GABA Targets for the Treatment of Cognitive Dysfunction in Schizophrenia.

Cognitive deficits, including impairments in working memory that have been linked to the prefrontal cortex, are among the most debilitating and difficult to treat features of schizophrenia. Consequently, the identification of potential targets informed by the pathophysiology of the illness is needed to develop novel pharmacological approaches for ameliorating these deficits. Postmortem studies of the prefrontal cortex in schizophrenia subjects have revealed disturbances restricted to a subpopulation of inhibitory neurons that includes chandelier neurons, whose axon terminals synapse on the axon initial segment of pyramidal neurons. Chandelier neurons play an important role in synchronizing pyramidal neuron activity and appear to be a critical component of the prefrontal cortical circuitry that subserves working memory function. Therefore, in this paper we review evidence suggesting that drugs which selectively enhance chandelier neuron-mediated inhibition of prefrontal pyramidal neurons may improve working memory dysfunction in schizophrenia. Potential novel targets for such agents include GABA(A) receptors that contain the α(2) subunit. In addition, we discuss potential complementary mechanisms for enhancing inhibitory input to pyramidal cell bodies, including drugs with activity at the CB1 receptor of the endocannabinoid system. The development of pathophysiologically-based treatments that selectively remediate disturbances in specific neural circuits underlying working memory may provide an effective approach to improving cognitive deficits in schizophrenia.

[1]  E. Gordon,et al.  Synchronous Gamma activity: a review and contribution to an integrative neuroscience model of schizophrenia , 2003, Brain Research Reviews.

[2]  P. Somogyi,et al.  Glutamate decarboxylase‐immunoreactive terminals of Golgi‐impregnated axoaxonic cells and of presumed basket cells in synaptic contact with pyramidal neurons of the cat's visual cortex , 1983, The Journal of comparative neurology.

[3]  P. Somogyi,et al.  Differential synaptic localization of two major gamma-aminobutyric acid type A receptor alpha subunits on hippocampal pyramidal cells. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[4]  S. Hyman,et al.  Medicine. What are the right targets for psychopharmacology? , 2003, Science.

[5]  Sophia Vinogradov,et al.  Association of anticholinergic load with impairment of complex attention and memory in schizophrenia. , 2004, The American journal of psychiatry.

[6]  M. L. Pucak,et al.  Synaptic targets of pyramidal neurons providing intrinsic horizontal connections in monkey prefrontal cortex , 1998, The Journal of comparative neurology.

[7]  T. Rülicke,et al.  Molecular and neuronal substrate for the selective attenuation of anxiety. , 2000, Science.

[8]  R. Buchanan,et al.  Diazepam treatment of early signs of exacerbation in schizophrenia. , 1999, The American journal of psychiatry.

[9]  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.

[10]  Paul J. Harrison,et al.  Laser-assisted microdissection: methods for the molecular analysis of psychiatric disorders at a cellular resolution , 2004, Biological Psychiatry.

[11]  L. Ferraro,et al.  Cannabinoid receptor agonist WIN 55,212‐2 inhibits rat cortical dialysate γ‐aminobutyric acid levels , 2001 .

[12]  M. Egan,et al.  Complexity of prefrontal cortical dysfunction in schizophrenia: more than up or down. , 2003, The American journal of psychiatry.

[13]  C. Adamsson,et al.  Cannabis and schizophrenia: a longitudinal study of cases treated in Stockholm County , 1993, Acta psychiatrica Scandinavica.

[14]  P. Goldman-Rakic,et al.  Isodirectional tuning of adjacent interneurons and pyramidal cells during working memory: evidence for microcolumnar organization in PFC. , 1999, Journal of neurophysiology.

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

[16]  P. Somogyi,et al.  Differential synaptic localization of two major y-aminobutyric acid type A receptor a subunits on hippocampal pyramidal cells , 1996 .

[17]  F. Benes,et al.  GABAergic Interneurons: Implications for Understanding Schizophrenia and Bipolar Disorder , 2001, Neuropsychopharmacology.

[18]  A. Mikami,et al.  Functional brain mapping of the macaque related to spatial working memory as revealed by PET. , 2004, Cerebral cortex.

[19]  Tamás F Freund,et al.  Interneuron Diversity series: Rhythm and mood in perisomatic inhibition , 2003, Trends in Neurosciences.

[20]  D S Rae,et al.  Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiologic Catchment Area (ECA) Study. , 1990, JAMA.

[21]  L. Acsády,et al.  Distinct interneuron types express m2 muscarinic receptor immunoreactivity on their dendrites or axon terminals in the hippocampus , 1997, Neuroscience.

[22]  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.

[23]  J. Kleinman,et al.  Selective abnormalities of prefrontal serotonergic receptors in schizophrenia. A postmortem study. , 1993, Archives of general psychiatry.

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

[25]  J. Deakin,et al.  Autoradiography with [3H]8-OH-DPAT reveals increases in 5-HT1A receptors in ventral prefrontal cortex in schizophrenia , 1996, Biological Psychiatry.

[26]  T. Freund,et al.  GABAergic interneurons are the targets of cannabinoid actions in the human hippocampus , 2000, Neuroscience.

[27]  R. Gur,et al.  Neuropsychological deficits in neuroleptic naive patients with first-episode schizophrenia. , 1994, Archives of general psychiatry.

[28]  Ken Mackie,et al.  Presynaptically Located CB1 Cannabinoid Receptors Regulate GABA Release from Axon Terminals of Specific Hippocampal Interneurons , 1999, The Journal of Neuroscience.

[29]  N. Cozzi,et al.  5-HT2A receptor antagonists inhibit potassium-stimulated gamma-aminobutyric acid release in rat frontal cortex. , 1996, European journal of pharmacology.

[30]  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.

[31]  Glyn Lewis,et al.  Self reported cannabis use as a risk factor for schizophrenia in Swedish conscripts of 1969: historical cohort study , 2002, BMJ : British Medical Journal.

[32]  P. Seeburg,et al.  Structural and functional basis for GABAA receptor heterogeneity , 1988, Nature.

[33]  Françoise Condé,et al.  Local circuit neurons immunoreactive for calretinin, calbindin D‐28k or parvalbumin in monkey prefronatal cortex: Distribution and morphology , 1994, The Journal of comparative neurology.

[34]  C. Tanaka,et al.  Increase in serotonin 5-HT1A receptors in prefrontal and temporal cortices of brains from patients with chronic schizophrenia. , 1991, Life sciences.

[35]  H. Meltzer,et al.  Serotonin2 (5-HT2) receptor binding in the frontal cortex of schizophrenic patients , 1991, Journal of Neural Transmission / General Section JNT.

[36]  J. Trojanowski,et al.  Gene expression profile for schizophrenia: discrete neuron transcription patterns in the entorhinal cortex. , 2002, Archives of general psychiatry.

[37]  W H Wong,et al.  Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[38]  B. Dean,et al.  Decreased frontal cortical serotonin2A receptors in schizophrenia , 1996, Schizophrenia Research.

[39]  P. Somogyi,et al.  Synchronization of neuronal activity in hippocampus by individual GABAergic interneurons , 1995, Nature.

[40]  A. Hoffman,et al.  Functional localization of cannabinoid receptors and endogenous cannabinoid production in distinct neuron populations of the hippocampus , 2003, The European journal of neuroscience.

[41]  D. Weinberger,et al.  Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia. I. Regional cerebral blood flow evidence. , 1986, Archives of general psychiatry.

[42]  Henry Markram,et al.  Interneuron Diversity series: Molecular and genetic tools to study GABAergic interneuron diversity and function , 2004, Trends in Neurosciences.

[43]  K. Mackie,et al.  Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system , 1998, Neuroscience.

[44]  P. Goldman-Rakic,et al.  Abnormally high neuronal density in the schizophrenic cortex. A morphometric analysis of prefrontal area 9 and occipital area 17. , 1995, Archives of general psychiatry.

[45]  J. Pernier,et al.  Induced gamma-band activity during the delay of a visual short-term memory task in humans. , 1998, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[46]  T. Sawaguchi,et al.  Delayed response deficits produced by local injection of bicuculline into the dorsolateral prefrontal cortex in Japanese macaque monkeys , 2004, Experimental Brain Research.

[47]  R. Nicoll,et al.  Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses , 2001, Nature.

[48]  F. Benes,et al.  Up-regulation of GABAA receptor binding on neurons of the prefrontal cortex in schizophrenic subjects , 1996, Neuroscience.

[49]  H. Haas,et al.  5-HT inhibits lateral entorhinal cortical neurons of the rat in vitro by activation of potassium channel-coupled 5-HT1A receptors , 1997, Brain Research.

[50]  N. Newberry,et al.  Actions of 5-HT on human neocortical neurones in vitro , 1999, Brain Research.

[51]  P. Dingemans,et al.  Cannabis abuse and the course of recent onset schizophrenic disorders , 1993, Schizophrenia Research.

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

[53]  Catherine Tallon-Baudry,et al.  Induced γ-Band Activity during the Delay of a Visual Short-Term Memory Task in Humans , 1998, The Journal of Neuroscience.

[54]  A. Sampson,et al.  GABA transporter-1 mRNA in the prefrontal cortex in schizophrenia: decreased expression in a subset of neurons. , 2001, The American journal of psychiatry.

[55]  A. Hoffman,et al.  Mechanisms of Cannabinoid Inhibition of GABAASynaptic Transmission in the Hippocampus , 2000, The Journal of Neuroscience.

[56]  Alexander L. Miller,et al.  Executive-frontal lobe cognitive dysfunction in schizophrenia: A symptom subtype analysis , 1998, Psychiatry Research.

[57]  Michael F. Green,et al.  What are the functional consequences of neurocognitive deficits in schizophrenia? , 1996, The American journal of psychiatry.

[58]  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.

[59]  Philip D. Harvey,et al.  Symptoms, cognitive functioning, and adaptive skills in geriatric patients with lifelong schizophrenia: a comparison across treatment sites. , 1998, The American journal of psychiatry.

[60]  C. Beasley,et al.  Selective deficits in prefrontal cortical GABAergic neurons in schizophrenia defined by the presence of calcium-binding proteins , 2002, Biological Psychiatry.

[61]  G. Knudsen,et al.  The 5-HT1A serotonin receptor is located on calbindin- and parvalbumin-containing neurons in the rat brain , 2003, Brain Research.

[62]  A. Sampson,et al.  Reciprocal alterations in pre- and postsynaptic inhibitory markers at chandelier cell inputs to pyramidal neurons in schizophrenia. , 2002, Cerebral cortex.

[63]  M. Egan,et al.  Comparison of Cognitive Performances During a Placebo Period and an Atypical Antipsychotic Treatment Period in Schizophrenia: Critical Examination of Confounds , 2003, Neuropsychopharmacology.

[64]  German Barrionuevo,et al.  Synaptic targets of the intrinsic axon collaterals of supragranular pyramidal neurons in monkey prefrontal cortex , 2001, The Journal of comparative neurology.

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

[66]  Sven Andréasson,et al.  CANNABIS AND SCHIZOPHRENIA A Longitudinal Study of Swedish Conscripts , 1987, The Lancet.

[67]  P. Goldman-Rakic.  Cellular basis of working memory , 1995, Neuron.

[68]  A. Aguzzi,et al.  A Highly Sensitive Immunofluorescence Procedure for Analyzing the Subcellular Distribution of GABAA Receptor Subunits in the Human Brain , 1998, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[69]  J. Raymond,et al.  Multiplicity of mechanisms of serotonin receptor signal transduction. , 2001, Pharmacology & therapeutics.

[70]  H. Meltzer,et al.  Serotonin1A receptors are increased in postmortem prefrontal cortex in schizophrenia , 1996, Brain Research.

[71]  G. Tamás,et al.  Cholinergic activation and tonic excitation induce persistent gamma oscillations in mouse somatosensory cortex in vitro , 1998, The Journal of physiology.

[72]  P. Goldman-Rakic,et al.  A role for inhibition in shaping the temporal flow of information in prefrontal cortex , 2002, Nature Neuroscience.

[73]  M. Scanziani,et al.  Enforcement of Temporal Fidelity in Pyramidal Cells by Somatic Feed-Forward Inhibition , 2001, Science.

[74]  J. Cohen,et al.  Functional hypofrontality and working memory dysfunction in schizophrenia. , 1998, The American journal of psychiatry.

[75]  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.

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

[77]  R. Coppola,et al.  Physiological dysfunction of the dorsolateral prefrontal cortex in schizophrenia revisited. , 2000, Cerebral cortex.

[78]  P. Goldman-Rakic,et al.  Mnemonic coding of visual space in the monkey's dorsolateral prefrontal cortex. , 1989, Journal of neurophysiology.

[79]  Andras Nagy,et al.  Cre recombinase: The universal reagent for genome tailoring , 2000, Genesis.

[80]  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.

[81]  J. Lund,et al.  Local circuit neurons of developing and mature macaque prefrontal cortex: Golgi and immunocytochemical characteristics , 1993, The Journal of comparative neurology.

[82]  P. Goldman-Rakic,et al.  Segregation of serotonin 5‐HT2A and 5‐HT3 receptors in inhibitory circuits of the primate cerebral cortex , 2000, The Journal of comparative neurology.

[83]  M. Krebs,et al.  Is substance abuse in schizophrenia related to impulsivity, sensation seeking, or anhedonia? , 2001, The American journal of psychiatry.

[84]  K. Mackie,et al.  Cannabinoid CB1 receptors are localized primarily on cholecystokinin-containing GABAergic interneurons in the rat hippocampal formation , 1999, Neuroscience.

[85]  J. DeFelipe.  Types of neurons, synaptic connections and chemical characteristics of cells immunoreactive for calbindin-D28K, parvalbumin and calretinin in the neocortex , 1997, Journal of Chemical Neuroanatomy.

[86]  J. Fritschy,et al.  GABAA‐receptor heterogeneity in the adult rat brain: Differential regional and cellular distribution of seven major subunits , 1995, The Journal of comparative neurology.

[87]  Chris J. McBain,et al.  Interneurons unbound , 2001, Nature Reviews Neuroscience.

[88]  Sohee Park,et al.  Schizophrenics show spatial working memory deficits. , 1992, Archives of general psychiatry.

[89]  D. Pickar,et al.  National Institute of Mental Health longitudinal study of chronic schizophrenia. Prognosis and predictors of outcome. , 1991, Archives of general psychiatry.

[90]  T. Kuno,et al.  Decreased serotonin S2 and increased dopamine D2 receptors in chronic schizophrenics , 1986, Biological Psychiatry.

[91]  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.

[92]  A Reichenberg,et al.  Behavioral and intellectual markers for schizophrenia in apparently healthy male adolescents. , 1999, The American journal of psychiatry.

[93]  T. Woo,et al.  Schizophrenia and the parvalbumin-containing class of cortical local circuit neurons. , 1997, The American journal of psychiatry.

[94]  R. Roth,et al.  5-HT2 Receptor Regulation of Extracellular GABA Levels in the Prefrontal Cortex , 1999, Neuropsychopharmacology.

[95]  Daniel R Weinberger,et al.  Microarray analysis of gene expression in the prefrontal cortex in schizophrenia: a preliminary study , 2002, Schizophrenia Research.

[96]  P. Goldman-Rakic,et al.  Serotonergic axons in monkey prefrontal cerebral cortex synapse predominantly on interneurons as demonstrated by serial section electron microscopy , 1996, The Journal of comparative neurology.

[97]  Andreas Zimmer,et al.  The Cannabinoid CB1 Receptor Mediates Retrograde Signals for Depolarization-Induced Suppression of Inhibition in Cerebellar Purkinje Cells , 2002, The Journal of Neuroscience.

[98]  R. Andrade,et al.  5-Hydroxytryptamine2 receptor facilitates GABAergic neurotransmission in rat hippocampus. , 1998, The Journal of pharmacology and experimental therapeutics.

[99]  D. Lewis,et al.  Parvalbumin‐immunoreactive axon terminals in macaque monkey and human prefrontal cortex: Laminar, regional, and target specificity of type I and type II synapses , 1999, The Journal of comparative neurology.

[100]  Brian Sheitman,et al.  Neurocognitive effects of clozapine, olanzapine, risperidone, and haloperidol in patients with chronic schizophrenia or schizoaffective disorder. , 2002, The American journal of psychiatry.

[101]  M. Vreugdenhil,et al.  Parvalbumin-deficiency facilitates repetitive IPSCs and gamma oscillations in the hippocampus. , 2003, Journal of neurophysiology.

[102]  David A Lewis,et al.  Pyramidal neuron local axon terminals in monkey prefrontal cortex: differential targeting of subclasses of GABA neurons. , 2003, Cerebral cortex.

[103]  G. Marks,et al.  Increased γ- and Decreased δ-Oscillations in a Mouse Deficient for a Potassium Channel Expressed in Fast-Spiking Interneurons , 1999 .

[104]  Edith Hamel,et al.  5-HT3 Receptors Mediate Serotonergic Fast Synaptic Excitation of Neocortical Vasoactive Intestinal Peptide/Cholecystokinin Interneurons , 2002, The Journal of Neuroscience.

[105]  D. Yurgelun-Todd,et al.  The residual cognitive effects of heavy marijuana use in college students. , 1996, JAMA.

[106]  David A. Lewis,et al.  Impaired prefrontal inhibition in schizophrenia: relevance for cognitive dysfunction , 2002, Physiology & Behavior.

[107]  R. Pertwee,et al.  Correlation between cannabinoid mediated effects on paired pulse depression and induction of long term potentiation in the rat hippocampal slice , 1998, Neuropharmacology.

[108]  O. Bertrand,et al.  Sustained and transient oscillatory responses in the gamma and beta bands in a visual short-term memory task in humans , 1999, Visual Neuroscience.

[109]  M. Martinez-Arevalo,et al.  Cannabis Consumption as a Prognostic Factor in Schizophrenia , 1994, British Journal of Psychiatry.

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

[111]  T. Woo,et al.  A subclass of prefrontal gamma-aminobutyric acid axon terminals are selectively altered in schizophrenia. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[112]  Alex M Thomson,et al.  Physiological and morphological diversity of immunocytochemically defined parvalbumin‐ and cholecystokinin‐positive interneurones in CA1 of the adult rat hippocampus , 2002, The Journal of comparative neurology.

[113]  R. Gur,et al.  Neurocognitive Performance and Clinical Changes in Olanzapine-Treated Patients with Schizophrenia , 2003, Neuropsychopharmacology.

[114]  G. Aghajanian,et al.  Serotonin Induces Excitatory Postsynaptic Potentials in Apical Dendrites of Neocortical Pyramidal Cells , 1997, Neuropharmacology.

[115]  L. Kochan,et al.  GABA and Schizophrenia: A Review of Basic Science and Clinical Studies , 2003, Journal of clinical psychopharmacology.

[116]  P. Allebeck,et al.  CANNABIS AND SCHIZOPHRENIA , 1988, The Lancet.

[117]  A. Erisir,et al.  Muscarinic receptor M2 in cat visual cortex: Laminar distribution, relationship to γ‐aminobutyric acidergic neurons, and effect of cingulate lesions , 2001, The Journal of comparative neurology.

[118]  J. B. Levitt,et al.  Patterns of intrinsic and associational circuitry in monkey prefrontal cortex , 1996, The Journal of comparative neurology.

[119]  Javier DeFelipe,et al.  Pyramidal cell axons show a local specialization for GABA and 5‐HT inputs in monkey and human cerebral cortex , 2001, The Journal of comparative neurology.

[120]  G. Marks,et al.  Increased gamma- and decreased delta-oscillations in a mouse deficient for a potassium channel expressed in fast-spiking interneurons. , 1999, Journal of neurophysiology.

[121]  M. Kano,et al.  Endogenous Cannabinoids Mediate Retrograde Signals from Depolarized Postsynaptic Neurons to Presynaptic Terminals , 2001, Neuron.

[122]  P. Goldman-Rakic,et al.  Elevated neuronal density in prefrontal area 46 in brains from schizophrenic patients: Application of a three‐dimensional, stereologic counting method , 1998, The Journal of comparative neurology.

[123]  Y. Kubota,et al.  Neurochemical features and synaptic connections of large physiologically-identified GABAergic cells in the rat frontal cortex , 1998, Neuroscience.

[124]  N L Harrison,et al.  Activation and deactivation rates of recombinant GABA(A) receptor channels are dependent on alpha-subunit isoform. , 1997, Biophysical journal.

[125]  J. Cohen,et al.  Relation of prefrontal cortex dysfunction to working memory and symptoms in schizophrenia. , 2001, The American journal of psychiatry.

[126]  Y. Kawaguchi.  Physiological subgroups of nonpyramidal cells with specific morphological characteristics in layer II/III of rat frontal cortex , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[127]  H. Häfner,et al.  Cannabis, Vulnerability, and the Onset of Schizophrenia: An Epidemiological Perspective∗ , 2000, The Australian and New Zealand journal of psychiatry.

[128]  E. Azmitia,et al.  Serotonin1A receptors at the axon initial segment of prefrontal pyramidal neurons in schizophrenia. , 2004, The American journal of psychiatry.

[129]  Anatol C. Kreitzer,et al.  Cerebellar Depolarization-Induced Suppression of Inhibition Is Mediated by Endogenous Cannabinoids , 2001, The Journal of Neuroscience.

[130]  J. Lund,et al.  Heterogeneity of chandelier neurons in monkey neocortex: Corticotropin‐releasing factor‐and parvalbumin‐immunoreactive populations , 1990, The Journal of comparative neurology.

[131]  R. McCarley,et al.  Abnormal Neural Synchrony in Schizophrenia , 2003, The Journal of Neuroscience.

[132]  Jane S. Paulsen,et al.  Neuropsychological deficits in schizophrenics. Relationship to age, chronicity, and dementia. , 1994, Archives of general psychiatry.

[133]  P. Soubrié,et al.  Improvement of memory in rodents by the selective CB1 cannabinoid receptor antagonist, SR 141716 , 1996, Psychopharmacology.

[134]  S. Frangou.  The treatment of cognitive dysfunction in schizophrenia , 2005 .

[135]  F. Bloom,et al.  The 5-HT3 Receptor Is Present in Different Subpopulations of GABAergic Neurons in the Rat Telencephalon , 1997, The Journal of Neuroscience.

[136]  A. Sampson,et al.  Lamina-specific alterations in the dopamine innervation of the prefrontal cortex in schizophrenic subjects. , 1999, The American journal of psychiatry.

[137]  M. Naus,et al.  Cognitive correlates of long-term cannabis use in Costa Rican men. , 1996, Archives of general psychiatry.

[138]  H. Markram,et al.  Organizing principles for a diversity of GABAergic interneurons and synapses in the neocortex. , 2000, Science.

[139]  Paul J. Harrison,et al.  5-HT1A and 5-HT2A Receptor mRNAs and Binding Site Densities Are Differentially Altered in Schizophrenia , 1996, Neuropsychopharmacology.

[140]  N. Andreasen,et al.  A longitudinal study of symptom dimensions in schizophrenia. Prediction and patterns of change. , 1995, Archives of general psychiatry.