Abstract
Introduction
Cannabis use is a well-established component risk factor for schizophrenia; however, the mechanisms by which cannabis use increases schizophrenia risk are unclear. Animal models can elucidate mechanisms by which chronic cannabinoid treatment can induce schizophrenia-relevant neural changes, in a standardised manner often not possible using patient-based data.
Methods
We review recent literature (within the past 10 years) using animal models of chronic and subchronic treatment with cannabinoids which target the cannabinoid 1 receptor [i.e. ∆9-tetrahydrocannabinol, CP55,940 and WIN55,212-2]. Schizophrenia-relevant behavioural consequences of chronic cannabinoid treatment are first briefly summarised, followed by a detailed account of changes to several receptor systems [e.g. cannabinoid, dopaminergic, glutamatergic, γ-aminobutyric acid (GABAe)rgic, serotonergic, noradrenergic], dendritic spine morphology and inflammatory markers following chronic cannabinoids. We distinguish between adolescent and adult cannabinoid treatments, to determine if adolescence is a period of susceptibility to schizophrenia-relevant molecular changes.
Results
Chronic cannabinoid treatment induces behaviours relevant to positive, negative and cognitive symptoms of schizophrenia. Chronic cannabinoids also cause region- and subtype-specific changes to receptor systems (e.g. cannabinoid, dopaminergic, glutamatergic, GABAergic), as well as changes in dendritic spine morphology and upregulation of inflammatory markers. These changes often align with molecular changes observed in post-mortem tissue from schizophrenia patients and correspond with schizophrenia-relevant behavioural change in rodents. There is some indication that adolescence is a period of susceptibility to cannabinoid-induced schizophrenia-relevant neural change, but more research in this field is required to confirm this hypothesis.
Conclusions
Animal models indicate several molecular mechanisms by which chronic cannabinoids contribute to schizophrenia-relevant neural and behavioural change. It is likely that a number of these mechanisms are simultaneously impacted by chronic cannabinoids, thereby increasing schizophrenia risk in individuals who use cannabis. Understanding how cannabinoids can affect several molecular targets provides critical insight into the complex relationship between cannabis use and schizophrenia risk.
Similar content being viewed by others
References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Henquet C, Murray R, Linszen D, van Os J. The environment and schizophrenia: the role of cannabis use. Schizophr Bull. 2005;31(3):608–12.
Large M, Sharma S, Compton MT, Slade T, Nielssen O. Cannabis use and earlier onset of psychosis: a systematic meta-analysis. Arch Gen Psychiatry. 2011;68(6):555–61.
Caspi A, Moffitt TE, Cannon M, McClay J, Murray R, Harrington H, et al. Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene X environment interaction. Biol Psychiatry. 2005;57(10):1117–27.
•• Rubino T, Parolaro D. The impact of exposure to cannabinoids in adolescence: insights from animal models. Biol Psychiatry. 2016;79(7):578–85. Review describing how chronic adolescent cannabinoid exposure affects behavioural domains relevant to schizophrenia.
•• Radhakrishnan R, Wilkinson ST, D’Souza DC. Gone to pot—a review of the association between cannabis and psychosis. Front psych. 2014;5:54. Review describing acute and long-term effects of cannabinoids on schizophrenia symptoms in human patients, as well as moderators of cannabis-induced behaviours (e.g. genetic risk) and provides potential mechanisms for cannabinoid-induced psychosis.
D’Souza DC, Sewell RA, Ranganathan M. Cannabis and psychosis/schizophrenia: human studies. Eur Arch Psychiatry Clin Neurosci. 2009;259(7):413–31.
• Lubman DI, Cheetham A, Yucel M. Cannabis and adolescent brain development. Pharmacol Ther. 2015;148:1–16. Review of human literature which proposes potential mechanisms for adolescent susceptibility to cannabis-induced psychosis.
Spear LP. The adolescent brain and age-related behavioral manifestations. Neurosci Biobehav Rev. 2000;24(4):417–63.
Sengupta P. The laboratory rat: relating its age with human’s. Int J Prev Med. 2013;4(6):624–30.
Enayatfard L, Rostami F, Nasoohi S, Oryan S, Ahmadiani A, Dargahi L. Dual role of PPAR-gamma in induction and expression of behavioral sensitization to cannabinoid receptor agonist WIN55,212-2. NeuroMolecular Med. 2013;15(3):523–35.
Fanarioti E, Mavrikaki M, Panagis G, Mitsacos A, Nomikos GG, Giompres P. Behavioral and neurochemical changes in mesostriatal dopaminergic regions of the rat after chronic administration of the cannabinoid receptor agonist WIN55,212-2. Int J Neuropsychopharmacol. 2014;18(6)
Ginovart N, Tournier BB, Moulin-Sallanon M, Steimer T, Ibanez V, Millet P. Chronic delta(9)-tetrahydrocannabinol exposure induces a sensitization of dopamine D(2)/(3) receptors in the mesoaccumbens and nigrostriatal systems. Neuropsychopharmacology. 2012;37(11):2355–67.
Gomes FV, Guimaraes FS, Grace AA. Effects of pubertal cannabinoid administration on attentional set-shifting and dopaminergic hyper-responsivity in a developmental disruption model of schizophrenia. Int J Neuropsychopharmacol. 2014;18(2)
Harte LC, Dow-Edwards D. Sexually dimorphic alterations in locomotion and reversal learning after adolescent tetrahydrocannabinol exposure in the rat. Neurotoxicol Teratol. 2010;32(5):515–24.
Klug M, van den Buuse M. An investigation into “two hit” effects of BDNF deficiency and young-adult cannabinoid receptor stimulation on prepulse inhibition regulation and memory in mice. Front Behav Neurosci. 2013;7:149.
Long LE, Chesworth R, Huang XF, McGregor IS, Arnold JC, Karl T. Transmembrane domain Nrg1 mutant mice show altered susceptibility to the neurobehavioural actions of repeated THC exposure in adolescence. Int J Neuropsychopharmacol. 2013;16(1):163–75.
O’Brien LD, Wills KL, Segsworth B, Dashney B, Rock EM, Limebeer CL, et al. Effect of chronic exposure to rimonabant and phytocannabinoids on anxiety-like behavior and saccharin palatability. Pharmacol Biochem Behav. 2013;103(3):597–602.
O’Tuathaigh CM, Hryniewiecka M, Behan A, Tighe O, Coughlan C, Desbonnet L, et al. Chronic adolescent exposure to delta-9-tetrahydrocannabinol in COMT mutant mice: impact on psychosis-related and other phenotypes. Neuropsychopharmacology. 2010;35(11):2262–73.
Puighermanal E, Busquets-Garcia A, Gomis-Gonzalez M, Marsicano G, Maldonado R, Ozaita A. Dissociation of the pharmacological effects of THC by mTOR blockade. Neuropsychopharmacology. 2013;38(7):1334–43.
Tai S, Hyatt WS, Gu C, Franks LN, Vasiljevik T, Brents LK, et al. Repeated administration of phytocannabinoid delta(9)-THC or synthetic cannabinoids JWH-018 and JWH-073 induces tolerance to hypothermia but not locomotor suppression in mice, and reduces CB1 receptor expression and function in a brain region-specific manner. Pharmacol Res. 2015;102:22–32.
Wiley JL, Burston JJ. Sex differences in delta(9)-tetrahydrocannabinol metabolism and in vivo pharmacology following acute and repeated dosing in adolescent rats. Neurosci Lett. 2014;576:51–5.
Wiley JL, Evans RL, Grainger DB, Nicholson KL. Age-dependent differences in sensitivity and sensitization to cannabinoids and ‘club drugs’ in male adolescent and adult rats. Addict Biol. 2008;13(3–4):277–86.
Zamberletti E, Beggiato S, Steardo L Jr, Prini P, Antonelli T, Ferraro L, et al. Alterations of prefrontal cortex GABAergic transmission in the complex psychotic-like phenotype induced by adolescent delta-9-tetrahydrocannabinol exposure in rats. Neurobiol Dis. 2014;63:35–47.
• Bambico FR, Nguyen NT, Katz N, Gobbi G. Chronic exposure to cannabinoids during adolescence but not during adulthood impairs emotional behaviour and monoaminergic neurotransmission. Neurobiol Dis. 2010;37(3):641–55. Compares chronic WIN-55,212-2 treatment in adolescent and adult rats; demonstrates long-lasting effects of adolescent, but not adult WIN-55, 212-2 on sucrose preference, as well as serotonergic and noradrenergic cell firing.
Klein C, Karanges E, Spiro A, Wong A, Spencer J, Huynh T, et al. Cannabidiol potentiates delta(9)-tetrahydrocannabinol (THC) behavioural effects and alters THC pharmacokinetics during acute and chronic treatment in adolescent rats. Psychopharmacology. 2011;218(2):443–57.
Leweke FM, Schneider M. Chronic pubertal cannabinoid treatment as a behavioural model for aspects of schizophrenia: effects of the atypical antipsychotic quetiapine. Int J Neuropsychopharmacol. 2011;14(1):43–51.
O’Tuathaigh CM, Clarke G, Walsh J, Desbonnet L, Petit E, O’Leary C, et al. Genetic vs. pharmacological inactivation of COMT influences cannabinoid-induced expression of schizophrenia-related phenotypes. Int J Neuropsychopharmacol. 2012;15(9):1331–42.
Quinn HR, Matsumoto I, Callaghan PD, Long LE, Arnold JC, Gunasekaran N, et al. 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. 2008;33(5):1113–26.
Realini N, Vigano D, Guidali C, Zamberletti E, Rubino T, Parolaro D. Chronic URB597 treatment at adulthood reverted most depressive-like symptoms induced by adolescent exposure to THC in female rats. Neuropharmacology. 2011;60(2–3):235–43.
Rubino T, Vigano D, Realini N, Guidali C, Braida D, Capurro V, et al. Chronic delta 9-tetrahydrocannabinol during adolescence provokes sex-dependent changes in the emotional profile in adult rats: behavioral and biochemical correlates. Neuropsychopharmacology. 2008;33(11):2760–71.
Zamberletti E, Gabaglio M, Prini P, Rubino T, Parolaro D. Cortical neuroinflammation contributes to long-term cognitive dysfunctions following adolescent delta-9-tetrahydrocannabinol treatment in female rats. Eur Neuropsychopharmacol. 2015;25(12):2404–15.
Abboussi O, Tazi A, Paizanis E, El Ganouni S. Chronic exposure to WIN55,212-2 affects more potently spatial learning and memory in adolescents than in adult rats via a negative action on dorsal hippocampal neurogenesis. Pharmacol Biochem Behav. 2014;120:95–102.
Abboussi O, Said N, Fifel K, Lakehayli S, Tazi A, El Ganouni S. Behavioral effects of D3 receptor inhibition and 5-HT4 receptor activation on animals undergoing chronic cannabinoid exposure during adolescence. Metab Brain Dis. 2016;31(2):321–7.
Abush H, Akirav I. Short- and long-term cognitive effects of chronic cannabinoids administration in late-adolescence rats. PLoS One. 2012;7(2):e31731.
Cha YM, Jones KH, Kuhn CM, Wilson WA, Swartzwelder HS. Sex differences in the effects of delta9-tetrahydrocannabinol on spatial learning in adolescent and adult rats. Behav Pharmacol. 2007;18(5–6):563–9.
Cutando L, Busquets-Garcia A, Puighermanal E, Gomis-Gonzalez M, Delgado-Garcia JM, Gruart A, et al. Microglial activation underlies cerebellar deficits produced by repeated cannabis exposure. J Clin Invest. 2013;123(7):2816–31.
Gleason KA, Birnbaum SG, Shukla A, Ghose S. Susceptibility of the adolescent brain to cannabinoids: long-term hippocampal effects and relevance to schizophrenia. Transl Psychiatry. 2012;2:e199.
Higuera-Matas A, Botreau F, Miguens M, Del Olmo N, Borcel E, Perez-Alvarez L, et al. Chronic periadolescent cannabinoid treatment enhances adult hippocampal PSA-NCAM expression in male Wistar rats but only has marginal effects on anxiety, learning and memory. Pharmacol Biochem Behav. 2009;93(4):482–90.
Irimia C, Polis IY, Stouffer D, Parsons LH. Persistent effects of chronic delta9-THC exposure on motor impulsivity in rats. Psychopharmacology. 2015;232(16):3033–43.
Kirschmann EK, Pollock MW, Nagarajan V, Torregrossa MM. Effects of adolescent cannabinoid self-administration in rats on addiction-related behaviors and working memory. Neuropsychopharmacology. 2017;42(5):989–1000.
Lovelace JW, Corches A, Vieira PA, Hiroto AS, Mackie K, Korzus E. An animal model of female adolescent cannabinoid exposure elicits a long-lasting deficit in presynaptic long-term plasticity. Neuropharmacology. 2015;99:242–55.
Raver SM, Haughwout SP, Keller A. Adolescent cannabinoid exposure permanently suppresses cortical oscillations in adult mice. Neuropsychopharmacology. 2013;38(12):2338–47.
Renard J, Krebs MO, Jay TM, Le Pen G. Long-term cognitive impairments induced by chronic cannabinoid exposure during adolescence in rats: a strain comparison. Psychopharmacology. 2013;225(4):781–90.
Rubino T, Realini N, Braida D, Guidi S, Capurro V, Vigano D, et al. Changes in hippocampal morphology and neuroplasticity induced by adolescent THC treatment are associated with cognitive impairment in adulthood. Hippocampus. 2009;19(8):763–72.
Rubino T, Realini N, Braida D, Alberio T, Capurro V, Vigano D, et al. The depressive phenotype induced in adult female rats by adolescent exposure to THC is associated with cognitive impairment and altered neuroplasticity in the prefrontal cortex. Neurotox Res. 2009;15(4):291–302.
Rubino T, Prini P, Piscitelli F, Zamberletti E, Trusel M, Melis M, et al. Adolescent exposure to THC in female rats disrupts developmental changes in the prefrontal cortex. Neurobiol Dis. 2015;73:60–9.
Steel RW, Miller JH, Sim DA, Day DJ. Learning impairment by delta(9)-tetrahydrocannabinol in adolescence is attributable to deficits in chunking. Behav Pharmacol. 2011;22(8):837–46.
Tantra M, Krocher T, Papiol S, Winkler D, Rockle I, Jatho J, et al. St8sia2 deficiency plus juvenile cannabis exposure in mice synergistically affect higher cognition in adulthood. Behav Brain Res. 2014;275:166–75.
Verrico CD, Gu H, Peterson ML, Sampson AR, Lewis DA. Repeated delta9-tetrahydrocannabinol exposure in adolescent monkeys: persistent effects selective for spatial working memory. Am J Psychiatry. 2014;171(4):416–25.
Weed PF, Filipeanu CM, Ketchum MJ, Winsauer PJ. Chronic delta9-tetrahydrocannabinol during adolescence differentially modulates striatal CB1 receptor expression and the acute and chronic effects on learning in adult rats. J Pharmacol Exp Ther. 2016;356(1):20–31.
Winsauer PJ, Daniel JM, Filipeanu CM, Leonard ST, Hulst JL, Rodgers SP, et al. Long-term behavioral and pharmacodynamic effects of delta-9-tetrahydrocannabinol in female rats depend on ovarian hormone status. Addict Biol. 2011;16(1):64–81.
Winsauer PJ, Sutton JL. Chronic administration during early adulthood does not alter the hormonally-dependent disruptive effects of delta-9-tetrahydrocannabinol (delta9-THC) on complex behavior in female rats. Pharmacol Biochem Behav. 2014;117:118–27.
Llorente-Berzal A, Fuentes S, Gagliano H, Lopez-Gallardo M, Armario A, Viveros MP, et al. Sex-dependent effects of maternal deprivation and adolescent cannabinoid treatment on adult rat behaviour. Addict Biol. 2011;16(4):624–37.
Marusich JA, Lefever TW, Antonazzo KR, Craft RM, Wiley JL. Evaluation of sex differences in cannabinoid dependence. Drug Alcohol Depend. 2014;137:20–8.
Silva L, Black R, Michaelides M, Hurd YL, Dow-Edwards D. Sex and age specific effects of delta-9-tetrahydrocannabinol during the periadolescent period in the rat: the unique susceptibility of the prepubescent animal. Neurotoxicol Teratol. 2016;58:88–100.
Tournier BB, Ginovart N. Repeated but not acute treatment with (9)-tetrahydrocannabinol disrupts prepulse inhibition of the acoustic startle: reversal by the dopamine D(2)/(3) receptor antagonist haloperidol. Eur Neuropsychopharmacol. 2014;24(8):1415–23.
Wegener N, Koch M. Behavioural disturbances and altered Fos protein expression in adult rats after chronic pubertal cannabinoid treatment. Brain Res. 2009;1253:81–91.
Gur RE, Keshavan MS, Lawrie SM. Deconstructing psychosis with human brain imaging. Schizophr Bull. 2007;33(4):921–31.
• Jones CA, Watson DJ, Fone KC. Animal models of schizophrenia. Br J Pharmacol. 2011;164(4):1162–94. Review describing genetic, pharmacological, neurodevelopmental and lesion-induced animal models of schizophrenia.
Perry W, Minassian A, Henry B, Kincaid M, Young JW, Geyer MA. Quantifying over-activity in bipolar and schizophrenia patients in a human open field paradigm. Psychiatry Res. 2010;178(1):84–91.
Perry W, Minassian A, Paulus MP, Young JW, Kincaid MJ, Ferguson EJ, et al. A reverse-translational study of dysfunctional exploration in psychiatric disorders: from mice to men. Arch Gen Psychiatry. 2009;66(10):1072–80.
Mei L, Xiong WC. Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. Nat Rev Neurosci. 2008;9(6):437–52.
Williams HJ, Owen MJ, O’Donovan MC. Is COMT a susceptibility gene for schizophrenia? Schizophr Bull. 2007;33(3):635–41.
Han S, Yang BZ, Kranzler HR, Oslin D, Anton R, Farrer LA, et al. Linkage analysis followed by association show NRG1 associated with cannabis dependence in African Americans. Biol Psychiatry. 2012;72(8):637–44.
Pertwee RG. Ligands that target cannabinoid receptors in the brain: from THC to anandamide and beyond. Addict Biol. 2008;13(2):147–59.
Powell CM, Miyakawa T. Schizophrenia-relevant behavioral testing in rodent models: a uniquely human disorder? Biol Psychiatry. 2006;59(12):1198–207.
•• Pratt J, Winchester C, Dawson N, Morris B. Advancing schizophrenia drug discovery: optimizing rodent models to bridge the translational gap. Nat Rev Drug Discov. 2012;11(7):560–79. Critical review of animal models for schizophrenia. Outlines limitations and suggests improvements to currently used models.
Powell SB, Weber M, Geyer MA. Genetic models of sensorimotor gating: relevance to neuropsychiatric disorders. Curr Top Behav Neurosci. 2012;12:251–318.
Behan AT, Hryniewiecka M, O’Tuathaigh CM, Kinsella A, Cannon M, Karayiorgou M, et al. Chronic adolescent exposure to delta-9-tetrahydrocannabinol in COMT mutant mice: impact on indices of dopaminergic, endocannabinoid and GABAergic pathways. Neuropsychopharmacology. 2012;37(7):1773–83.
Lopez-Gallardo M, Lopez-Rodriguez AB, Llorente-Berzal A, Rotllant D, Mackie K, Armario A, et al. Maternal deprivation and adolescent cannabinoid exposure impact hippocampal astrocytes, CB1 receptors and brain-derived neurotrophic factor in a sexually dimorphic fashion. Neuroscience. 2012;204:90–103.
Silva L, Harte-Hargrove L, Izenwasser S, Frank A, Wade D, Dow-Edwards D. Sex-specific alterations in hippocampal cannabinoid 1 receptor expression following adolescent delta-9-tetrahydrocannabinol treatment in the rat. Neurosci Lett. 2015;602:89–94.
Thibault K, Carrel D, Bonnard D, Gallatz K, Simon A, Biard M, et al. Activation-dependent subcellular distribution patterns of CB1 cannabinoid receptors in the rat forebrain. Cereb Cortex. 2013;23(11):2581–91.
Higuera-Matas A, Botreau F, Del Olmo N, Miguens M, Olias O, Montoya GL, et al. Periadolescent exposure to cannabinoids alters the striatal and hippocampal dopaminergic system in the adult rat brain. Eur Neuropsychopharmacol. 2010;20(12):895–906.
Lobo MK, Zaman S, Damez-Werno DM, Koo JW, Bagot RC, DiNieri JA, et al. DeltaFosB induction in striatal medium spiny neuron subtypes in response to chronic pharmacological, emotional, and optogenetic stimuli. J Neurosci. 2013;33(47):18381–95.
Fan N, Yang H, Zhang J, Chen C. Reduced expression of glutamate receptors and phosphorylation of CREB are responsible for in vivo delta9-THC exposure-impaired hippocampal synaptic plasticity. J Neurochem. 2010;112(3):691–702.
Renard J, Vitalis T, Rame M, Krebs MO, Lenkei Z, Le Pen G, et al. Chronic cannabinoid exposure during adolescence leads to long-term structural and functional changes in the prefrontal cortex. Eur Neuropsychopharmacol. 2016;26(1):55–64.
Candelaria-Cook FT, Hamilton DA. Chronic cannabinoid agonist (WIN 55,212-2) exposure alters hippocampal dentate gyrus spine density in adult rats. Brain Res. 2014;1542:104–10.
• Moretti S, Franchi S, Castelli M, Amodeo G, Somaini L, Panerai A, et al. Exposure of adolescent mice to delta-9-tetrahydrocannabinol induces long-lasting modulation of pro- and anti-inflammatory cytokines in hypothalamus and hippocampus similar to that observed for peripheral macrophages. J NeuroImmune Pharmacol. 2015;10(2):371–9. Demonstrates that adolescent, but not adult THC treatment causes long-lasting changes to inflammatory markers in the hippocampus and hypothalamus.
Volk DW, Eggan SM, Horti AG, Wong DF, Lewis DA. Reciprocal alterations in cortical cannabinoid. Receptor 1 binding relative to protein immunoreactivity and transcript levels in schizophrenia. Schizophr Res. 2014;159(1):124–9.
Rais M, van Haren NE, Cahn W, Schnack HG, Lepage C, Collins L, et al. Cannabis use and progressive cortical thickness loss in areas rich in CB1 receptors during the first five years of schizophrenia. Eur Neuropsychopharmacol. 2010;20(12):855–65.
Rapp C, Walter A, Studerus E, Bugra H, Tamagni C, Rothlisberger M, et al. Cannabis use and brain structural alterations of the cingulate cortex in early psychosis. Psychiatry Res. 2013;214(2):102–8.
Seillier A, Martinez AA, Giuffrida A. Phencyclidine-induced social withdrawal results from deficient stimulation of cannabinoid CB(1) receptors: implications for schizophrenia. Neuropsychopharmacology. 2013;38(9):1816–24.
Seeman P. Atypical antipsychotics: mechanism of action. Can J Psychiatr. 2002;47(1):27–38.
Bolkan SS, Carvalho Poyraz F, Kellendonk C. Using human brain imaging studies as a guide toward animal models of schizophrenia. Neuroscience. 2016;321:77–98.
Brisch R, Saniotis A, Wolf R, Bielau H, Bernstein HG, Steiner J, et al. The role of dopamine in schizophrenia from a neurobiological and evolutionary perspective: old fashioned, but still in vogue. Front psych. 2014;5:47.
Howes OD, Kambeitz J, Kim E, Stahl D, Slifstein M, Abi-Dargham A, et al. The nature of dopamine dysfunction in schizophrenia and what this means for treatment. Arch Gen Psychiatry. 2012;69(8):776–86.
Kambeitz J, Abi-Dargham A, Kapur S, Howes OD. Alterations in cortical and extrastriatal subcortical dopamine function in schizophrenia: systematic review and meta-analysis of imaging studies. Br J Psychiatry. 2014;204(6):420–9.
Fusar-Poli P, Meyer-Lindenberg A. Striatal presynaptic dopamine in schizophrenia, part I: meta-analysis of dopamine active transporter (DAT) density. Schizophr Bull. 2013;39(1):22–32.
Moghaddam B, Javitt D. From revolution to evolution: the glutamate hypothesis of schizophrenia and its implication for treatment. Neuropsychopharmacology. 2012;37(1):4–15.
Poels EM, Kegeles LS, Kantrowitz JT, Javitt DC, Lieberman JA, Abi-Dargham A, et al. Glutamatergic abnormalities in schizophrenia: a review of proton MRS findings. Schizophr Res. 2014;152(2–3):325–32.
Balu DT, Coyle JT. The NMDA receptor ‘glycine modulatory site’ in schizophrenia: D-serine, glycine, and beyond. Curr Opin Pharmacol. 2015;20:109–15.
Hu W, MacDonald ML, Elswick DE, Sweet RA. The glutamate hypothesis of schizophrenia: evidence from human brain tissue studies. Ann N Y Acad Sci. 2015;1338:38–57.
Kristiansen LV, Huerta I, Beneyto M, Meador-Woodruff JH. NMDA receptors and schizophrenia. Curr Opin Pharmacol. 2007;7(1):48–55.
Vinkers CH, Mirza NR, Olivier B, Kahn RS. The inhibitory GABA system as a therapeutic target for cognitive symptoms in schizophrenia: investigational agents in the pipeline. Expert Opin Investig Drugs. 2010;19(10):1217–33.
Lewis DA, Curley AA, Glausier JR, Volk DW. Cortical parvalbumin interneurons and cognitive dysfunction in schizophrenia. Trends Neurosci. 2012;35(1):57–67.
Tse MT, Piantadosi PT, Floresco SB. Prefrontal cortical gamma-aminobutyric acid transmission and cognitive function: drawing links to schizophrenia from preclinical research. Biol Psychiatry. 2015;77(11):929–39.
Selvaraj S, Arnone D, Cappai A, Howes O. Alterations in the serotonin system in schizophrenia: a systematic review and meta-analysis of postmortem and molecular imaging studies. Neurosci Biobehav Rev. 2014;45:233–45.
Yamamoto K, Hornykiewicz O. Proposal for a noradrenaline hypothesis of schizophrenia. Prog Neuro-Psychopharmacol Biol Psychiatry. 2004;28(5):913–22.
Muntoni AL, Pillolla G, Melis M, Perra S, Gessa GL, Pistis M. Cannabinoids modulate spontaneous neuronal activity and evoked inhibition of locus coeruleus noradrenergic neurons. Eur J Neurosci. 2006;23(9):2385–94.
Selemon LD, Zecevic N. Schizophrenia: a tale of two critical periods for prefrontal cortical development. Transl Psychiatry. 2015;5:e623.
Moyer CE, Shelton MA, Sweet RA. Dendritic spine alterations in schizophrenia. Neurosci Lett. 2015;601:46–53.
Leza JC, Garcia-Bueno B, Bioque M, Arango C, Parellada M, Do K, et al. Inflammation in schizophrenia: a question of balance. Neurosci Biobehav Rev. 2015;55:612–26.
Feigenson KA, Kusnecov AW, Silverstein SM. Inflammation and the two-hit hypothesis of schizophrenia. Neurosci Biobehav Rev. 2014;38:72–93.
Watkins CC, Andrews SR. Clinical studies of neuroinflammatory mechanisms in schizophrenia. Schizophr Res. 2016;176(1):14–22.
Flatow J, Buckley P, Miller BJ. Meta-analysis of oxidative stress in schizophrenia. Biol Psychiatry. 2013;74(6):400–9.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
The authors declare that they have no conflicts of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Additional information
This article is part of the Topical Collection on Genetics and Neuroscience
Rights and permissions
About this article
Cite this article
Chesworth, R., Karl, T. Molecular Basis of Cannabis-Induced Schizophrenia-Relevant Behaviours: Insights from Animal Models. Curr Behav Neurosci Rep 4, 254–279 (2017). https://doi.org/10.1007/s40473-017-0120-y
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40473-017-0120-y