2004) Dynamic Mapping of Human Cortical Development during Childhood through Early Adulthood. Proceedings of the National Academy of Sciences of the United States of America, 101, 8174-8179. https://doi.org/10.1073/pnas.0402680101
Sowell, E.R., Thompson, P.M., Tessner, K.D. and Toga, A.W. (2001) Mapping Continued Brain Growth and Gray Matter Density Reduction in Dorsal Frontal Cortex: Inverse Relationships during Postadolescent Brain Maturation. Journal of Neuroscience, 21, 8819-8829. https://doi.org/10.1523/JNEUROSCI.21-22-08819.2001
Schulz, K.M. and Sisk, C.L. (2016) The Organizing Actions of Adolescent Gonadal Steroid Hormones on Brain and Behavioral Development. Neuroscience and Biobehavioral Reviews, 70, 148-158. https://doi.org/10.1016/j.neubiorev.2016.07.036
Badre, D., Kayser, A.S. and D’Esposito, M. (2010) Frontal Cortex and the Discovery of Abstract Action Rules. Neuron, 66, 315-326. https://doi.org/10.1016/j.neuron.2010.03.025
Dow-Edwards, D., MacMaster, F.P., Peterson, B.S., Niesink, R., Andersen, S. and Braams, B.R. (2019) Experience during Adolescence Shapes Brain Development: From Synapses and Networks to Normal and Pathological Behavior. Neurotoxicology and Teratology, 76, Article ID: 106834. https://doi.org/10.1016/j.ntt.2019.106834
Winters, K.C., Fahnhorst, T., Botzet, A., Lee, S. and Lalone, B. (2012) Brief Intervention for Drug-Abusing Adolescents in a School Setting: Outcomes and Mediating Factors. Journal of Substance Abuse Treatment, 42, 279-288. https://doi.org/10.1016/j.jsat.2011.08.005
Pascual, M., Montesinos, J. and Guerri, C. (2018) Role of the Innate Immune System in the Neuropathological Consequences Induced by Adolescent Binge Drinking. Journal of Neuroscience Research, 96, 765-780. https://doi.org/10.1002/jnr.24203
Citri, A. and Malenka, R.C. (2008) Synaptic Plasticity: Multiple Forms, Functions, and Mechanisms. Neuropsychopharmacology 33, 18-41. https://doi.org/10.1038/sj.npp.1301559
Colonnese, M.T. and Constantine-Paton, M. (2006) Developmental Period for N-methyl-D-aspartate (NMDA) Receptor-Dependent Synapse Elimination Correlated with Visuotopic Map Refinement. Journal of Comparative Neurology, 494, 738-751. https://doi.org/10.1002/cne.20841
Hofer, M. and Constantine-Paton, M. (1994) Regulation of N-methyl-D-aspartate (NMDA) Receptor Function during the Rearrangement of Developing Neuronal Connections. Progress in Brain Research, 102, 277-285. https://doi.org/10.1016/S0079-6123(08)60546-4
Tyler, M.W., Yourish, H.B., Ionescu, D.F. and Haggarty, S.J. (2017) Classics in Chemical Neuroscience: Ketamine. ACS Chemical Neuroscience, 8, 1122-1134. https://doi.org/10.1021/acschemneuro.7b00074
Colwell, C.S., Cepeda, C., Crawford, C. and Levine, M.S. (1998) Postnatal Development of Glutamate Receptor-Mediated Responses in the Neostriatum. Developmental Neuroscience, 20, 154-163. https://doi.org/10.1159/000017310
Henson, M.A., Roberts, A.C., Salimi, K., Vadlamudi, S., Hamer, R.M., Gilmore, J.H., Jarskog, F. and Philpot, B.D. (2008) Developmental Regulation of the NMDA Receptor Subunits, NR3A and NR1, in Human Prefrontal Cortex. Cerebral Cortex, 18, 2560-2573. https://doi.org/10.1093/cercor/bhn017
Insel, T.R., Miller, L.P. and Gelhard, R.E. (1990) The Ontogeny of Excitatory Amino Acid Receptors in Rat Forebrain-I. N-methyl-D-aspartate and Quisqualate Receptors. Neuroscience, 35, 31-43. https://doi.org/10.1016/0306-4522(90)90117-M
Luo, J., Bosy, T.Z., Wang, Y., Yasuda, R.P. and Wolfe, B.B. (1996) Ontogeny of NMDA R1 Subunit Protein Expression in Five Regions of Rat Brain. Developmental Brain Research, 92, 10-17. https://doi.org/10.1016/0165-3806(95)00191-3
Bates, M.L.S. and Trujillo, K.A. (2019) Long-Lasting Effects of Repeated Ketamine Administration in Adult and Adolescent Rats. Behavioural Brain Research, 369, Article ID: 111928. https://doi.org/10.1016/j.bbr.2019.111928
Adriani, W., Granstrem, O., Macri, S., Izykeonva, G., Dambinova, S. and Laviola, G. (2004) Behavioral and Neurochemical Vulnerability during Adolescence in Mice: Studies with Nicotine. Neuropsychopharmacology, 29, 869-878. https://doi.org/10.1038/sj.npp.1300366
Adriani, W., Macri, S., Pacifici, R. and Laviola, G. (2002) Peculiar Vulnerability to Nicotine Oral Self-Administration in Mice during Early Adolescence. Neuropsychopharmacology, 27, 212-224. https://doi.org/10.1016/S0893-133X(02)00295-6
Dao, J.M., McQuown, S.C., Loughlin, S.E., Belluzzi, J.D. and Leslie, F.M. (2011) Nicotine Alters Limbic Function in Adolescent Rat by a 5-HT1A Receptor Mechanism. Neuropharmacology, 36, 1319-1331. https://doi.org/10.1038/npp.2011.8
Einon, D.F. and Morgan, M.J. (1977) A Critical Period for Social Isolation in the Rat. Developmental Psychobiology, 10, 123-132. https://doi.org/10.1002/dev.420100205
Onaolapo, A.Y., Ayeni, O.J., Ogundeji, M.O., Ajao, A., Onaolapo, O.J. and Owolabi, A.R. (2019) Subchronic Ketamine Alters Behaviour, Metabolic Indices and Brain Morphology in Adolescent Rats: Involvement of Oxidative Stress, Glutamate Toxicity and Caspase-3-Mediated Apoptosis. Journal of Chemical Neuroanatomy, 96, 22-33. https://doi.org/10.1016/j.jchemneu.2018.12.002
Varlinskaya, E.I., Truxell, E.M. and Spear, L.P. (2014) Chronic Intermittent Ethanol during Adolescence: Effects on Social Behavior and Ethanol Sensitivity in Adulthood. Alcohol, 48, 433-444. https://doi.org/10.1016/j.alcohol.2014.01.012
Sung, J., Wang, Y., Chandrasekaran, S., Witten, D.M. and Price, N.D. (2012) Molecular Signatures from Omics Data: From Chaos to Consensus. Biotechnology Journal, 7, 946-957. https://doi.org/10.1002/biot.201100305
Lu, Y., Allen, M., Halt, A.R., Weisenhaus, M., Dallapiazza, R.F., Hall, D.D., et al. (2007) Age-Dependent Requirement of AKAP150-Anchored PKA and GluR2-Lacking AMPA Receptors in LTP. EMBO Journal, 26, 4879-4890. https://doi.org/10.1038/sj.emboj.7601884
Rudy, J.W. (2014) The Neurobiology of Learning and Memory, 2nd Edition, Sinauer (US), Sunderland.
Spear, L.P. (2011) Brain Development. In: Brown, B.B. and Prinstein, M.J., Eds., Encyclopedia of Adolescence, Academic Press, London, 87-95. https://doi.org/10.1016/B978-0-12-373951-3.00006-5
Sleigh, J., Harvey, M., Voss, L. and Denny, B. (2014) Ketamine—More Mechanisms of Action than Just NMDA Blockade. Trends in Anaesthesia and Critical Care, 4, 76-81. https://doi.org/10.1016/j.tacc.2014.03.002
Cai, Y.C., Ma, L., Fan, G.H., Zhao, J., Jiang, L.Z. and Pei, G. (1997) Activation of N-methyl-D-aspartate Receptor Attenuates Acute Responsiveness of Delta-Opioid Receptors. Molecular Pharmacology, 51, 583-587. https://doi.org/10.1124/mol.51.4.583
Wang, M., Wong, A.H. and Liu, F. (2012) Interactions between NMDA and Dopamine Receptors: A Potential Therapeutic Target. Brain Research, 1476, 154-163. https://doi.org/10.1016/j.brainres.2012.03.029