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Anxiety and cognitive-related effects of Δ 9-tetrahydrocannabinol (THC) are differentially mediated through distinct GSK-3 vs. Akt-mTOR pathways in the nucleus accumbens of male rats

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Abstract

Rationale

Δ9-tetrahydrocannabinol (THC) is the primary psychoactive compound in cannabis and is responsible for cannabis-related neuropsychiatric side effects, including abnormal affective processing, cognitive and sensory filtering deficits and memory impairments. A critical neural region linked to the psychotropic effects of THC is the nucleus accumbens shell (NASh), an integrative mesocorticolimbic structure that sends and receives inputs from multiple brain areas known to be dysregulated in various disorders, including schizophrenia and anxiety-related disorders. Considerable evidence demonstrates functional differences between posterior vs. anterior NASh sub-regions in the processing of affective and cognitive behaviours influenced by THC. Nevertheless, the neuroanatomical regions and local molecular pathways responsible for these psychotropic effects are not currently understood.

Objectives

The objectives of this study were to characterize the effects of intra-accumbens THC in the anterior vs. posterior regions of the NASh during emotional memory formation, sensorimotor gating and anxiety-related behaviours.

Methods

We performed an integrative series of translational behavioural pharmacological studies examining anxiety, sensorimotor gating and fear-related associative memory formation combined with regionally specific molecular signalling analyses in male Sprague Dawley rats.

Results

We report that THC in the posterior NASh causes distortions in emotional salience attribution, impaired sensory filtering and memory retention and heightened anxiety, through a glycogen-synthase-kinase-3 (GSK-3)-β-catenin dependent signalling pathway. In contrast, THC in the anterior NASh produces anxiolytic effects via modulation of protein kinase B (Akt) phosphorylation states.

Conclusions

These findings reveal critical new insights into the neuroanatomical and molecular mechanisms associated with the differential neuropsychiatric side effects of THC in dissociable nucleus accumbens sub-regions.

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References

  • Ahmad T, Lauzon NM, de Jaeger X, Laviolette SR (2013) Cannabinoid transmission in the prelimbic cortex bidirectionally controls opiate reward and aversion signaling through dissociable kappa versus -opiate receptor dependent mechanisms. J Neurosci 33:15642–15651

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Aleman A, Kahn RS, Selten J (2003) Sex differences in the risk of schizophrenia: evidence from meta-analysis. Arch Gen Psychiatry 60:565–571

    Article  PubMed  Google Scholar 

  • Asif-Malik A, Dautan D, Young AMJ, Gerdjikov TV (2017) Altered cortico-striatal crosstalk underlies object recognition memory deficits in the sub-chronic phencyclidine model of schizophrenia. Brain Struct Funct 222:3179–3190

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Behrendt RP (2016) Hallucinatory experience as aberrant event memory formation: implications for the pathophysiology of schizophrenia. Prog Neuro-Psychopharm Biol Psychiatry 71:203–209

    Article  CAS  Google Scholar 

  • Bergeron Y, Chagniel L, Bureau G, Massicotte G, Cyr M (2014) mTOR signaling contributes to motor skill learning in mice. Frontiers Mol Neurosci 7:1–11

    Article  Google Scholar 

  • Bhattacharyya S, Crippa JA, Allen P, Martin-Santos R, Borgwardt S, Fusar-Poli P et al (2012) Induction of psychosis by 9-tetrahydrocannabinol reflects modulation of prefrontal and striatal function during attentional salience processing. Arch Gen Psychiatry 69:27–36

    Article  CAS  PubMed  Google Scholar 

  • Bhattacharyya S, Fusar-Poli P, Borgwardt S, Martin-Santos R, Nosarti C, O’Carrol C et al (2009) Modulation of mediotemporal and ventrostriatal function in humans by Δ 9-tetrahydrocannabinol. Arch General Psychiatry 66:442–451

    Article  CAS  Google Scholar 

  • Bhattacharyya S, Morrison PD, Fusar-Poli P, Martin-Santos R, Borgwardt S, Winton-Brown T et al (2010) Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology. Neuropsychopharmacology 35:764–774

    Article  CAS  PubMed  Google Scholar 

  • Bossong MG, Mehta MA, Van Berckel BNM, Howes OD, Kahn RS, Stokes PRA (2015) Further human evidence for striatal dopamine release induced by administration of δ9-tetrahydrocannabinol (THC): selectivity to limbic striatum. Psychopharmacology 232:2723–2729

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bousman CA, Glatt SJ, Chandler SD, Lohr J, Kremen WS, Tsuang MT, Everall IP (2013) Negative symptoms of psychosis correlate with gene expression of the Wnt/-catenin signaling pathway in peripheral blood. Psychiatry J 2013:852930

    Article  PubMed  PubMed Central  Google Scholar 

  • Buonocore M, Bosia M, Baraldi MA, Bechi M, Spangaro M, Cocchi F et al (2018) Exploring anxiety in schizophrenia: new light on a hidden figure. Psychiatry Res 268:312–316

    Article  PubMed  Google Scholar 

  • Castro DC, Terry RA, Berridge KC (2016) Orexin in rostral hotspot of nucleus accumbens enhances sucrose “liking” and intake but scopolamine in caudal shell shifts “liking” toward “disgust” and “fear.” Neuropsychopharmacology 41:2101–2111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chadha R, Meador-Woodruff JH (2020) Downregulated AKT-mTOR signaling pathway proteins in dorsolateral prefrontal cortex in schizophrenia. Neuropsychopharmacology 45:1059–1067

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cheer JF (2004) Cannabinoids enhance subsecond dopamine release in the nucleus accumbens of awake rats. J Neurosci 24:4393–4400

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Childs E, Lutz JA, de Wit H (2017) Dose-related effects of delta-9-THC on emotional responses to acute psychosocial stress. Drug Alcohol Dependence 177:136–144

    Article  CAS  PubMed  Google Scholar 

  • Cohen K, Weinstein A (2018) The effects of cannabinoids on executive functions: evidence from cannabis and synthetic cannabinoids—a systematic review. Brain Sci 8:40

    Article  PubMed Central  Google Scholar 

  • Conzelmann A, Pauli P, Mucha RF, Jacob CP, Gerdes ABM, Romanos J, Bahne CG, Heine M, Hummer A, Alpers GW, Fallgatter AJ, Warnke A, Lesch KP, Weyers P (2010) Early attentional deficits in an attention-to-prepulse paradigm in ADHD adults. J Abnormal Psychology 119:594–603

    Article  Google Scholar 

  • Craft RM, Marusich JA, Wiley JL (2013) Sex differences in cannabinoid pharmacology: a reflection of differences in the endocannabinoid system? Life Sci 92:476–481

    Article  CAS  PubMed  Google Scholar 

  • Cuesta S, Batuecas J, Severin MJ, Funes A, Rosso SB, Pacchioni AM (2017) Role of Wnt/β-catenin pathway in the nucleus accumbens in long-term cocaine-induced neuroplasticity: a possible novel target for addiction treatment. J Neurochemistry 140:114–125

    Article  CAS  Google Scholar 

  • Di Forti M, Iyegbe C, Sallis H, Kolliakou A, Falcone MA, Paparelli A, Sirianni M, La Cascia C, Stilo SA, Marques TR, Handley R, Mondelli V, Dazzan P, Pariante C, David AS, Morgan C, Powell J, Murray RM (2012) Confirmation that the Akt1 (rs2494732) genotype influences the risk of psychosis in cannabis users. Biol Psychiatry 72:811–816

    Article  PubMed  Google Scholar 

  • Ding ZB, Wu P, Luo YX, Shi HS, Shen HW, Wang SJ, Lu L (2013) Region-specific role of Rac in nucleus accumbens core and basolateral amygdala in consolidation and reconsolidation of cocaine-associated cue memory in rats. Psychopharmacology 228:427–437

    Article  CAS  PubMed  Google Scholar 

  • Draycott B, Loureiro M, Ahmad T, Tan H, Zunder J, Laviolette SR (2014) Cannabinoid transmission in the prefrontal cortex bi-phasically controls emotional memory formation via functional interactions with the ventral tegmental area. J Neurosci 34:13096–13109

    Article  PubMed  PubMed Central  Google Scholar 

  • Emamian ES (2012) Akt/GSK3 signaling pathway and schizophrenia. Front Mol Neurosci 5:33

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fadok JP, Darvas M, Dickerson TMK, Palmiter RD (2010) Long-term memory for pavlovian fear conditioning requires dopamine in the nucleus accumbens and basolateral amygdala. PLoS ONE 5:1–6

    Article  Google Scholar 

  • Fang X, Yu SX, Lu Y, Bast RC, Woodgett JR, Mills GB (2000) Phosphorylation and inactivation of glycogen synthase kinase 3 by protein kinase A. PNAS 97:11960–11965

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fitoussi A, Zunder J, Tan H, Laviolette SR (2018) Delta-9-tetrahydrocannabinol potentiates fear memory salience through functional modulation of mesolimbic dopaminergic activity states. Eur J Neurosci 47:1385–1400

    Article  PubMed  Google Scholar 

  • Fusar-Poli P, Crippa JA, Bhattacharyya S, Borgwardt SJ, Allen P, Martin-Santos R et al (2009) Distinct effects of delta-9-tetrahydrocannabinol and cannabidiol on neural activation during emotional processing. Arch Gen Psychiatry 66:95–105

    Article  CAS  PubMed  Google Scholar 

  • Florido A, Velasco ER, Soto-Faguás CM et al (2021) Sex differences in fear memory consolidation via Tac2 signaling in mice. Nat Commun 12:2496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Forbes NF, Carrick LA, McIntosh AM, Lawrie SM (2009) Working memory in schizophrenia: a meta-analysis. Psychol Med 39:889–905

    Article  CAS  PubMed  Google Scholar 

  • Gafford GM, Parsons RG, Helmstetter FJ (2013) Memory accuracy predicts hippocampal mTOR pathway activation following retrieval of contextual fear memory. Hippocampus 23:842–847

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • García C, Palomo-Garo C, Gómez-Gálvez Y, Fernández-Ruiz J (2016) Cannabinoid-dopamine interactions in the physiology and physiopathology of the basal ganglia. Br J Pharmacol 173:2069–2079

    Article  PubMed  Google Scholar 

  • Genn RF, Tucci S, Marco EM, Viveros MP, File SE (2004) Unconditioned and conditioned anxiogenic effects of the cannabinoid receptor agonist CP 55,940 in the social interaction test. Pharmacol Biochem Behav 77:567–573

    Article  CAS  PubMed  Google Scholar 

  • Grimes KM, Zanjani A, Zakzanis KK (2017) Memory impairment and the mediating role of task difficulty in patients with schizophrenia. Psychiatry Clin Neurosci 71:600–611

    Article  PubMed  Google Scholar 

  • Hermann H, Marsicano G, Lutz B (2002) Coexpression of the cannabinoid receptor type 1 with dopamine and serotonin receptors in distinct neuronal subpopulations of the adult mouse forebrain. Neuroscience 109:451–460

    Article  CAS  PubMed  Google Scholar 

  • Hudson R, Rushlow W, Laviolette SR (2018) Phytocannabinoids modulate emotional memory processing through interactions with the ventral hippocampus and mesolimbic dopamine system: implications for neuropsychiatric pathology. Psychopharmacology 235:447–458

    Article  CAS  PubMed  Google Scholar 

  • Hudson R, Renard J, Norris C, Rushlow WJ, Laviolette SR (2019) Cannabidiol counteracts the psychotropic side-effects of Δ-9-tetrahydrocannabinol in the ventral hippocampus through bidirectional control of ERK1–2 phosphorylation. J Neurosci 39:8762–8777

    Article  PubMed  PubMed Central  Google Scholar 

  • Jarome TJ, Perez GA, Hauser RM, Hatch KM, Lubin FD (2018) EZH2 methyltransferase activity controls Pten expression and mTOR signaling during fear memory reconsolidation. J Neurosci 38:10538–10618

    Article  Google Scholar 

  • Jobim PFC, Pedroso TR, Christoff RR, Werenicz A, Maurmann N, Reolon GK, Roesler R (2012) Inhibition of mTOR by rapamycin in the amygdala or hippocampus impairs formation and reconsolidation of inhibitory avoidance memory. Neurobiol Learn Mem 97:105–112

    Article  CAS  PubMed  Google Scholar 

  • Kasten CR, Zhang Y, Boehm SL (2017) Acute and long-term effects of Δ9-tetrahydrocannabinol on object recognition and anxiety-like activity are age- and strain-dependent in mice. Pharmacol Biochem Behav 163:9–19

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Katthagen T, Dammering F, Kathmann N, Kaminski J, Walter H, Heinz A, Schlagenhauf F (2016) Validating the construct of aberrant salience in schizophrenia — behavioral evidence for an automatic process. Schizophrenia Res: Cognition 6:22–27

    Google Scholar 

  • Khan SS, Lee FJ (2014) Delineation of domains within the cannabinoid CB1 and dopamine D2 receptors that mediate the formation of the heterodimer complex. J Mol Neurosci 53:10–21

    Article  CAS  PubMed  Google Scholar 

  • Klumpers F, Denys D, Kenemans JL, Grillon C, Van Der Aart J, Baas JMP (2012) Testing the effects of Δ9-THC and D-cycloserine on extinction of conditioned fear in humans. J Psychopharmacol 26:471–478

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Korem N, Lange R, Hillard CJ, Akirav I (2017) Role of beta-catenin and endocannabinoids in the nucleus accumbens in extinction in rats exposed to shock and reminders. Neuroscience 357:285–294

    Article  CAS  PubMed  Google Scholar 

  • Kozlovsky N, Belmaker RH, Agam G (2001) Low GSK-3 activity in frontal cortex of schizophrenic patients. Schizophr Res 52:101–105

    Article  CAS  PubMed  Google Scholar 

  • Laprairie RB, Stahl EL, Bohn LM (2017) Approaches to assess biased signaling at the CB1R receptor. Methods Enzymology 593:259–279

    Article  CAS  Google Scholar 

  • Lauzon NM, Bishop SF, Laviolette SR (2009) Dopamine D1 versus D4 receptors differentially modulate the encoding of salient versus nonsalient emotional information in the medial prefrontal cortex. J Neurosci 29:4836–4845

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Luo YX, Han H, Shao J, Gao Y, Yin X, Zhu WL et al (2016) mTOR signalling in the nucleus accumbens shell is critical for augmented effect of TFF3 on behavioural response to cocaine. Sci Reports 6:1–12

    Google Scholar 

  • Mahler SV, Smith KS, Berridge KC (2007) Endocannabinoid hedonic hotspot for sensory pleasure: anandamide in nucleus accumbens shell enhances “liking” of a sweet reward. Neuropsychopharmacology 32:2267–2278

    Article  CAS  PubMed  Google Scholar 

  • Malone DT, Taylor DA (2006) The effect of Δ9-tetrahydrocannabinol on sensorimotor gating in socially isolated rats. Behav Brain Res 166:101–109

    Article  CAS  PubMed  Google Scholar 

  • Mattfeld AT, Gluck MA, Stark CEL (2011) Functional specialization within the striatum along both the dorsal/ventral and anterior/posterior axes during associative learning via reward and punishment. Learn Mem 18:703–711

    Article  PubMed  PubMed Central  Google Scholar 

  • Mines MA, Jope RS (2012) Brain region differences in regulation of Akt and GSK3 by chronic stimulant administration in mice. Cell Signal 24:1398–1405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mines MA, Yuskaitis CJ, King MK, Beurel E, Jope RS (2010) GSK3 influences social preference and anxiety-related behaviors during social interaction in a mouse model of fragile X syndrome and autism. PLoS ONE 5(3):e9706

    Article  PubMed  PubMed Central  Google Scholar 

  • Mitchell MR, Berridge KC, Mahler SV (2018) Endocannabinoid-enhanced “liking” in nucleus accumbens shell hedonic hotspot requires endogenous opioid signals. Cannabis Cannabinoid Res 3:166–170

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morgan CJA, Freeman TP, Powell J, Curran HV (2016) Akt1 genotype moderates the acute psychotomimetic effects of naturalistically smoked cannabis in young cannabis smokers. Transl Psychiatry. 6(2):e738

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morgan CJA, Gardener C, Schafer G, Swan S, Demarchi C, Freeman TP et al (2012) Sub-chronic impact of cannabinoids in street cannabis on cognition, psychotic-like symptoms and psychological well-being. Psychological Med 42:391–400

    Article  CAS  Google Scholar 

  • Morra JT, Glick SD, Cheer JF (2012) Cannabinoid receptors mediate methamphetamine induction of high frequency gamma oscillations in the nucleus accumbens. Neuropharmacology 63:565–574

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morrison SC, Cohen AS (2014) The moderating effects of perceived intentionality: exploring the relationships between ideas of reference, paranoia and social anxiety in schizotypy. Cog Neuropsychiatry 19:527–539

    Article  Google Scholar 

  • Nelson AJD, Thur KE, Marsden CA, Cassaday HJ (2010) Dissociable roles of dopamine within the core and medial shell of the nucleus accumbens in memory for objects and place. Behav Neurosci 124:789–799

    Article  PubMed  PubMed Central  Google Scholar 

  • Norris C, Loureiro M, Kramar C, Zunder J, Renard J, Rushlow WJ, Laviolette SR (2016) Cannabidiol modulates fear memory formation through interactions with serotonergic transmission in the mesolimbic system. Neuropsychopharmacology 41:2839–2850

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Norris C, Szkudlarek HJ, Pereira B, Rushlow W, Laviolette SR (2019) The bivalent rewarding and aversive properties of Δ9-tetrahydrocannabinol are mediated through dissociable opioid receptor substrates and neuronal modulation mechanisms in distinct striatal sub-regions. Sci Rep 9:9760

    Article  PubMed  PubMed Central  Google Scholar 

  • Oleson EB, Cheer JF (2012) A brain on cannabinoids: the role of dopamine release in reward seeking. Cold Spring Harbor Perspect Med 2:1–14

    Article  Google Scholar 

  • Onaivi ES, Green MR, Martin BR (1990) Pharmacological characterization of cannabinoids in plus maze. Pharmacology 253:1002–1009

    CAS  Google Scholar 

  • Ozaita A, Puighermanal E, Maldonado R (2007) Regulation of PI3K/Akt/GSK-3 pathway by cannabinoids in the brain. J Neurochem 102:1105–1114

    Article  CAS  PubMed  Google Scholar 

  • Palaniyappan L, Simmonite M, White TP, Liddle EB, Liddle PF (2013) Neural primacy of the salience processing system in schizophrenia. Neuron 79:814–828

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Paxinos G, Watson C (2005) The rat brain in stereotaxic coordinates (6th ed.). San Diego, U.S.A.: Elsevier.

  • Paz-Alonso PM, Ghetti S, Ramsay I, Solomon M, Yoon J, Carter CS, Ragland JD (2013) Semantic processes leading to true and false memory formation in schizophrenia. Schizophrenia Res 147:320–325

    Article  Google Scholar 

  • Phillipson OT, Griffiths AC (1985) The topographic order of inputs to nucleus accumbens in the rat. Neuroscience 16:275–296

    Article  CAS  PubMed  Google Scholar 

  • Puighermanal E, Busquets-Garcia A, Gomis-González M, Marsicano G, Maldonado R, Ozaita A (2013) Dissociation of the pharmacological effects of THC by mTOR blockade. Neuropsychopharmacology 38:1334–1343

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Qiao X, Gai H, Su R, Deji C, Cui J, Lai J, Zhu Y (2018) PI3K-AKT-GSK3β-CREB signaling pathway regulates anxiety-like behavior in rats following alcohol withdrawal. J Affective Disorders 235:96–104

    Article  CAS  Google Scholar 

  • Quinn HR, Matsumoto I, Callaghan PD, Long LE, Arnold JC, Gunasekaran N et al (2008) Adolescent rats find repeated Δ9-THC less aversive than adult rats but display greater residual cognitive deficits and changes in hippocampal protein expression following exposure. Neuropsychopharmacology 33:1113–1126

    Article  PubMed  Google Scholar 

  • Renard J, Rosen LG, Loureiro M, De Oliveira C, Schmid S, Rushlow WJ, Laviolette SR (2017a) Adolescent cannabinoid exposure induces a persistent sub-cortical hyper-dopaminergic state and associated molecular adaptations in the prefrontal cortex. Cereb Cortex 27:1297–1310

    PubMed  Google Scholar 

  • Renard J, Szkudlarek HJ, Kramar CP, Jobson CEL, Moura K, Rushlow WJ, Laviolette SR (2017b) Adolescent THC exposure causes enduring prefrontal cortical disruption of GABAergic inhibition and dysregulation of sub-cortical dopamine function. Sci Reports 7:1–14

    CAS  Google Scholar 

  • Rubino T, Sala M, Viganò D, Braida D, Castiglioni C, Limonta V et al (2007) Cellular mechanisms underlying the anxiolytic effect of low doses of peripheral Δ9-tetrahydrocannabinol in rats. Neuropsychopharmacology 32:2036–2045

    Article  CAS  PubMed  Google Scholar 

  • Schramm-Sapyta NL, Cha YM, Chaudhry S, Wilson WA, Swartzwelder HS, Kuhn CM (2007) Differential anxiogenic, aversive, and locomotor effects of THC in adolescent and adult rats. Psychopharmacology 191:867–877

    Article  CAS  PubMed  Google Scholar 

  • Seillier A, Martinez AA, Giuffrida A (2020) Differential effects of Δ9-tetrahydrocannabinol dosing on correlates of schizophrenia in the sub-chronic PCP rat model. PLoS One. 15(3):e0230238

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shi X, Miller JS, Harper LJ, Poole RL, Gould TJ, Unterwald EM (2014) Reactivation of cocaine reward memory engages the Akt/GSK3/mTOR signaling pathway and can be disrupted by GSK3 inhibition. Psychopharmacology 231:3109–3118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sutton LP, Rushlow WJ (2012) The dopamine D2 receptor regulates Akt and GSK-3 via Dvl-3. Int J Neuropsychopharmacol 15:965–979

    Article  CAS  PubMed  Google Scholar 

  • Swartzwelder NA, Louise Risher M, Abdelwahab SH, D’Abo A, Rezvani AH, Levin ED, Acheson SK (2012) Effects of ethanol, Δ9-tetrahydrocannabinol, or their combination on object recognition memory and object preference in adolescent and adult male rats. Neurosci Lett 527:11–15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Swerdlow NR, Light GA, Thomas ML, Sprock J, Calkins ME, Green MF, Braff DL (2018) Deficient prepulse inhibition in schizophrenia in a multi-site cohort: internal replication and extension. Schizophrenia Res 198:6–15

    Article  Google Scholar 

  • Wang Y, Zhang H, Cui J et al (2019) Opiate-associated contextual memory formation and retrieval are differentially modulated by dopamine D1 and D2 signaling in hippocampal–prefrontal connectivity. Neuropsychopharmacol 44:334–343

    Article  CAS  Google Scholar 

  • Wickens RH, Quartarone SE, Beninger RJ (2016) Inhibition of glycogen synthase kinase-3 by SB 216763 affects acquisition at lower doses than expression of amphetamine-conditioned place preference in rats. Behav Pharmacol 28:262–271

    Article  Google Scholar 

  • Wynn JK, Dawson ME, Schell AM, McGee M, Salveson D, Green MF (2004) Prepulse facilitation and prepulse inhibition in schizophrenia patients and their unaffected siblings. Biol Psychiat 55:518–523

    Article  PubMed  Google Scholar 

  • Xu N, Zhou WJ, Wang Y, Huang SH, Li X, Chen ZY (2015) Hippocampal Wnt3a is necessary and sufficient for contextual fear memory acquisition and consolidation. Cereb Cortex 25:4062–4075

    Article  PubMed  Google Scholar 

  • Zangen A, Solinas M, Ikemoto S, Goldberg SR, Wise RA (2006) Two brain sites for cannabinoid reward. J Neurosci 26:4901–4907

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by the Canadian Institute of Health Research (PJT-159586), the Natural Science and Engineering Research Council of Canada (N.S.E.R.C.), CanaQuest Inc, MITACs and the J&J Memorial Tournament Fund.

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Authors and Affiliations

  1. Addiction Research Group, Schulich School of Medicine & Dentistry, University of Western Ontario, 468 Medical Science Building, Ontario, London, N6A5C1, Canada

    Roger Hudson, Christopher Norris, Hanna J. Szkudlarek, Dinat Khan, Susanne Schmid, Walter J. Rushlow & Steven R. Laviolette

  2. Department of Anatomy & Cell Biology, Schulich School of Medicine & Dentistry, University of Western Ontario London, Ontario, N6A5C1, Canada

    Roger Hudson, Christopher Norris, Hanna J. Szkudlarek, Dinat Khan, Susanne Schmid, Walter J. Rushlow & Steven R. Laviolette

  3. Department of Psychiatry, Schulich School of Medicine & Dentistry, University of Western Ontario London, Ontario, N6A5C1, Canada

    Walter J. Rushlow & Steven R. Laviolette

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  1. Roger Hudson
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Hudson, R., Norris, C., Szkudlarek, H.J. et al. Anxiety and cognitive-related effects of Δ 9-tetrahydrocannabinol (THC) are differentially mediated through distinct GSK-3 vs. Akt-mTOR pathways in the nucleus accumbens of male rats. Psychopharmacology 239, 509–524 (2022). https://doi.org/10.1007/s00213-021-06029-w

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