Skip to main content

Phytocannabinoids modulate emotional memory processing through interactions with the ventral hippocampus and mesolimbic dopamine system: implications for neuropsychiatric pathology

Abstract

Growing clinical and preclinical evidence suggests a potential role for the phytocannabinoid cannabidiol (CBD) as a pharmacotherapy for various neuropsychiatric disorders. In contrast, delta-9-tetrahydrocannabinol (THC), the primary psychoactive component in cannabis, is associated with acute and neurodevelopmental propsychotic side effects through its interaction with central cannabinoid type 1 receptors (CB1Rs). CB1R stimulation in the ventral hippocampus (VHipp) potentiates affective memory formation through inputs to the mesolimbic dopamine (DA) system, thereby altering emotional salience attribution. These changes in DA activity and salience attribution, evoked by dysfunctional VHipp regulatory actions and THC exposure, could predispose susceptible individuals to psychotic symptoms. Although THC can accelerate the onset of schizophrenia, CBD displays antipsychotic properties, can prevent the acquisition of emotionally irrelevant memories, and reverses amphetamine-induced neuronal sensitization through selective phosphorylation of the mechanistic target of rapamycin (mTOR) molecular signaling pathway. This review summarizes clinical and preclinical evidence demonstrating that distinct phytocannabinoids act within the VHipp and associated corticolimbic structures to modulate emotional memory processing through changes in mesolimbic DA activity states, salience attribution, and signal transduction pathways associated with schizophrenia-related pathology.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2

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 μ-opiate receptor dependent mechanisms. J Neurosci 33(39):15642–15651

    CAS  PubMed  Article  Google Scholar 

  • Akirav I (2011) The role of cannabinoids in modulating emotional and non-emotional memory processes in the hippocampus. Front Behav Neurosci 5(6):34

    CAS  PubMed  PubMed Central  Google Scholar 

  • Alimohamad H, Sutton L, Mouyal J, Rajakumar N, Rushlow WJ (2005a) The effects of antipsychotics on beta-catenin, glycogen synthase kinase-3 and dishevelled in the ventral midbrain of rats. J Neurochem 95(2):513–525

    CAS  PubMed  Article  Google Scholar 

  • Alimohamad H, Rajakumar N, Seah YH, Rushlow W (2005b) Antipsychotics alter the protein expression levels of β-catenin and GSK-3 in the rat medial prefrontal cortex and striatum. Biol Psychiatry 57(5):533–542

    CAS  PubMed  Article  Google Scholar 

  • Amaral DG (1987) Memory: anatomical organization of candidate brain regions. In: Mountcastle VB (ed) Handbook of physiology, the nervous system, Vol. V. Waverly Press, Baltimore, pp 211–294

    Google Scholar 

  • Andreasen NC, Flashman L, Flaum M, Arndt S, Swayze V, O’leary DS et al (1994) Regional brain abnormalities in schizophrenia measured with magnetic resonance imaging. JAMA 272(22):1763–1769

    CAS  PubMed  Article  Google Scholar 

  • Arnold JC, Boucher AA, Karl T (2012) The yin and yang of cannabis-induced psychosis: the actions of delta(9)-tetrahydrocannabinol and cannabidiol in rodent models of schizophrenia. Curr Pharm Des 18(32):5113–5130

    CAS  PubMed  Article  Google Scholar 

  • Beaulieu JM, Gainetdinov RR, Caron MG (2007) The Akt–GSK-3 signaling cascade in the actions of dopamine. Trends Pharmacol Sci 28(4):166–172

    CAS  PubMed  Article  Google Scholar 

  • Benes FM, Lim B, Matzilevich D, Walsh JP, Subburaju S, Minns M (2007) Regulation of the GABA cell phenotype in hippocampus of schizophrenics and bipolars. Proc Natl Acad Sci U S A 104(24):10164–10169

    CAS  PubMed  PubMed Central  Article  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(3):764–774

    CAS  PubMed  Article  Google Scholar 

  • Bhattacharyya S, Atakan Z, Martin-Santos R, Crippa J, McGuire P (2012a) Neural mechanisms for the cannabinoid modulation of cognition and affect in man: a critical review of neuroimaging studies. Curr Pharm Des 18(32):5045–5054

    CAS  PubMed  Article  Google Scholar 

  • Bhattacharyya S, Crippa JA, Allen P, Martin-Santos R, Borgwardt S, Fusar-Poli P et al (2012b) Induction of psychosis by delta-9-tetrahydrocannabinol reflects modulation of prefrontal and striatal function during attentional salience processing. Arch Gen Psychiatry 69(1):27–36

    CAS  PubMed  Article  Google Scholar 

  • Bhattacharyya S, Falkenberg I, Martin-Santos R, Atakan Z, Crippa JA, Giampietro V et al (2015) Cannabinoid modulation of functional connectivity within regions processing attentional salience. Neuropsychopharmacology 40(6):1343–1352

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Bisogno T, Hanuš L, De Petrocellis L, Tchilibon S, Ponde DE, Brandi I, Di Marzo V (2001) Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol 134(4):845–852

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Blaha CD, Yang CR, Floresco SB, Barr AM, Phillips AG (1997) Stimulation of the ventral subiculum of the hippocampus evokes glutamate receptor-mediated changes in dopamine efflux in the rat nucleus accumbens. Eur J Neurosci 9(5):902–911

    CAS  PubMed  Article  Google Scholar 

  • Blessing EM, Steenkamp MM, Manzanares J, Marmar CR (2015) Cannabidiol as a potential treatment for anxiety disorders. Neurotherapeutics 12(4):825–836

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Bossong MG, van Berckel BN, Boellaard R, Zuurman L, Schuit RC, Windhorst AD et al (2009) Delta-9-tetrahydrocannabinol induces dopamine release in the human striatum. Neuropsychopharmacology 34(3):759–766

    CAS  PubMed  Article  Google Scholar 

  • Bremner JD, Narayann M, Staib LH (1999) Neural correlates of memories of childhood sexual abuse in women with and without posttraumatic stress disorder. Am J Psychiatry 156:1787–1795

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bremner JD, Davis M, Southwick SM, Krystal JH, Charney, DS (1993) Neurobiology of posttraumatic stress disorder. Review of psychiatry 12:183–204

  • Bremner JD, Vythilingam M, Vermetten E (2003) MRI and PET study of deficits in hippocampal structure and function in women with childhood sexual abuse and posttraumatic stress disorder. Am J Psychiatry 160:924–932

    PubMed  Article  Google Scholar 

  • Burgdorf JR, Kilmer B, Pacula RL (2011) Heterogeneity in the composition of marijuana seized in California. Drug Alcohol Depend 117(1):59–61

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Campos AC, Ortega Z, Palazuelos J, Fogaça MV, Aguiar DC, Díaz-Alonso J et al (2013) The anxiolytic effect of cannabidiol on chronically stressed mice depends on hippocampal neurogenesis: involvement of the endocannabinoid system. Int J Neuropsychopharmacol 16(6):1407–1419

    CAS  PubMed  Article  Google Scholar 

  • Campos AC, Fogaça MV, Sonego AB, Guimarães FS (2016) Cannabidiol, neuroprotection and neuropsychiatric disorders. Pharmacol Res 112:119–127

    CAS  PubMed  Article  Google Scholar 

  • Canteras NS, Swanson LW (1992) Projections of the ventral subiculum to the amygdala, septum, and hypothalamus: a PHAL anterograde tract-tracing study in the rat. J Comp Neurol 324(2):180–194

    CAS  PubMed  Article  Google Scholar 

  • Carvalho CR, Takahashi RN (2017) Cannabidiol disrupts the reconsolidation of contextual drug-associated memories in Wistar rats. Addict Biol 22(3):742–751

    PubMed  Article  CAS  Google Scholar 

  • Caspari D (1999) Cannabis and schizophrenia: results of a follow-up study. Eur Arch Psychiatry Clin Neurosci 249(1):45–49

    CAS  PubMed  Article  Google Scholar 

  • Cass DK, Flores-Barrera E, Thomases DR, Vital WF, Caballero A, Tseng KY (2014) CB1 cannabinoid receptor stimulation during adolescence impairs the maturation of GABA function in the adult rat prefrontal cortex. Mol Psychiatry 19(5):536

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Chait LD, Zacny JP (1992) Reinforcing and subjective effects of oral Δ 9-THC and smoked marijuana in humans. Psychopharmacol 107(2):255–262

    CAS  Article  Google Scholar 

  • Cheer JF, Wassum KM, Heien ML, Phillips PE, Wightman RM (2004) Cannabinoids enhance subsecond dopamine release in the nucleus accumbens of awake rats. J Neurosci 24:4393–4400

    CAS  PubMed  Article  Google Scholar 

  • Constantinidis C, Goldman-Rakic PS (2002) Correlated discharges among putative pyramidal neurons and interneurons in the primate prefrontal cortex. J Neurophysiol 88(6):3487–3497

    PubMed  Article  Google Scholar 

  • Corcoran KA, Maren S (2001) Hippocampal inactivation disrupts contextual retrieval of fear memory after extinction. J Neurosci 21:1720–1726

    CAS  PubMed  Article  Google Scholar 

  • Costa-Mattioli M, Monteggia LM (2013) mTOR complexes in neurodevelopmental and neuropsychiatric disorders. Nat Neurosci 16(11):1537–1543

    CAS  PubMed  Article  Google Scholar 

  • Crosby EC, DeJonge BR, Schneider RC (1966) Evidence for some of the trends in the phylogenetic development of the vertebrate telencephalon. In: Evolution of the forebrain. Springer, USA, pp 117–135

    Chapter  Google Scholar 

  • Csernansky JG, Wang L, Jones D, Rastogi-Cruz D, Posener JA, Heydebrand G et al (2002) Hippocampal deformities in schizophrenia characterized by high dimensional brain mapping. Am J Psychiatry 159(12):2000–2006

    PubMed  Article  Google Scholar 

  • D’Souza DC, Perry E, MacDougall L, Ammerman Y, Cooper T, Wu Y et al (2004) The psychotomimetic effects of intravenous delta-9-tetrahydrocannabinol in healthy individuals: implications for psychosis. Neuropsychopharmacology 29(8):1558–1572

    PubMed  Article  CAS  Google Scholar 

  • D’Souza DC, Sewell RA, Ranganathan M (2009) Cannabis and psychosis/schizophrenia: human studies. Eur Arch Psychiatry Clin Neurosci 259(7):413–431

    PubMed  PubMed Central  Article  Google Scholar 

  • Das RK, Kamboj SK, Ramadas M, Yogan K, Gupta V, Redman E, Morgan CJ (2013) Cannabidiol enhances consolidation of explicit fear extinction in humans. Psychopharmacol 226(4):781–792

    CAS  Article  Google Scholar 

  • De Marchi N, De Petrocellis L, Orlando P, Daniele F, Fezza F, Di Marzo V (2003) Endocannabinoid signalling in the blood of patients with schizophrenia. Lipids Health Dis 2(1):5

    PubMed  PubMed Central  Article  Google Scholar 

  • Demirakca T, Sartorius A, Ende G, Meyer N, Welzel H, Skopp G et al (2011) Diminished gray matter in the hippocampus of cannabis users: possible protective effects of cannabidiol. Drug Alcohol Depend 114(2–3):242–245

    CAS  PubMed  Google Scholar 

  • Depue BE, Curran T, Banich MT (2007) Prefrontal regions orchestrate suppression of emotional memories via a two-phase process. Science 317(5835):215–219

    CAS  PubMed  Article  Google Scholar 

  • Deutch AY, Lee MC, Iadarola MJ (1992) Regionally specific effects of atypical antipsychotic drugs on striatal fos expression: the nucleus accumbens shell as a locus of antipsychotic action. Mol Cell Neurosci 3(4):332–341

    CAS  PubMed  Article  Google Scholar 

  • Di Forti M, Morgan C, Dazzan P, Pariante C, Mondelli V, Marques TR et al (2009) High-potency cannabis and the risk of psychosis. Br J Psychiatry 195:488–491

    PubMed  PubMed Central  Article  Google Scholar 

  • Do Monte FH, Souza RR, Bitencourt RM, Kroon JA, Takahashi RN (2013) Infusion of cannabidiol into infralimbic cortex facilitates fear extinction via CB1 receptors. Behav Brain Res 250:23–27

    PubMed  Article  CAS  Google Scholar 

  • Dolcos F, LaBar KS, Cabeza R (2004) Interaction between the amygdala and the medial temporal lobe memory system predicts better memory for emotional events. Neuron 42:855–863

    CAS  PubMed  Article  Google Scholar 

  • Dolder CR, Lacro JP, Dunn LB, Jeste DV (2002) Antipsychotic medication adherence: is there a difference between typical and atypical agents? Am J Psychiatry 159(1):103–108

    PubMed  Article  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(39):13096–13109

    PubMed  Article  CAS  Google Scholar 

  • Eggan SM, Hashimoto T, Lewis DA (2008) Reduced cortical cannabinoid 1 receptor messenger RNA and protein expression in schizophrenia. Arch Gen Psychiatry 65(7):772–784

    PubMed  PubMed Central  Article  Google Scholar 

  • Emamian ES (2012) AKT/GSK3 signaling pathway and schizophrenia. Front Mol Neurosci 5:1–10

    Article  CAS  Google Scholar 

  • Esposito G, Filippis DD, Cirillo C, Iuvone T, Capoccia E, Scuderi C et al (2013) Cannabidiol in inflammatory bowel diseases: a brief overview. Phytother Res 27(5):633–636

    CAS  PubMed  Article  Google Scholar 

  • Fergusson DM, Poulton R, Smith PF, Boden JM (2006) Cannabis and psychosis. BMJ 332(7534):172–175

    PubMed  PubMed Central  Article  Google Scholar 

  • Floresco SB, Todd CL, Grace AA (2001) Glutamatergic afferents from the hippocampus to the nucleus accumbens regulate activity of ventral tegmental area dopamine neurons. J Neurosci 21(13):4915–4922

    CAS  PubMed  Article  Google Scholar 

  • Floresco SB, West AR, Ash B, Moore H, Grace AA (2003) Afferent modulation of dopamine neuron firing differentially regulates tonic and phasic dopamine transmission. Nat Neurosci 6(9):968–973

    CAS  PubMed  Article  Google Scholar 

  • French ED, Dillon K, Wu X (1997) Cannabinoids excite dopamine neurons in the ventral tegmentum and substantia nigra. Neuroreport 8(3):649–652

    CAS  PubMed  Article  Google Scholar 

  • Freyberg Z, Ferando S, Javitch J (2010) Roles of the Akt/GSK-3 and Wnt signaling pathways in schizophrenia and antipsychotic drug activity. Am J Psychiatry, (April): 388–396

  • Gallinat J, Winterer G, Herrmann CS, Senkowski D (2004) Reduced oscillatory gamma-band responses in unmedicated schizophrenic patients indicate impaired frontal network processing. Clin Neurophysiol 115(8):1863–1874

    PubMed  Article  Google Scholar 

  • Galve-Roperh I, Aguado T, Palazuelos J, Guzmán M (2007) The endocannabinoid system and neurogenesis in health and disease. Neuroscientist 13(2):109

    CAS  PubMed  Article  Google Scholar 

  • Gilboa A, Shalev AY, Laor L, Lester H, Louzoun Y, Chisin R, Bonne O (2004) Functional connectivity of the prefrontal cortex and the amygdala in posttraumatic stress disorder. Biol Psychiatry 55(3):263–272

    PubMed  Article  Google Scholar 

  • Glangetas C, Fois GR, Jalabert M, Lecca S, Valentinova K, Meye FJ, Georges F (2015) Ventral subiculum stimulation promotes persistent hyperactivity of dopamine neurons and facilitates behavioral effects of cocaine. Cell Rep 13(10):2287–2296

    CAS  PubMed  Article  Google Scholar 

  • Gomes FV, Del Bel EA, Guimarães FS (2013) Cannabidiol attenuates catalepsy induced by distinct pharmacological mechanisms via 5-HT1A receptor activation in mice. Prog Neuro-Psychopharmacol Biol Psychiatry 46:43–47

    CAS  Article  Google Scholar 

  • Gomes, FV, Issy AC, Ferreira FR, Viveros MP, Del Bel EA, Guimarães FS (2015a) Cannabidiol attenuates sensorimotor gating disruption and molecular changes induced by chronic antagonism of NMDA receptors in mice. Int J Neuropsychopharmacol, 18(5)

  • Gomes FV, Llorente R, Del Bel EA, Viveros MP, López-Gallardo M, Guimarães FS (2015b) Decreased glial reactivity could be involved in the antipsychotic-like effect of cannabidiol. Schizophr Res 164(1):155–163

    PubMed  Article  Google Scholar 

  • Gonzalez-Burgos G, Lewis DA (2012) NMDA receptor hypofunction, parvalbumin-positive neurons, and cortical gamma oscillations in schizophrenia. Schizophr Bull 38(5):950–957

    PubMed  PubMed Central  Article  Google Scholar 

  • Gothelf D, Soreni N, Nachman RP, Tyano S, Hiss Y, Reiner O et al (2000) Evidence for the involvement of the hippocampus in the pathophysiology of schizophrenia. Eur Neuropsychopharmacol 10:389–395

    CAS  PubMed  Article  Google Scholar 

  • Goto Y, Grace AA (2008) Limbic and cortical information processing in the nucleus accumbens. Trends Neurosci 31(11):552–558

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Grace AA (2000) Gating of information flow within the limbic system and the pathophysiology of schizophrenia. Brain Res Rev 31:330e341

    Article  Google Scholar 

  • Grace AA (2010a) Dopamine system dysregulation by the ventral subiculum as the common pathophysiological basis for schizophrenia psychosis, psychostimulant abuse, and stress. Neurotox Res 18(3–4):367–376

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Grace AA (2010b) Ventral hippocampus, interneurons, and schizophrenia: a new understanding of the pathophysiology of schizophrenia and its implications for treatment and prevention. Curr Dir Psychol Sci 19(4):232–237

    Article  Google Scholar 

  • Grace AA (2012) Dopamine system dysregulation by the hippocampus: implications for the pathophysiology and treatment of schizophrenia. Neuropharmacology 62(3):1342–1348

    CAS  PubMed  Article  Google Scholar 

  • Grace AA (2016) Dysregulation of the dopamine system in the pathophysiology of schizophrenia and depression. Nature 17(8):524–532

    CAS  Google Scholar 

  • Grace AA (2017) Dopamine system dysregulation and the pathophysiology of schizophrenia: insights from the methylazoxymethanol acetate model. Biol Psychiatry 81(1):5–8

    CAS  PubMed  Article  Google Scholar 

  • Grace AA, Bunney BS (1984a) The control of firing pattern in nigral dopamine neurons: single spike firing. J Neurosci 4(11):2866–2876

    CAS  PubMed  Article  Google Scholar 

  • Grace AA, Bunney BS (1984b) The control of firing pattern in nigral dopamine neurons: burst firing. J Neurosci 4(11):2877–2890

    CAS  PubMed  Article  Google Scholar 

  • Green MF (1996) What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry 153(3):321

    CAS  PubMed  Article  Google Scholar 

  • Green MF, Kern RS, Heaton RK (2004) Longitudinal studies of cognition and functional outcome in schizophrenia: implications for MATRICS. Schizophr Res 72(1):41–51

    PubMed  Article  Google Scholar 

  • Groenewegen HJ, Vermeulen-Van d, Zee ET, Te Kortschot A, Witter MP (1987) Organization of the projections from the subiculum to the ventral striatum in the rat. A study using anterograde transport of Phaseolus vulgaris leucoagglutinin. Neuroscience 23(1):103–120

    CAS  PubMed  Article  Google Scholar 

  • Grotenhermen F (2003) Pharmacokinetics and pharmacodynamics of cannabinoids. Clin Pharmacokinet 42(4):327–360

    CAS  PubMed  Article  Google Scholar 

  • Gururajan A, Van Den Buuse M (2014) Is the mTOR-signalling cascade disrupted in schizophrenia? J Neurochem 129(3):377–387

    CAS  PubMed  Article  Google Scholar 

  • Haddad PM, Sharma SG (2007) Adverse effects of atypical antipsychotics: differential risk and clinical implications. CNS Drugs 21(11):911–936

    CAS  PubMed  Article  Google Scholar 

  • Hajos M, Hoffmann WE, Kocsis B (2008) Activation of cannabinoid-1 receptors disrupts sensory gating and neuronal oscillation: relevance to schizophrenia. Biol Psychiatry 63(11):1075–1083

    CAS  PubMed  Article  Google Scholar 

  • Hall W, Degenhardt L (2007) Prevalence and correlates of cannabis use in developed and developing countries. Curr Opin Psychiatry 20(4):393–397

    PubMed  Article  Google Scholar 

  • Heinz A, Schlagenhauf F (2010) Dopaminergic dysfunction in schizophrenia: salience attribution revisited. Schizophr Bull 36(3):472–485

    PubMed  PubMed Central  Article  Google Scholar 

  • Henquet C, Murray R, Linszen D, Van Os J (2005) The environment and schizophrenia: the role of cannabis use. Schizophr Bull 31(3):608–612

    PubMed  Article  Google Scholar 

  • Henquet C, Di Forti M, Morrison P, Kuepper R, Murray RM (2008) Gene-environment interplay between cannabis and psychosis. Schizophr Bull 34(6):1111–1121

    PubMed  PubMed Central  Article  Google Scholar 

  • Ho BC, Andreasen NC, Nopoulos P, Arndt S, Magnotta V, Flaum M (2003) Progressive structural brain abnormalities and their relationship to clinical outcome: a longitudinal magnetic resonance imaging study early in schizophrenia. Arch Gen Psychiatry 60(6):585–594

    PubMed  Article  Google Scholar 

  • Ichikawa J, Meltzer HY (1999) Relationship between dopaminergic and serotonergic neuronal activity in the frontal cortex and the action of typical and atypical antipsychotic drugs. Eur Arch Psychiatry Clin Neurosci 249(4):90–98

    PubMed  Article  Google Scholar 

  • Iseger TA, Bossong MG (2015) A systematic review of the antipsychotic properties of cannabidiol in humans. Schizophr Res 162(1):153–161

    PubMed  Article  Google Scholar 

  • Iversen SD, Iversen LL (2007) Dopamine: 50 years in perspective. Trends Neurosci 30(5):188–193

    CAS  PubMed  Article  Google Scholar 

  • Kathmann M, Flau K, Redmer A, Tränkle C, Schlicker E (2006) Cannabidiol is an allosteric modulator at mu-and delta-opioid receptors. Naunyn Schmiedeberg's Arch Pharmacol 372(5):354–361

    CAS  Article  Google Scholar 

  • Kandel DB, Logan JA (1984) Patterns of drug use from adolescence to young adulthood: periods of risk for initiation, continued use, and discontinuation. Am J Public Health 74(7):660–666

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Kapur S (2003) Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia. Am J Psychiatry 160:13e23

    Article  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. Schizophr Res Cogn 6:22–27

    PubMed  PubMed Central  Article  Google Scholar 

  • Kozlovsky N, Shanon-Weickert C, Tomaskovic-Crook E, Kleinman JE, Belmaker RH, Agam G (2004) Reduced GSK-3 mRNA levels in postmortem dorsolateral prefrontal cortex of schizophrenic patients. J Neural Transm 111(12):1583–1592

    CAS  PubMed  Article  Google Scholar 

  • Kramar C, Loureiro M, Renard J, Laviolette SR (2017) Palmitoylethanolamide modulates GPR55 receptor signaling in the ventral hippocampus to regulate mesolimbic dopamine activity, social interaction, and memory processing. Cannabis Cannabinoid Res 2(1):8–20

    PubMed  PubMed Central  Article  Google Scholar 

  • Laruelle M, Abi-Dargham A, van Dyck CH, Gil R, D’Souza CD, Erdos J et al (1996) Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. Proc Natl Acad Sci U S A 93:9235–9240

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Laviolette SR (2007) Dopamine modulation of emotional processing in cortical and subcortical neural circuits: evidence for a final common pathway in schizophrenia? Schizophr Bull 33(4):971–981

    PubMed  PubMed Central  Article  Google Scholar 

  • Laviolette SR, Grace AA (2006) The roles of cannabinoid and dopamine receptor systems in neural emotional learning circuits: implications for schizophrenia and addiction. Cell Mol Life Sci 63(14):1597–1613

    CAS  PubMed  Article  Google Scholar 

  • Legault M, Wise RA (1999) Injections of N-methyl-D-aspartate into the ventral hippocampus increase extracellular dopamine in the ventral tegmental area and nucleus accumbens. Synapse 31(4):241–249

    CAS  PubMed  Article  Google Scholar 

  • Legault M, Rompré PP, Wise RA (2000) Chemical stimulation of the ventral hippocampus elevates nucleus accumbens dopamine by activating dopaminergic neurons of the ventral tegmental area. J Neurosci 20(4):1635–1642

    CAS  PubMed  Article  Google Scholar 

  • Lenzenweger MF, Dworkin RH (1998) Origins and development of schizophrenia: advances in experimental psychopathology. American Psychological Association

  • Levine SZ, Rabinowitz J (2009) A population-based examination of the role of years of education, age of onset, and sex on the course of schizophrenia. Psychiatry Res 168(1):11–17

    PubMed  Article  Google Scholar 

  • Leweke FM, Schneider U, Thies M, Münte TF, Emrich HM (1999) Effects of synthetic Δ9-tetrahydrocannabinol on binocular depth inversion of natural and artificial objects in man. Psychopharmacol 142(3):230–235

    CAS  Article  Google Scholar 

  • Leweke FM, Koethe D (2008) Cannabis and psychiatric disorders: it is not only addiction. Addict Biol 13(2):264–275

    PubMed  Article  Google Scholar 

  • Leweke FM, Piomelli D, Pahlisch F, Muhl D, Gerth CW, Hoyer C et al (2012) Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry 2(3):e94

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Lewis DA, Hashimoto T, Volk DW (2005) Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci 6(4):312–324

    CAS  PubMed  Article  Google Scholar 

  • Linge R, Jiménez-Sánchez L, Campa L, Pilar-Cuéllar F, Vidal R, Pazos A, Adell A, Díaz Á (2016) Cannabidiol induces rapid-acting antidepressant-like effects and enhances cortical 5-HT/glutamate neurotransmission: role of 5-HT 1A receptors. Neuropharmacology, 103:16–26

  • Liu Y, Pham X, Zhang L, Chen P, Burzynski G, McGaughey DM et al (2015) Functional variants in DPYSL2 sequence increase risk of schizophrenia and suggest a link to mTOR signaling. G3 (Bethesda) 5(1):61–72

    CAS  Article  Google Scholar 

  • Lodge DJ, Grace AA (2006) The hippocampus modulates dopamine neuron responsivity by regulating the intensity of phasic neuron activation. Neuropsychopharmacology 31(7):1356–1361

    CAS  PubMed  Article  Google Scholar 

  • Lodge DJ, Grace AA (2007) Aberrant hippocampal activity underlies the dopamine dysregulation in an animal model of schizophrenia. J Neurosci 27(42):11424–11430

    CAS  PubMed  Article  Google Scholar 

  • Long LE, Malone DT, Taylor DA (2006) Cannabidiol reverses MK-801-induced disruption of prepulse inhibition in mice. Neuropsychopharmacology 31(4):795

    CAS  PubMed  Article  Google Scholar 

  • Loureiro M, Renard J, Zunder J, Laviolette SR (2015) Hippocampal cannabinoid transmission modulates dopamine neuron activity: impact on rewarding memory formation and social interaction. Neuropsychopharmacology 40(6):1436–1447

    PubMed  PubMed Central  Article  Google Scholar 

  • Loureiro M, Kramar C, Renard J, Rosen LG, Laviolette SR (2016) Cannabinoid transmission in the hippocampus activates nucleus accumbens neurons and modulates reward and aversion-related emotional salience. Biol Psychiatry 80(3):216–225

    CAS  PubMed  Article  Google Scholar 

  • Luo J, Chen J, Deng ZL, Luo X, Song WX, Ka S et al (2007) Wnt signaling and human diseases: what are the therapeutic implications? Lab Investig 87(2):97–103

    CAS  PubMed  Article  Google Scholar 

  • Malone DT, Jongejan D, Taylor DA (2009) Cannabidiol reverses the reduction in social interaction produced by low dose delta(9)-tetrahydrocannabinol in rats. Pharmacol Biochem Behav 93:91–96

    CAS  PubMed  Article  Google Scholar 

  • Martin-Santos RA, Crippa J, Batalla A, Bhattacharyya S, Atakan Z, Borgwardt S et al (2012) Acute effects of a single, oral dose of d9-tetrahydrocannabinol (THC) and cannabidiol (CBD) administration in healthy volunteers. Curr Pharm Des 18(32):4966–4979

    CAS  PubMed  Article  Google Scholar 

  • Mathalon DH, Sullivan EV, Lim KO, Pfefferbaum A (2001) Progressive brain volume changes and the clinical course of schizophrenia in men: a longitudinal magnetic resonance imaging study. Arch Gen Psychiatry 58(2):148–157

    CAS  PubMed  Article  Google Scholar 

  • McGrath J, Saha S, Welham J, El Saadi O, MacCauley C, Chant D (2004) A systematic review of the incidence of schizophrenia: the distribution of rates and the influence of sex, urbanicity, migrant status and methodology. BMC Med 2:13

    PubMed  PubMed Central  Article  Google Scholar 

  • McGrath J, Saha S, Chant D, Welham J (2008) Schizophrenia: a concise overview of incidence, prevalence, and mortality. Epidemiol Rev 30:67–76

    PubMed  Article  Google Scholar 

  • McGaugh JL (2004) The amygdala modulates the consolidation of memories of emotionally arousing experiences. Annu Rev Neurosci 27:1–28

    CAS  PubMed  Article  Google Scholar 

  • McLaughlin PJ, Brown CM, Winston KM, Thakur G, Lu D, Makriyannis A, Salamone JD (2005) The novel cannabinoid agonist AM 411 produces a biphasic effect on accuracy in a visual target detection task in rats. Behav Pharmacol 16(5–6):477–486

    CAS  PubMed  Article  Google Scholar 

  • McNally RJ, Litz BT, Prassas A, Shin LM, Weathers FW (1994) Emotional priming of autobiographical memory in post-traumatic stress disorder. Cogn Emot 8(4):351–367

    Article  Google Scholar 

  • Meltzer HY (1999) The role of serotonin in antipsychotic drug action. Neuropsychopharmacology 21:106S–115S

    CAS  PubMed  Article  Google Scholar 

  • Meyer-Lindenberg AS, Olsen RK, Kohn PD, Brown T, Egan MF, Weinberger DR, Berman KF (2005) Regionally specific disturbance of dorsolateral prefrontal-hippocampal functional connectivity in schizophrenia. Arch Gen Psychiatry 62(4):379–386

    PubMed  Article  Google Scholar 

  • Milad MR, Quirk GJ (2002) Neurons in medial prefrontal cortex signal memory for fear extinction. Nature 420(6911):70

    CAS  PubMed  Article  Google Scholar 

  • Moore H, Jentsch JD, Ghajarnia M, Geyer MA, Grace AA (2006) A neurobehavioral systems analysis of adult rats exposed to methylazoxymethanol acetate on E17: implications for the neuropathology of schizophrenia. Biol Psychiatry 60(3):253–264

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Moreira FA, Guimarães FS (2005) Cannabidiol inhibits the hyperlocomotion induced by psychotomimetic drugs in mice. Eur J Pharmacol 512(2–3):199–205

    CAS  PubMed  Article  Google Scholar 

  • Morgan CA, 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):1–6

    Article  Google Scholar 

  • Müller H, Sperling W, Köhrmann M, Huttner HB, Kornhuber J, Maler JM (2010) The synthetic cannabinoid spice as a trigger for an acute exacerbation of cannabis induced recurrent psychotic episodes. Schizophr Res 118(1):309–310

    PubMed  Article  Google Scholar 

  • Murray GK, Corlett PR, Clark L, Pessiglione M, Blackwell AD, Honey G et al (2008) Substantia nigra/ventral tegmental reward prediction error disruption in psychosis. J Mol Psychiatry 13(3):267–276

    CAS  Article  Google Scholar 

  • Nelson MD, Saykin AJ, Flashman LA, Riordan HJ (1998) Hippocampal volume reduction in schizophrenia as assessed by magnetic resonance imaging: a meta-analytic study. Arch Gen Psychiatry 55(5):433–440

    CAS  PubMed  Article  Google Scholar 

  • Newcomer JW, Farber NB, Jevtovic-Todorovic V, Selke G, Melson AK, Hershey T et al (1999) Ketamine-induced NMDA receptor hypofunction as a model of memory impairment and psychosis. Neuropsychopharmacology 20(2):106–118

    CAS  PubMed  Article  Google Scholar 

  • Norris C, Loureiro M, Kramar C, Zunder J, Renard J, Rushlow W, Laviolette SR (2016) Cannabidiol modulates fear memory formation through interactions with serotonergic transmission in the mesolimbic system. Neuropsychopharmacology 41(12):2839–2850

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Ohman A, Flykt A, Esteves F (2001) Emotion drives attention: detecting the snake in the grass. J Exp Psychol Gen 130(3):466–478

    CAS  PubMed  Article  Google Scholar 

  • Olfson M, Mechanic D, Hansell S, Boyer C, Walkup J, Weiden PJ (2000) Predicting medication noncompliance after hospital discharge among patients with schizophrenia. Psychiatr Serv 47(2):216–222

    Article  Google Scholar 

  • Ozaita A, Puighermanal E, Maldonado R (2007) Regulation of PI3K/Akt/GSK-3 pathway by cannabinoids in the brain. J Neurochem 102(4):1105–1114

    CAS  PubMed  Article  Google Scholar 

  • Quinn HR, Matsumoto I, Callaghan PD, Long LE, Arnold JC, Gunasekaran N et al (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(5):1113–1126

    PubMed  Article  Google Scholar 

  • Palaniyappan L, Simmonite M, White TP, Liddle EB, Liddle PF (2013) Neural primacy of the salience processing system in schizophrenia. Neuron 79(4):814–828

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Parker LA, Burton P, Sorge RE, Yakiwchuk C, Mechoulam R (2004) Effect of low doses of delta9-tetrahydrocannabinol and cannabidiol on the extinction of cocaine-induced and amphetamine-induced conditioned place preference learning in rats. Psychopharmacology 175:360–366

    CAS  PubMed  Article  Google Scholar 

  • Paronis CA, Nikas SP, Shukla VG, Makriyannis A (2012) Delta-9-tetrahydrocannabinol acts as a partial agonist/antagonist in mice. Behav Pharmacol 23(8):802

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Pearlson AG, McKiernan K, Lloyd D, Kiehl KA, Calhoun VD (2007) Aberrant default mode functional connectivity in schizophrenia. Am J Psychiatry 1643:450–457

    Google Scholar 

  • Pedrazzi JC, Issy AC, Gomes FV, Guimarães FS, Del-Bel EA (2015) Cannabidiol effects in the prepulse inhibition disruption induced by amphetamine. Psychopharmacol 232(16):3057–3065

    CAS  Article  Google Scholar 

  • Peres FF, Levin R, Suiama MA, Diana MC, Gouva DA, Almeida V et al (2016) Cannabidiol prevents motor and cognitive impairments induced by reserpine in rats. Front Pharmacol 7:1–10

    Google Scholar 

  • Pertwee RG (2005) Cannabidiol as a potential medicine. Cannabinoids as Therapeutics: 47–65. Birkhäuser Basel

  • Pertwee RG (2008) The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin. Br J Pharmacol 153(2):199–215

    CAS  PubMed  Article  Google Scholar 

  • Pijlman FT, Rigter SM, Hoek J, Goldschmidt HM, Niesink RM (2005) Strong increase in total delta-9-THC in cannabis preparations sold in Dutch coffee shops. Addict Biol 10(June):171–180

    CAS  PubMed  Article  Google Scholar 

  • Platt B, Kamboj S, Morgan CJ, Curran HV (2010) Processing dynamic facial affect in frequent cannabis-users: evidence of deficits in the speed of identifying emotional expressions. Drug Alcohol Depend 112(1):27–32

    PubMed  Article  Google Scholar 

  • Protopopescu X, Pan H, Tuescher O, Cloitre M, Goldstein M, Engelien W et al (2005) Differential time courses and specificity of amygdala activity in posttraumatic stress disorder subjects and normal control subjects. Biol Psychiatry 57(5):464–473

    PubMed  Article  Google Scholar 

  • Puighermanal E, Marsicano G, Busquets-Garcia A, Lutz B, Maldonado R, Ozaita A (2009) Cannabinoid modulation of hippocampal long-term memory is mediated by mTOR signaling. Nat Neurosci 12(9):1152–1158

    CAS  PubMed  Article  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(7):1334–1343

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Rauch SL, Shin LM, Whalen PJ, Pitman RK (1998) Neuroimaging and the neuroanatomy of posttraumatic stress disorder. CNS Spectr 3(S2):30–41

    Article  Google Scholar 

  • Ren Y, Whittard J, Higuera-Matas A, Morris CV, Hurd YL (2009) Cannabidiol, a nonpsychotropic component of cannabis, inhibits cue-induced heroin seeking and normalizes discrete mesolimbic neuronal disturbances. J Neurosci 29(47):14764–14769

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Renard J, Loureiro M, Rosen LG, Zunder J, de Oliveira C, Schmid S et al (2016a) Cannabidiol counteracts amphetamine-induced neuronal and behavioral sensitization of the mesolimbic dopamine pathway through a novel mTOR/p70S6 kinase signaling pathway. J Neurosci 36(18):5160–5169

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Renard J, Rosen LG, Loureiro M, De Oliveira C, Schmid S, Rushlow WJ, Laviolette SR (2016b) Adolescent cannabinoid exposure induces a persistent sub-cortical hyper-dopaminergic state and associated molecular adaptations in the prefrontal cortex. Cereb Cortex: bhv335

  • Renard J, Norris C, Rushlow W, Laviolette SR (2017) Neuronal and molecular effects of cannabidiol on the mesolimbic dopamine system: implications for novel schizophrenia treatments. Neurosci Biobehav Rev 75:157–165

    CAS  PubMed  Article  Google Scholar 

  • Resick PA, Miller MW (2009) Posttraumatic stress disorder: anxiety or traumatic stress disorder? J Trauma Stress 22(5):384–390

    PubMed  Article  Google Scholar 

  • Rey AA, Purrio M, Viveros MP, Lutz B (2012) Biphasic effects of cannabinoids in anxiety responses: CB1 and GABAB receptors in the balance of GABAergic and glutamatergic neurotransmission. Neuropsychopharmacology 37(12):2624

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Robinson TE, Becker JB (1986) Enduring changes in brain and behavior produced by chronic amphetamine administration: a review and evaluation of animal models of amphetamine psychosis. Brain Res Rev 11(2):157–198

    CAS  Article  Google Scholar 

  • Russo EB, Burnett A, Hall B, Parker KK (2005) Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochem Res 30:1037–1043

    CAS  PubMed  Article  Google Scholar 

  • Ryberg E, Larsson N, Sjögren S, Hjorth S, Hermansson NO, Leonova J, Elebring T, Nilsson K, Drmota T, Greasley PJ (2007) The orphan receptor GPR55 is a novel cannabinoid receptor. Br J Pharmacol 152:1092–1101

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Seeman P (2016) Cannabidiol is a partial agonist at dopamine D2High receptors, predicting its antipsychotic clinical dose. Transl Psychiatry 6(10):e920

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Seeman P, Lee T (1975) Antipsychotic drugs: direct correlation between clinical potency and presynaptic action on dopamine neurons. Science 188(4194):1217–1219

    CAS  PubMed  Article  Google Scholar 

  • Shin LM, Rauch SL, Pitman RK (2006) Amygdala, medial prefrontal cortex, and hippocampal function in PTSD. Ann N Y Acad Sci 1071(1):67–79

    PubMed  Article  Google Scholar 

  • Soares Vde P, Campos AC, Bortoli VC, Zangrossi H Jr, Guimarães FS, Zuardi AW (2010) Intra-dorsal periaqueductal gray administration of cannabidiol blocks panic-like response by activating 5-HT1A receptors. Behav Brain Res 213:225–229

    PubMed  Article  CAS  Google Scholar 

  • Stern CA, Gazarini L, Takahashi RN, Guimaraes FS, Bertoglio LJ (2012) On disruption of fear memory by reconsolidation blockade: evidence from cannabidiol treatment. Neuropsychopharmacology 37(9):2132

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Sugranyes G, Flamarique I, Parellada E, Baeza I, Goti J, Fernandez-Egea E, Bernardo M (2009) Cannabis use and age of diagnosis of schizophrenia. Eur Psychiatry 24(5):282–286

    PubMed  Article  Google Scholar 

  • Sutton LP, Honardoust D, Mouyal J, Rajakumar N, Rushlow WJ (2007) Activation of the canonical Wnt pathway by the antipsychotics haloperidol and clozapine involves dishevelled-3. J Neurochem 102:153–169

    CAS  PubMed  Article  Google Scholar 

  • Szeszko PR, Goldberg E, Gunduz-Bruce H, Ashtari M, Robinson D, Malhotra AK et al (2003) Smaller anterior hippocampal formation volume in antipsychotic-naive patients with first-episode schizophrenia. Am J Psychiatry 160(12):2190–2197

    PubMed  Article  Google Scholar 

  • Takács VT, Szőnyi A, Freund TF, Nyiri G, Gulyás AI (2015) Quantitative ultrastructural analysis of basket and axo-axonic cell terminals in the mouse hippocampus. Brain Struct Funct 220(2):919–940

    PubMed  Article  Google Scholar 

  • Tandon R, Gaebel W, Barch DM, Bustillo J, Gur RE, Heckers S et al (2013) Definition and description of schizophrenia in the DSM-5. Schizophr Res 150(1):3–10

    PubMed  Article  Google Scholar 

  • Thomas A, Baillie GL, Phillips AM, Razdan RK, Ross RA, Pertwee RG (2007) Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. Br J Pharmacol 150:613–623

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Thome J, Frewen P, Daniels JK, Densmore M, Lanius RA (2014) Altered connectivity within the salience network during direct eye gaze in PTSD. Borderline Personal Disord Emot Dysregul 1(1):17

    PubMed  PubMed Central  Article  Google Scholar 

  • Tobler PN, Fiorillo CD, Schultz W (2005) Adaptive coding of reward value by dopamine neurons. Science 307(5715):1642–1645

    CAS  PubMed  Article  Google Scholar 

  • Uhlhaas PJ, Linden DE, Singer W, Haenschel C, Lindner M, Maurer K, Rodriguez E (2006) Dysfunctional long-range coordination of neural activity during gestalt perception in schizophrenia. J Neurosci 26(31):8168–8175

    CAS  PubMed  Article  Google Scholar 

  • Yücel M, Solowij N, Respondek C, Whittle S, Fornito A, Pantelis C, Lubman DI (2008) Regional brain abnormalities associated with long-term heavy cannabis use. Arch Gen Psychiatry 65(6):694–701

    PubMed  Article  Google Scholar 

  • Zuardi AW, Crippa JA, Hallak JE, Moreira FA, Guimarães FS (2006a) Cannabidiol, a cannabis sativa constituent, as an antipsychotic drug. Braz J Med Biol Res 39(4):421–429

    CAS  PubMed  Article  Google Scholar 

  • Zuardi AW, Hallak JE, Dursun SM, Morais SL, Faria Sanches R, Musty RE, Crippa JA (2006b) Cannabidiol monotherapy for treatment-resistant schizophrenia. J Psychopharmacol 20(5):683–686

    CAS  PubMed  Article  Google Scholar 

  • Zuardi AW, Crippa JA, Hallak JE, Bhattacharyya S, Atakan Z, Martín-Santos R et al (2012) A critical review of the antipsychotic effects of cannabidiol: 30 years of a translational investigation. Curr Pharm Des 18(32):5131–5140

    CAS  PubMed  Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Steven R. Laviolette.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Hudson, R., Rushlow, W. & Laviolette, S.R. Phytocannabinoids modulate emotional memory processing through interactions with the ventral hippocampus and mesolimbic dopamine system: implications for neuropsychiatric pathology. Psychopharmacology 235, 447–458 (2018). https://doi.org/10.1007/s00213-017-4766-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-017-4766-7

Keywords

  • Cannabidiol
  • THC
  • Memory
  • Psychosis
  • Rapamycin
  • Endocannabinoid
  • Emotional salience
  • Dopamine
  • Schizophrenia