Abstract
Rationale and objectives
Adolescence is a sensitive period of brain development, during which there may be a heightened vulnerability to the effects of drug use. Despite this, the long-term effects of cannabis use during this developmental period on cognition are poorly understood.
Methods
We exposed adolescent rats to escalating doses of Δ9-tetrahydrocannabinol (THC)—the primary psychoactive component of cannabis—or vehicle solution during postnatal days (PND) 35–45, a period of development that is analogous to human adolescence (THC doses: PND 35–37, 2.5 mg/kg; PND 38–41, 5 mg/kg; PND 42–45, 10 mg/kg). After a period of abstinence, in adulthood, rats were tested on an automated touchscreen version of a paired-associates learning (PAL) task to assess their ability to learn and recall object-location associations. Prepulse inhibition (PPI) of the startle response was also measured at three time points (5 days, 4 months, and 6 months after exposure) to assess sensorimotor gating, the ability to filter out insignificant sensory information from the environment.
Results
Compared to rats exposed to vehicle alone, rats exposed to THC during adolescence took longer to learn the PAL task when tested in adulthood, even when trials contained visually identical stimuli that differed only in location. Despite this, no differences were observed later in testing, when trials contained visually distinct stimuli in different locations. Rats exposed to THC also displayed impairments in sensorimotor gating, as measured by prepulse inhibition of the startle response, though this deficit did appear to decrease over time.
Conclusion
Taken together, THC exposure during adolescence produces long-term deficits in associative learning and sensorimotor gating, though the impact of these deficits seems to diminish with time. Thus, adolescence may represent a period of neurocognitive development that is vulnerable to the harms of cannabis use, though the stability of such harms is uncertain.
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References
Addington J, Addington D, Maticka-Tyndale E (1991) Cognitive functioning and positive and negative symptoms in schizophrenia. Schizophr Res 5:123–134. https://doi.org/10.1016/0920-9964(91)90039-T
Andersen SL (2003) Trajectories of brain development: point of vulnerability or window of opportunity? Neurosci Biobehav Rev 27:3–18. https://doi.org/10.1016/S0149-7634(03)00005-8
Andréasson S, Engström A, Allebeck P, Rydberg U (1987) Cannabis and schizophrenia. A longitudinal study of Swedish conscripts. Lancet 330:1483–1486. https://doi.org/10.1016/S0140-6736(87)92620-1
Arseneault L, Cannon M, Witton J, Murray RM (2004) Causal association between cannabis and psychosis: examination of the evidence. Br J Psychiatry 184:110–117. https://doi.org/10.1192/bjp.184.2.110
Barnett JH, Sahakian BJ, Werners U et al (2005) Visuospatial learning and executive function are independently impaired in first-episode psychosis. Psychol Med 35:1031–1041. https://doi.org/10.1017/S0033291704004301
Blackwell AD, Sahakian BJ, Vesey R, Semple JM, Robbins TW, Hodges JR (2004) Detecting dementia: novel neuropsychological markers of preclinical Alzheimer’s disease. Dement Geriatr Cogn Disord 17:42–48. https://doi.org/10.1159/000074081
Braff DL, Geyer MA (1990) Sensorimotor gating and schizophrenia. Human and animal model studies. Arch Gen Psychiatry 47:181–188. https://doi.org/10.1001/archpsyc.1990.01810140081011
Braff DL, Geyer MA, Light GA, Sprock J, Perry W, Cadenhead KS, Swerdlow NR (2001) Impact of prepulse characteristics on the detection of sensorimotor gating deficits in schizophrenia. Schizophr Res 49:171–178. https://doi.org/10.1016/S0920-9964(00)00139-0
Cha YM, White AM, Kuhn CM, Wilson WA, Swartzwelder HS (2006) Differential effects of delta9-THC on learning in adolescent and adult rats. Pharmacol Biochem Behav 83:448–455. https://doi.org/10.1016/j.pbb.2006.03.006
Cha YM, Jones KH, Kuhn CM, Wilson WA, Swartzwelder HS (2007) Sex differences in the effects of delta9-tetrahydrocannabinol on spatial learning in adolescent and adult rats. Behav Pharmacol 18:563–569. https://doi.org/10.1097/FBP.0b013e3282ee7b7e
Dougherty DM, Mathias CW, Dawes MA, Furr RM, Charles NE, Liguori A, Shannon EE, Acheson A (2013) Impulsivity, attention, memory, and decision-making among adolescent marijuana users. Psychopharmacology 226:307–319. https://doi.org/10.1007/s00213-012-2908-5
Ehrenreich H, Rinn T, Kunert HJ et al (1999) Specific attentional dysfunction in adults following early start of cannabis use. Psychopharmacology 142:295–301. https://doi.org/10.1007/S002130050892
Ersche KD, Clark L, London M et al (2007) Europe PMC Funders Group Profile of executive and memory function associated with amphetamine and opiate dependence. Neuropsychopharmacology 31(5):1036–1047. https://doi.org/10.1038/sj.npp.1300889.Profile
Fehr KA, Kalant H, Eugene LeBlanc A (1976) Residual learning deficit after heavy exposure to cannabis or alcohol in rats. Science 192(4245):1249–1251. https://doi.org/10.1126/science.1273591
Fontes MA, Bolla KI, Cunha PJ, Almeida PP, Jungerman F, Laranjeira RR, Bressan RA, Lacerda ALT (2011) Cannabis use before age 15 and subsequent executive functioning. Br J Psychiatry 198:442–447. https://doi.org/10.1192/bjp.bp.110.077479
González S, Cebeira M, Fernández-Ruiz J (2005) Cannabinoid tolerance and dependence: a review of studies in laboratory animals. Pharmacol Biochem Behav 81:300–318. https://doi.org/10.1016/j.pbb.2005.01.028
Gruber SA, Sagar KA, Dahlgren MK, Racine M, Lukas SE (2012) Age of onset of marijuana use and executive function. Psychol Addict Behav 26:496–506. https://doi.org/10.1037/a0026269.Age
Hanson K, Winward J (2010) Longitudinal study of cognition among adolescent marijuana users over three weeks of abstinence. Addict Behav 35:970–976. https://doi.org/10.1016/j.addbeh.2010.06.012.Longitudinal
Harvey MA, Sellman JD, Porter RJ, Frampton CM (2007) The relationship between non-acute adolescent cannabis use and cognition. Drug Alcohol Rev 26:309–319. https://doi.org/10.1080/09595230701247772
Huestis MA, Henningfield JE, Cone EJ (1992) Blood cannabinoids. ii. Models for the prediction of time of marijuana exposure from plasma concentrations of ∆9-tetrahydrocannabinol (THC) and 11-nor-9-carboxy-∆9-tetrahydrocannabinol (THCCOOH). J Anal Toxicol 16:283–290. https://doi.org/10.1093/jat/16.5.283
Johnston LD, Miech RA, O’Malley PM et al (2018) Monitoring the future national survey results on drug use: 1975–2017: overview, key findings on adolescent drug use. Institute for Social Research, The University of Michigan, Ann Arbor. https://doi.org/10.1017/CBO9781107415324.004
Klein C, Karanges E, Spiro A, Wong A, Spencer J, Huynh T, Gunasekaran N, Karl T, Long LE, Huang XF, Liu K, Arnold JC, McGregor IS (2011) Cannabidiol potentiates Δ 9-tetrahydrocannabinol (THC) behavioural effects and alters THC pharmacokinetics during acute and chronic treatment in adolescent rats. Psychopharmacology 218:443–457. https://doi.org/10.1007/s00213-011-2342-0
Lindgren JE, Ohlsson A, Agurell S, Hollister L, Gillespie H (1981) Clinical effects and plasma levels of ??9-tetrahydrocannabinol (??9-THC) in heavy and light users of cannabis. Psychopharmacology 74:208–212. https://doi.org/10.1007/BF00427095
Manrique-Garcia E, Zammit S, Dalman C, Hemmingsson T, Andreasson S, Allebeck P (2012) Cannabis, schizophrenia and other non-affective psychoses: 35 years of follow-up of a population-based cohort. Psychol Med 42:1321–1328. https://doi.org/10.1017/S0033291711002078
Medina KL, Hanson KL, Schweinsburf AD et al (2007) Neuropsychological functioning in adolescent marijuana users: subtle deficits detectable after a month of abstinence. J Int Neuropsychol Soc 13:807–820. https://doi.org/10.1017/S1355617707071032
Meier MH, Caspi A, Ambler A, Harrington H, Houts R, Keefe RSE, McDonald K, Ward A, Poulton R, Moffitt TE (2012) Persistent cannabis users show neuropsychological decline from childhood to midlife. Proc Natl Acad Sci 109:E2657–E2664. https://doi.org/10.1073/pnas.1206820109
Meier MH, Caspi A, Danese A, Fisher HL, Houts R, Arseneault L, Moffitt TE (2018) Associations between adolescent cannabis use and neuropsychological decline: a longitudinal co-twin control study. Addiction 113:257–265. https://doi.org/10.1111/add.13946
Nagai H, Egashira N, Sano K, Ogata A, Mizuki A, Mishima K, Iwasaki K, Shoyama Y, Nishimura R, Fujiwara M (2006) Antipsychotics improve Δ9-tetrahydrocannabinol-induced impairment of the prepulse inhibition of the startle reflex in mice. Pharmacol Biochem Behav 84:330–336. https://doi.org/10.1016/j.pbb.2006.05.018
Nakamura EM, Aparecida E, Valhia G et al (1991) Reversible effects of acute and long-term administration of (THC) on memory in the rat. Drug and Alcohol Dependence 28:167–175. https://doi.org/10.1016/0376-8716(91)90072-7
Owen AM, Sahakian BJ, Semple J, Polkey CE, Robbins TW (1995) Visuo-spatial short-term recognition memory and learning after temporal lobe excisions, frontal lobe excisions or amygdalo-hippocampectomy in man. Neuropsychologia 33:1–24. https://doi.org/10.1016/0028-3932(94)00098-A
Paule MG, Allen RR, Bailey JR, Scallet AC, Ali SF, Brown RM, Slikker W Jr (1992) Chronic marijuana smoke exposure in the rhesus monkey. II: Effects on progressive ratio and conditioned position responding. J Pharmacol Exp Ther 260:210–222. https://doi.org/10.1109/ISDA.2010.5687059
Perry W, Minassian A, Feifel D, Braff DL (2001) Sensorimotor gating deficits in bipolar disorder patients with acute psychotic mania. Biol Psychiatry 50:418–424. https://doi.org/10.1016/S0006-3223(01)01184-2
Pope HG, Gruber AJ, Yurgelun-Todd D (1995) The residual neuropsychological effects of cannabis: the current status of research. Drug Alcohol Depend 38:25–34. https://doi.org/10.1016/0376-8716(95)01097-I
Pope HG, Gruber AJ, Hudson JI et al (2003) Early-onset cannabis use and cognitive deficits: what is the nature of the association? Drug Alcohol Depend 69:303–310. https://doi.org/10.1016/S0376-8716(02)00334-4
Quinn HR, Matsumoto I, Callaghan PD, Long LE, Arnold JC, Gunasekaran N, Thompson MR, Dawson B, Mallet PE, Kashem MA, Matsuda-Matsumoto H, Iwazaki T, McGregor IS (2008) Adolescent rats find repeated delta(9)-THC less aversive than adult rats but display greater residual cognitive deficits and changes in hippocampal protein expression following exposure. Neuropsychopharmacology 33:1113–1126. https://doi.org/10.1038/sj.npp.1301475
Renard J, Krebs MO, Jay TM, Le Pen G (2013) Long-term cognitive impairments induced by chronic cannabinoid exposure during adolescence in rats: a strain comparison. Psychopharmacology 225:781–790. https://doi.org/10.1007/s00213-012-2865-z
Renard J, Rosen LG, Loureiro M et al (2016) Adolescent cannabinoid exposure induces a persistent sub-cortical hyper-dopaminergic state and associated molecular adaptations in the prefrontal cortex. Cereb Cortex 27(2):1297–1310. https://doi.org/10.1093/cercor/bhv335
Rice D, Barone S (2000) Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ Health Perspect 108:511–533. https://doi.org/10.2307/3454543
Rubino T, Realini N, Braida D, Guidi S, Capurro V, Viganò D, Guidali C, Pinter M, Sala M, Bartesaghi R, Parolaro D (2009) Changes in hippocampal morphology and neuroplasticity induced by adolescent THC treatment are associated with cognitive impairment in adulthood. Hippocampus 19:763–772. https://doi.org/10.1002/hipo.20554
Sahakian BJ, Owen AM (1992) Computerized assessment in neuropsychiatry using CANTAB: discussion paper. R Soc Med 85:399–402. https://doi.org/10.1177/014107689208500711
Schneider M (2013) Adolescence as a vulnerable period to alter rodent behavior. Cell Tissue Res 354:99–106. https://doi.org/10.1007/s00441-013-1581-2
Schneider M, Koch M (2003) Chronic pubertal, but not adult chronic cannabinoid treatment impairs sensorimotor gating, recognition memory, and the performance in a progressive ratio task in adult rats. Neuropsychopharmacology 28:1760–1769. https://doi.org/10.1038/sj.npp.1300225
Schneider M, Drews E, Koch M (2003) Behavioral effects in adult rats of chronic prepubertal treatment with the cannabinoid receptor agonist. 447–454
Schwartz RH, Gruenewald PJ, Klitzner M, Fedio P (1989) Short-term memory impairment in cannabis-dependent adolescents. Am J Dis Child 143:1214–1219. https://doi.org/10.1001/archpedi.1989.02150220110030
Schweinsburg AD, Nagel BJ, Schweinsburg BC, Park A, Theilmann RJ, Tapert SF (2008) Abstinent adolescent marijuana users show altered fMRI response during spatial working memory. Psychiatry Res - Neuroimaging 163:40–51. https://doi.org/10.1016/j.pscychresns.2007.04.018
Solowij N, Pesa N (2011) Cannabis and cognition: short-and long-term effects. Marijuana Madness Second Ed 91–102. doi: https://doi.org/10.1017/CBO9780511706080.009
Solowij N, Stephens RS, Roffman RA, Babor T, Kadden R, Miller M, Christiansen K, McRee B, Vendetti J, Marijuana Treatment Project Research Group (2002) Cognitive functioning of long-term heavy cannabis users seeking treatment.[comment][erratum appears in JAMA2002 Apr 3;287(13):1651]. Jama 287:1123–1131
Solowij N, Respondek C, Whittle S (2008) Visuospatial memory deficits in long term heavy cannabis users: relation to psychotic symptoms and regional brain volumes. XXVI CINP Congr 13-17 July. Munich Int J Neuropsychopharmacol 11:242
Solowij N, Jones KA, Rozman ME, Davis SM, Ciarrochi J, Heaven PCL, Lubman DI, Yücel M (2011) Verbal learning and memory in adolescent cannabis users, alcohol users and non-users. Psychopharmacology 216:131–144. https://doi.org/10.1007/s00213-011-2203-x
Spear LP (2000) The adolescent brain and age-related behavioral manifestations. Neurosci Biobehav Rev 24:417–463
Stiglick A, Kalant H (1983) Psychopharmacology behavioral effects of prolonged administration of a 9-tetrahydrocannabinol in the rat. Psychopharmacology 80:325–330
Stiglick A, Kalant H (1985) Residual effects of chronic cannabis treatment on behavior in mature rats. Psychopharmacology 85:436–439. https://doi.org/10.1007/BF00429660
Talpos JC, Winters BD, Dias R, Saksida LM, Bussey TJ (2009) A novel touchscreen-automated paired-associate learning (PAL) task sensitive to pharmacological manipulation of the hippocampus: a translational rodent model of cognitive impairments in neurodegenerative disease. Psychopharmacology 205:157–168. https://doi.org/10.1007/s00213-009-1526-3
Talpos JC, Aerts N, Fellini L, Steckler T (2014) A touch-screen based paired-associates learning (PAL) task for the rat may provide a translatable pharmacological model of human cognitive impairment. Pharmacol Biochem Behav 122:97–106. https://doi.org/10.1016/j.pbb.2014.03.014
Tenn CC, Kapur S, Fletcher PJ (2005) Sensitization to amphetamine, but not phencyclidine, disrupts prepulse inhibition and latent inhibition. Psychopharmacology 180:366–376. https://doi.org/10.1007/s00213-005-2253-z
Van Den Buuse M (2010) Modeling the positive symptoms of schizophrenia in genetically modified mice: pharmacology and methodology aspects. Schizophr Bull 36:246–270. https://doi.org/10.1093/schbul/sbp132
Acknowledgements
Andrew R. Abela was supported by fellowships from the Centre for Addiction and Mental Health (CAMH) and the Canadian Institutes of Health Research (CIHR).
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Abela, A.R., Rahbarnia, A., Wood, S. et al. Adolescent exposure to Δ9-tetrahydrocannabinol delays acquisition of paired-associates learning in adulthood. Psychopharmacology 236, 1875–1886 (2019). https://doi.org/10.1007/s00213-019-5171-1
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DOI: https://doi.org/10.1007/s00213-019-5171-1