Reduced cortical cannabinoid 1 receptor messenger RNA and protein expression in schizophrenia.

CONTEXT Cannabis use is associated with both impaired cognitive functions, including working memory, and an increased risk of schizophrenia. Schizophrenia is characterized by impairments in working memory that are associated with reduced gamma-aminobutyric acid (GABA) neurotransmission in the dorsolateral prefrontal cortex. The cannabinoid 1 receptor (CB1R) is highly expressed in the dorsolateral prefrontal cortex, is contained in the axon terminals of a subpopulation of perisomatic-targeting GABA neurons, and, when activated, suppresses the release of GABA. OBJECTIVE To determine the potential relationship between CB1R signaling and altered GABA neurotransmission in schizophrenia by evaluating CB1R messenger RNA (mRNA) and protein expression in the dorsolateral prefrontal cortex. DESIGN In situ hybridization and immunocytochemistry techniques were used to examine the cortical levels of CB1R mRNA and protein, respectively. SETTING Brain specimens were obtained from autopsies conducted at the Allegheny County Medical Examiner's Office, Pittsburgh, Pennsylvania. PARTICIPANTS Postmortem brain specimens from 23 pairs of subjects with schizophrenia and age-, sex-, and postmortem interval-matched comparison subjects, as well as brain specimens from 18 macaque monkeys with long-term exposure to haloperidol, olanzapine, or placebo. MAIN OUTCOME MEASURES Optical density measures of CB1R mRNA expression and protein levels and correlations with previously reported glutamic acid decarboxylase 67 and cholecystokinin mRNA measures. RESULTS Levels of CB1R mRNA were significantly lower by 14.8% in the subjects with schizophrenia. Similarly, CB1R protein levels, assessed by radioimmunocytochemistry and standard immunocytochemistry, were significantly decreased by 11.6% and 13.9%, respectively. Group differences in CB1R mRNA levels were significantly correlated with those in glutamic acid decarboxylase 67 and cholecystokinin mRNA levels. Expression of CB1R mRNA was not changed in antipsychotic-exposed monkeys, and neither CB1R mRNA levels nor protein levels were affected by potential confounding factors in the subjects with schizophrenia. CONCLUSIONS This combination of findings suggests the testable hypothesis that reduced CB1R mRNA and protein levels in schizophrenia represent a compensatory mechanism to increase GABA transmission from perisomatic-targeting cholecystokinin interneurons with impaired GABA synthesis.

[1]  J. Negrete,et al.  Cannabis affects the severity of schizophrenic symptoms: results of a clinical survey , 1986, Psychological Medicine.

[2]  T. Sawaguchi,et al.  Delayed response deficit in monkeys by locally disturbed prefrontal neuronal activity by bicuculline , 1988, Behavioural Brain Research.

[3]  M. Herkenham,et al.  Cannabinoid receptor localization in brain. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[4]  D. Lewis,et al.  Cholecystokinin innervation of monkey prefrontal cortex:An immunohistochemical study , 1990, The Journal of comparative neurology.

[5]  W. Slikker,et al.  Chronic exposure toΔ9-tetrahydrocannabinol fails to irreversibly alter brain cannabinoid receptors , 1991, Brain Research.

[6]  M. Herkenham,et al.  Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study , 1991, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[7]  M. Herkenham,et al.  Cannabinoid receptor binding and messenger RNA expression in human brain: An in vitro receptor autoradiography and in situ hybridization histochemistry study of normal aged and Alzheimer's brains , 1994, Neuroscience.

[8]  P. Massi,et al.  Chronic CP-55,940 alters cannabinoid receptor mRNA in the rat brain: an in situ hybridization study. , 1994, Neuroreport.

[9]  P S Goldman-Rakic,et al.  Cytoarchitectonic definition of prefrontal areas in the normal human cortex: I. Remapping of areas 9 and 46 using quantitative criteria. , 1995, Cerebral cortex.

[10]  E. G. Jones,et al.  Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics. , 1995, Archives of general psychiatry.

[11]  R. Faull,et al.  Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain , 1997, Neuroscience.

[12]  R. Hampson,et al.  Effects of long-term exposure to Δ9-THC on expression of cannabinoid receptor (CB1) mRNA in different rat brain regions , 1998 .

[13]  R. Hampson,et al.  Effects of long-term exposure to delta9-THC on expression of cannabinoid receptor (CB1) mRNA in different rat brain regions. , 1998, Brain research. Molecular brain research.

[14]  J. Manzanares,et al.  Time‐course of the cannabinoid receptor down‐regulation in the adult rat brain caused by repeated exposure to Δ9‐tetrahydrocannabinol , 1998, Synapse.

[15]  J. M. Moerschbaecher,et al.  Cannabinoid ligands and their effects on learning and performance in rhesus monkeys. , 1999, Behavioural pharmacology.

[16]  J. Pierri,et al.  Alterations in chandelier neuron axon terminals in the prefrontal cortex of schizophrenic subjects. , 1999, The American journal of psychiatry.

[17]  J. Ramos,et al.  Cannabinoid receptor binding and mRNA levels in several brain regions of adult male and female rats perinatally exposed to delta9-tetrahydrocannabinol. , 1999, Drug and alcohol dependence.

[18]  H. Emrich,et al.  Elevated endogenous cannabinoids in schizophrenia. , 1999, Neuroreport.

[19]  G. Marsicano,et al.  Expression of the cannabinoid receptor CB1 in distinct neuronal subpopulations in the adult mouse forebrain , 1999, The European journal of neuroscience.

[20]  A. Sampson,et al.  Decreased glutamic acid decarboxylase67 messenger RNA expression in a subset of prefrontal cortical gamma-aminobutyric acid neurons in subjects with schizophrenia. , 2000, Archives of general psychiatry.

[21]  P. Goldman-Rakic,et al.  Destruction and Creation of Spatial Tuning by Disinhibition: GABAA Blockade of Prefrontal Cortical Neurons Engaged by Working Memory , 2000, The Journal of Neuroscience.

[22]  I. Módy,et al.  Cannabinoids inhibit hippocampal GABAergic transmission and network oscillations , 2000, The European journal of neuroscience.

[23]  L. Glantz,et al.  Normal cellular levels of synaptophysin mRNA expression in the prefrontal cortex of subjects with schizophrenia , 2000, Biological Psychiatry.

[24]  T. Goldberg,et al.  Cognitive impairment in schizophrenia is the core of the disorder. , 2000, Critical reviews in neurobiology.

[25]  P. Massi,et al.  Changes in the Cannabinoid Receptor Binding, G Protein Coupling, and Cyclic AMP Cascade in the CNS of Rats Tolerant to and Dependent on the Synthetic Cannabinoid Compound CP55,940 , 2000, Journal of neurochemistry.

[26]  Yogesh K. Dwivedi,et al.  Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: a postmortem brain study. , 2000, Archives of general psychiatry.

[27]  T. Freund,et al.  Novel cannabinoid-sensitive receptor mediates inhibition of glutamatergic synaptic transmission in the hippocampus , 2001, Neuroscience.

[28]  M. Egan,et al.  Prefrontal neurons and the genetics of schizophrenia , 2001, Biological Psychiatry.

[29]  C. Breivogel,et al.  Evidence for a new G protein-coupled cannabinoid receptor in mouse brain. , 2001, Molecular pharmacology.

[30]  B. Dean,et al.  Studies on [3H]CP-55940 binding in the human central nervous system: regional specific changes in density of cannabinoid-1 receptors associated with schizophrenia and cannabis use , 2001, Neuroscience.

[31]  P. Somogyi,et al.  Input‐dependent synaptic targeting of α2‐subunit‐containing GABAA receptors in synapses of hippocampal pyramidal cells of the rat , 2001, The European journal of neuroscience.

[32]  D. Parolaro,et al.  Chronic exposure to morphine, cocaine or ethanol in rats produced different effects in brain cannabinoid CB(1) receptor binding and mRNA levels. , 2002, Drug and alcohol dependence.

[33]  Thomas Babor,et al.  Cognitive functioning of long-term heavy cannabis users seeking treatment. , 2002, JAMA.

[34]  M. Kano,et al.  Presynaptic Cannabinoid Sensitivity Is a Major Determinant of Depolarization-Induced Retrograde Suppression at Hippocampal Synapses , 2002, The Journal of Neuroscience.

[35]  A. Sampson,et al.  Gene Expression Deficits in a Subclass of GABA Neurons in the Prefrontal Cortex of Subjects with Schizophrenia , 2003, The Journal of Neuroscience.

[36]  Michael Koch,et al.  Chronic Pubertal, but not Adult Chronic Cannabinoid Treatment Impairs Sensorimotor Gating, Recognition Memory, and the Performance in a Progressive Ratio Task in Adult Rats , 2003, Neuropsychopharmacology.

[37]  L. Petrocellis,et al.  Endocannabinoid signalling in the blood of patients with schizophrenia , 2003, Lipids in Health and Disease.

[38]  D. Lewis,et al.  Selective alterations in prefrontal cortical GABA neurotransmission in schizophrenia: a novel target for the treatment of working memory dysfunction , 2004, Psychopharmacology.

[39]  T. Freund,et al.  Role of endogenous cannabinoids in synaptic signaling. , 2003, Physiological reviews.

[40]  Y. Hurd,et al.  Preferential limbic expression of the cannabinoid receptor mRNA in the human fetal brain , 2003, Neuroscience.

[41]  Marc W Howard,et al.  Gamma oscillations correlate with working memory load in humans. , 2003, Cerebral cortex.

[42]  Joachim Klosterkötter,et al.  Cerebrospinal Anandamide Levels are Elevated in Acute Schizophrenia and are Inversely Correlated with Psychotic Symptoms , 2004, Neuropsychopharmacology.

[43]  Huda Akil,et al.  Systematic changes in gene expression in postmortem human brains associated with tissue pH and terminal medical conditions. , 2004, Human molecular genetics.

[44]  J. Manzanares,et al.  Chronic ethanol consumption regulates cannabinoid CB1 receptor gene expression in selected regions of rat brain. , 2004, Alcohol and alcoholism.

[45]  Ralitza Gueorguieva,et al.  The Psychotomimetic Effects of Intravenous Delta-9-Tetrahydrocannabinol in Healthy Individuals: Implications for Psychosis , 2004, Neuropsychopharmacology.

[46]  Therese Garrick,et al.  Selective antagonist [3H]SR141716A binding to cannabinoid CB1 receptors is increased in the anterior cingulate cortex in schizophrenia , 2004, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[47]  John R. Huguenard,et al.  Long-lasting self-inhibition of neocortical interneurons mediated by endocannabinoids , 2004, Nature.

[48]  S. Hestrin,et al.  Electrical Coupling among Irregular-Spiking GABAergic Interneurons Expressing Cannabinoid Receptors , 2004, The Journal of Neuroscience.

[49]  B. Alger,et al.  Inhibition of cyclooxygenase-2 potentiates retrograde endocannabinoid effects in hippocampus , 2004, Nature Neuroscience.

[50]  D. Lewis,et al.  Cortical inhibitory neurons and schizophrenia , 2005, Nature Reviews Neuroscience.

[51]  Peter B. Jones,et al.  Cannabis use and outcome of recent onset psychosis , 2005, European Psychiatry.

[52]  Judit K. Makara,et al.  Selective inhibition of 2-AG hydrolysis enhances endocannabinoid signaling in hippocampus , 2005, Nature Neuroscience.

[53]  A. Christopoulos,et al.  Allosteric Modulation of the Cannabinoid CB1 Receptor , 2005, Molecular Pharmacology.

[54]  Ken Mackie,et al.  Endocannabinoid Signaling in Rat Somatosensory Cortex: Laminar Differences and Involvement of Specific Interneuron Types , 2005, The Journal of Neuroscience.

[55]  A. Sampson,et al.  Relationship of Brain-Derived Neurotrophic Factor and Its Receptor TrkB to Altered Inhibitory Prefrontal Circuitry in Schizophrenia , 2005, The Journal of Neuroscience.

[56]  Ralitza Gueorguieva,et al.  Delta-9-tetrahydrocannabinol effects in schizophrenia: Implications for cognition, psychosis, and addiction , 2005, Biological Psychiatry.

[57]  R. Murray,et al.  The environment and schizophrenia: the role of cannabis use. , 2005, Schizophrenia bulletin.

[58]  David A Lewis,et al.  GABA Targets for the Treatment of Cognitive Dysfunction in Schizophrenia. , 2005, Current neuropharmacology.

[59]  J. Addington,et al.  Outcome of a first episode of psychosis in adolescence: a 2-year follow-up , 2005, Psychiatry Research.

[60]  Zhuoxin Sun,et al.  The Influence of Chronic Exposure to Antipsychotic Medications on Brain Size before and after Tissue Fixation: A Comparison of Haloperidol and Olanzapine in Macaque Monkeys , 2005, Neuropsychopharmacology.

[61]  T. Freund,et al.  Molecular Composition of the Endocannabinoid System at Glutamatergic Synapses , 2006, The Journal of Neuroscience.

[62]  Vivien Chevaleyre,et al.  Endocannabinoid-mediated synaptic plasticity in the CNS. , 2006, Annual review of neuroscience.

[63]  Carol A. Tamminga,et al.  Human postmortem tissue: What quality markers matter? , 2006, Brain Research.

[64]  Bruce L McNaughton,et al.  Cannabinoids reveal importance of spike timing coordination in hippocampal function , 2006, Nature Neuroscience.

[65]  C. Carter,et al.  Impairments in frontal cortical γ synchrony and cognitive control in schizophrenia , 2006, Proceedings of the National Academy of Sciences.

[66]  C. Carter,et al.  Impairments in frontal cortical gamma synchrony and cognitive control in schizophrenia. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[67]  Xu-Feng Huang,et al.  Increased cannabinoid receptor density in the posterior cingulate cortex in schizophrenia , 2006, Experimental Brain Research.

[68]  Masahiko Watanabe,et al.  The CB1 Cannabinoid Receptor Is the Major Cannabinoid Receptor at Excitatory Presynaptic Sites in the Hippocampus and Cerebellum , 2006, The Journal of Neuroscience.

[69]  Michael B. Mayhew,et al.  Allelic variation in GAD1 (GAD67) is associated with schizophrenia and influences cortical function and gene expression , 2007, Molecular Psychiatry.

[70]  M. Kano,et al.  Presynaptic Monoacylglycerol Lipase Activity Determines Basal Endocannabinoid Tone and Terminates Retrograde Endocannabinoid Signaling in the Hippocampus , 2007, The Journal of Neuroscience.

[71]  Peter B. Jones,et al.  Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review , 2007, The Lancet.

[72]  David A Lewis,et al.  Immunocytochemical distribution of the cannabinoid CB1 receptor in the primate neocortex: a regional and laminar analysis. , 2006, Cerebral cortex.

[73]  Edward O. Mann,et al.  Role of GABAergic inhibition in hippocampal network oscillations , 2007, Trends in Neurosciences.

[74]  I. Soltesz,et al.  Cell type–specific gating of perisomatic inhibition by cholecystokinin , 2007, Nature Neuroscience.

[75]  B. Kocsis,et al.  Activation of Cannabinoid-1 Receptors Disrupts Sensory Gating and Neuronal Oscillation: Relevance to Schizophrenia , 2008, Biological Psychiatry.

[76]  H. M. Morris,et al.  Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia , 2008, Molecular Psychiatry.