Emergent pharmacology of conscious experience: new perspectives in substance addiction

We here review experimental findings relevant for the pharmacology of conscious experience, an issue largely neglected in pharmacological research. First, we focus on self‐awareness, a pivotal component of conscious experience and its integration within the global neuronal network (GNW), a theoretical concept that unifies convergent approaches on the neural bases of conscious processing. We report recent evidence to show that self‐awareness mobilizes a paralimbic circuitry of γ synchrony, and that such synchrony is, in particular, regulated by GABA interneurons under the control of acetylcholine and dopamine. Recent data illustrate that these neurotransmitters establish a causal relationship with the control of self‐awareness. The hypothesis is presented that not only is self‐awareness chemically regulated, but the reverse may be true. Long‐term deficit in self‐control of drug intake would result in compulsive substance use, accompanied, in particular, with lesions of the paralimbic circuitry of self‐awareness, leading to aggravation of substance abuse, resulting in addiction in a vicious circle. Finally, we propose that the emergent pharmacology of conscious experience may provide new perspectives, not only in substance addiction but also in the many other pathological conditions with deficient self‐awareness.—Changeux, J. ‐P., Lou, H. C. Emergent pharmacology of conscious experience: new perspectives in substance addiction. FASEB J. 25, 2098‐2108 (2011). www.fasebj.org

[1]  Eugenio Rodriguez,et al.  Neural synchrony and the development of cortical networks , 2010, Trends in Cognitive Sciences.

[2]  R. Zafonte,et al.  Fast awakening from minimally conscious state with apomorphine , 2009, Brain injury.

[3]  R. Lydic,et al.  γ-Aminobutyric Acid–mediated Neurotransmission in the Pontine Reticular Formation Modulates Hypnosis, Immobility, and Breathing during Isoflurane Anesthesia , 2008, Anesthesiology.

[4]  E. Gordon,et al.  "Missing links" in borderline personality disorder: loss of neural synchrony relates to lack of emotion regulation and impulse control. , 2006, Journal of psychiatry & neuroscience : JPN.

[5]  I. Fried,et al.  Neural “Ignition”: Enhanced Activation Linked to Perceptual Awareness in Human Ventral Stream Visual Cortex , 2009, Neuron.

[6]  J. Changeux,et al.  β2-Containing Nicotinic Receptors Contribute to the Organization of Sleep and Regulate Putative Micro-Arousals in Mice , 2004, The Journal of Neuroscience.

[7]  Frank Herbert Missing Link , 2010 .

[8]  A. Hartley,et al.  Locating and fractionating working memory using functional neuroimaging: Storage, maintenance, and executive functions , 2000, Microscopy research and technique.

[9]  H. Damasio,et al.  Damage to the Insula Disrupts Addiction to Cigarette Smoking , 2007, Science.

[10]  H. Sackeim,et al.  Parietal cortex and representation of the mental Self. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[11]  J. Changeux,et al.  Opinion TRENDS in Cognitive Sciences Vol.10 No.5 May 2006 Conscious, preconscious, and subliminal processing: a testable taxonomy , 2022 .

[12]  J. Rho,et al.  Molecular Biology and Ontogeny of γ-Aminobutyric Acid (GABA) Receptors in the Mammalian Central Nervous System , 2003 .

[13]  J. Wess,et al.  A Subpopulation of Neuronal M4 Muscarinic Acetylcholine Receptors Plays a Critical Role in Modulating Dopamine-Dependent Behaviors , 2010, The Journal of Neuroscience.

[14]  E. Gordon,et al.  Neural synchrony in patients with a first episode of schizophrenia: tracking relations with grey matter and symptom profile. , 2009, Journal of psychiatry & neuroscience : JPN.

[15]  Marcel P. Jackowski,et al.  Prenatal and Adolescent Exposure to Tobacco Smoke Modulates the Development of White Matter Microstructure , 2007, The Journal of Neuroscience.

[16]  T. Ergenoğlu,et al.  DRD4 and DAT1 polymorphisms modulate human gamma band responses. , 2007, Cerebral cortex.

[17]  J. Gardiner Episodic memory and autonoetic consciousness: a first-person approach. , 2001, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[18]  Philippe Faure,et al.  Executive and social behaviors under nicotinic receptor regulation , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[19]  F. Varela,et al.  Perception's shadow: long-distance synchronization of human brain activity , 1999, Nature.

[20]  P. Rochat Self-perception and action in infancy , 1998, Experimental Brain Research.

[21]  R. Dolan,et al.  Threatening a rubber hand that you feel is yours elicits a cortical anxiety response , 2007, Proceedings of the National Academy of Sciences.

[22]  S. Hestrin,et al.  Electrical synapses between Gaba-Releasing interneurons , 2001, Nature Reviews Neuroscience.

[23]  E. Maguire,et al.  The functional neuroanatomy of comprehension and memory: the importance of prior knowledge. , 1999, Brain : a journal of neurology.

[24]  Joachim Gross,et al.  Coherence in consciousness: Paralimbic gamma synchrony of self‐reference links conscious experiences , 2009, Human brain mapping.

[25]  M. Buchsbaum,et al.  Cerebral metabolic consequences of electrical cutaneous stimulation in normal individuals. , 1983, Human neurobiology.

[26]  J. Changeux,et al.  The Emergence of Human Consciousness: From Fetal to Neonatal Life , 2009, Pediatric Research.

[27]  J. Nigg,et al.  Effects of alcoholism severity and smoking on executive neurocognitive function. , 2009, Addiction.

[28]  N. Franks,et al.  Sleep and general anesthesia , 2011, Canadian journal of anaesthesia = Journal canadien d'anesthesie.

[29]  Bruce Luber,et al.  Self-specific processing in the default network: a single-pulse TMS study , 2010, Experimental Brain Research.

[30]  Ricardo Tapia,et al.  Microinjections of muscimol and bicuculline into the pontine reticular formation modify the sleep-waking cycle in the rat , 1991, Neuroscience Letters.

[31]  Nikolaos Koutsouleris,et al.  Striatal dopamine transporter availability is associated with the productive psychotic state in first episode, drug–naive schizophrenic patients , 2006, European Archives of Psychiatry and Clinical Neuroscience.

[32]  Antoine Bechara,et al.  Decision-making and impulse control after frontal lobe injuries , 2005, Current opinion in neurology.

[33]  S. Dehaene,et al.  Converging Intracranial Markers of Conscious Access , 2009, PLoS biology.

[34]  J. Changeux,et al.  A prokaryotic proton-gated ion channel from the nicotinic acetylcholine receptor family , 2007, Nature.

[35]  R. Olsen,et al.  THEME ISSUE: MECHANISMS OF ANESTHESIA GABAA receptors as molecular targets of general anesthetics: identification of binding sites provides clues to allosteric modulation Les récepteurs GABAA comme cibles moléculaires des anesthésiques généraux: l’identification des sites de liaison procure des , 2011 .

[36]  Michele Zoli,et al.  Structural and functional diversity of native brain neuronal nicotinic receptors. , 2009, Biochemical pharmacology.

[37]  S Dehaene,et al.  A neuronal model of a global workspace in effortful cognitive tasks. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[38]  S. Gallagher Philosophical conceptions of the self: implications for cognitive science , 2000, Trends in Cognitive Sciences.

[39]  R. Olsen,et al.  Identification of a GABAA Receptor Anesthetic Binding Site at Subunit Interfaces by Photolabeling with an Etomidate Analog , 2006, The Journal of Neuroscience.

[40]  B. Libet Brain stimulation in the study of neuronal functions for conscious sensory experiences. , 1982, Human neurobiology.

[41]  J. Changeux,et al.  Nicotine addiction and nicotinic receptors: lessons from genetically modified mice , 2010, Nature Reviews Neuroscience.

[42]  Kim Mouridsen,et al.  Dopaminergic stimulation enhances confidence and accuracy in seeing rapidly presented words. , 2011, Journal of vision.

[43]  Ralph Lydic,et al.  GABAA Receptors in the Pontine Reticular Formation of C57BL/6J Mouse Modulate Neurochemical, Electrographic, and Behavioral Phenotypes of Wakefulness , 2010, The Journal of Neuroscience.

[44]  Noelle M. Nelson,et al.  Making choices impairs subsequent self-control: a limited-resource account of decision making, self-regulation, and active initiative. , 2008, Journal of personality and social psychology.

[45]  K. Deisseroth,et al.  Parvalbumin neurons and gamma rhythms enhance cortical circuit performance , 2009, Nature.

[46]  C. Mulle,et al.  Evidence for "preterminal" nicotinic receptors on GABAergic axons in the rat interpeduncular nucleus , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[47]  Hugh Garavan,et al.  Executive Dysfunction in Cocaine Addiction: Evidence for Discordant Frontal, Cingulate, and Cerebellar Activity , 2004, The Journal of Neuroscience.

[48]  N. Schiff Recovery of consciousness after severe brain injury: The role of arousal regulation mechanisms and some speculation on the heart-brain interface , 2010, Cleveland Clinic Journal of Medicine.

[49]  Abraham Z. Snyder,et al.  A default mode of brain function: A brief history of an evolving idea , 2007, NeuroImage.

[50]  T. Robbins,et al.  Neural systems of reinforcement for drug addiction: from actions to habits to compulsion , 2005, Nature Neuroscience.

[51]  A. Macdermott,et al.  Presynaptic ionotropic receptors and control of transmitter release , 2004, Nature Reviews Neuroscience.

[52]  M. Picciotto,et al.  Cortico-Thalamic Connectivity is Vulnerable to Nicotine Exposure During Early Postnatal Development through α4/β2/α5 Nicotinic Acetylcholine Receptors , 2010, Neuropsychopharmacology.

[53]  B. Baars A cognitive theory of consciousness , 1988 .

[54]  J. Changeux,et al.  Experimental and Theoretical Approaches to Conscious Processing , 2011, Neuron.

[55]  Zhen Yan,et al.  Dopamine D4 Receptors Regulate AMPA Receptor Trafficking and Glutamatergic Transmission in GABAergic Interneurons of Prefrontal Cortex , 2009, The Journal of Neuroscience.

[56]  A. Damasio,et al.  Investigating the biology of consciousness. , 1998, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[57]  Baoci Shan,et al.  Disrupted White Matter Integrity in Heroin Dependence: A Controlled Study Utilizing Diffusion Tensor Imaging , 2008, The American journal of drug and alcohol abuse.

[58]  R. Riggs,et al.  Positive outcomes in traumatic brain injury-vegetative state: patients treated with bromocriptine. , 2001, Archives of physical medicine and rehabilitation.

[59]  Peter Redgrave,et al.  A direct projection from superior colliculus to substantia nigra for detecting salient visual events , 2003, Nature Neuroscience.

[60]  Philippe Faure,et al.  Hierarchical Control of Dopamine Neuron-Firing Patterns by Nicotinic Receptors , 2006, Neuron.

[61]  T. Kjaer,et al.  Interaction between precuneus and dorsolateral prefrontal cortex may play a unitary role in consciousness-A principal component analysis of rCBF , 2000 .

[62]  G. Koob,et al.  Individual differences in prefrontal cortex function and the transition from drug use to drug dependence , 2010, Neuroscience & Biobehavioral Reviews.

[63]  F. Bermpohl,et al.  Cortical midline structures and the self , 2004, Trends in Cognitive Sciences.

[64]  C. Carter,et al.  Impaired Prefrontal Cortical Function and Disrupted Adaptive Cognitive Control in Methamphetamine Abusers: A Functional Magnetic Resonance Imaging Study , 2009, Biological Psychiatry.

[65]  J. Changeux,et al.  Nicotinic and muscarinic modulations of excitatory synaptic transmission in the rat prefrontal cortexin vitro , 1993, Neuroscience.

[66]  W. Singer,et al.  Short- and Long-Term Effects of Cholinergic Modulation on Gamma Oscillations and Response Synchronization in the Visual Cortex , 2004, The Journal of Neuroscience.

[67]  T. Kjaer,et al.  A 15O‐H2O PET study of meditation and the resting state of normal consciousness , 1999, Human brain mapping.

[68]  R. Metherate,et al.  Nicotinic control of axon excitability regulates thalamocortical transmission , 2007, Nature Neuroscience.

[69]  Virginia S. Y. Kwan,et al.  Assessing the neural correlates of self-enhancement bias: a transcranial magnetic stimulation study , 2007, Experimental Brain Research.

[70]  R. Dolan,et al.  Dopamine-dependent prediction errors underpin reward-seeking behaviour in humans , 2006, Nature.

[71]  Antoine Taly,et al.  Nicotinic receptors: allosteric transitions and therapeutic targets in the nervous system , 2009, Nature Reviews Drug Discovery.

[72]  K. Zilles,et al.  Neural Correlates of First-Person Perspective as One Constituent of Human Self-Consciousness , 2004, Journal of Cognitive Neuroscience.

[73]  J. Changeux,et al.  A neuronal network model linking subjective reports and objective physiological data during conscious perception , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[74]  E. Lambe,et al.  Nicotine Induces Glutamate Release from Thalamocortical Terminals in Prefrontal Cortex , 2003, Neuropsychopharmacology.

[75]  O. Paulsen,et al.  Cholinergic induction of network oscillations at 40 Hz in the hippocampus in vitro , 1998, Nature.

[76]  R. Clauss,et al.  Clinical and brain SPECT scan response to zolpidem in patients after brain damage , 2010, Arzneimittelforschung.

[77]  J S Fowler,et al.  Long‐Term frontal brain metabolic changes in cocaine abusers , 1992, Synapse.

[78]  T. Kjaer,et al.  Precuneus–Prefrontal Activity during Awareness of Visual Verbal Stimuli , 2001, Consciousness and Cognition.

[79]  A. Smith,et al.  Large-scale heterogeneity of the fossil record: implications for Phanerozoic biodiversity studies. , 2001, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[80]  J. Changeux,et al.  Nicotinic and muscarinic receptors in the rat prefrontal cortex: Differential roles in working memory, response selection and effortful processing , 1995, Psychopharmacology.

[81]  F. Helmstetter,et al.  An updated unified pharmacophore model of the benzodiazepine binding site on gamma-aminobutyric acid(a) receptors: correlation with comparative models. , 2007, Current medicinal chemistry.

[82]  J. Gotman,et al.  Correlation of high-frequency oscillations with the sleep–wake cycle and cognitive activity in humans , 1999, Neuroscience.

[83]  Fiona E. N. LeBeau,et al.  Recruitment of Parvalbumin-Positive Interneurons Determines Hippocampal Function and Associated Behavior , 2007, Neuron.

[84]  L. Hechtman,et al.  Comorbidity in Adults with Attention-Deficit Hyperactivity Disorder , 2009, Canadian journal of psychiatry. Revue canadienne de psychiatrie.

[85]  J. Rothstein,et al.  Climbing Fiber Activation of EAAT4 Transporters and Kainate Receptors in Cerebellar Purkinje Cells , 2004, The Journal of Neuroscience.

[86]  J. Changeux,et al.  Sevoflurane Anesthesia Alters Exploratory and Anxiety-like Behavior in Mice Lacking the β2 Nicotinic Acetylcholine Receptor Subunit , 2008, Anesthesiology.

[87]  Masahiko Watanabe,et al.  Preferential Localization of Muscarinic M1 Receptor on Dendritic Shaft and Spine of Cortical Pyramidal Cells and Its Anatomical Evidence for Volume Transmission , 2010, The Journal of Neuroscience.

[88]  Gerhard Werner,et al.  Brain dynamics across levels of organization , 2007, Journal of Physiology-Paris.

[89]  Caspar M. Schwiedrzik,et al.  Expectations Change the Signatures and Timing of Electrophysiological Correlates of Perceptual Awareness , 2011, The Journal of Neuroscience.

[90]  H. Baghdoyan,et al.  GABAA receptors inhibit acetylcholine release in cat pontine reticular formation: implications for REM sleep regulation. , 2004, Journal of neurophysiology.

[91]  C. Frith,et al.  How do we predict the consequences of our actions? a functional imaging study , 1998, Neuropsychologia.

[92]  J. Fox,et al.  Frequency and synchrony of tetanically-induced, gamma-frequency population discharges in the rat hippocampal slice: the effect of diazepam and propofol , 1998, Neuroscience Letters.

[93]  R. Clauss,et al.  Neurotransmitters in coma, vegetative and minimally conscious states, pharmacological interventions. , 2010, Medical hypotheses.

[94]  Michael H. Buonocore,et al.  Cognitive Control and White Matter Callosal Microstructure in Methamphetamine-Dependent Subjects: A Diffusion Tensor Imaging Study , 2009, Biological Psychiatry.

[95]  Michel Cabanac,et al.  The emergence of consciousness in phylogeny , 2009, Behavioural Brain Research.

[96]  Antoine Bechara,et al.  Negative emotion-driven impulsivity predicts substance dependence problems. , 2007, Drug and alcohol dependence.

[97]  D. Lewis,et al.  GABA neurons and the mechanisms of network oscillations: implications for understanding cortical dysfunction in schizophrenia. , 2008, Schizophrenia bulletin.

[98]  J. Changeux The Ferrier Lecture 1998 The molecular biology of consciousness investigated with genetically modified mice , 2006, Philosophical Transactions of the Royal Society B: Biological Sciences.

[99]  Stefan Gazdzinski,et al.  Tract-based spatial statistics (TBSS) of diffusion tensor imaging data in alcohol dependence: Abnormalities of the motivational neurocircuitry , 2009, Psychiatry Research: Neuroimaging.

[100]  J. Waddington,et al.  Neurochemical changes in dopamine D1, D3 and D1/D3 receptor knockout mice. , 2003, European journal of pharmacology.

[101]  L. Krimer,et al.  Dopamine increases inhibition in the monkey dorsolateral prefrontal cortex through cell type-specific modulation of interneurons. , 2006, Cerebral cortex.

[102]  Troels W. Kjær,et al.  Reflective Self-Awareness and Conscious States: PET Evidence for a Common Midline Parietofrontal Core , 2002, NeuroImage.

[103]  R. Traub,et al.  Disruption of synchronous gamma oscillations in the rat hippocampal slice: A common mechanism of anaesthetic drug action , 1998, British journal of pharmacology.

[104]  Akira Matsumura,et al.  Levodopa treatment for patients in persistent vegetative or minimally conscious states , 2005, Neuropsychological rehabilitation.

[105]  S. Kumra,et al.  Diffusion abnormalities in adolescents and young adults with a history of heavy cannabis use. , 2009, Journal of psychiatric research.

[106]  G. Marks,et al.  Blockade of GABA, type A, receptors in the rat pontine reticular formation induces rapid eye movement sleep that is dependent upon the cholinergic system , 2008, Neuroscience.

[107]  Chen,et al.  A functional magnetic resonance imaging study , 2011 .

[108]  T. Kjaer,et al.  Increased dopamine tone during meditation-induced change of consciousness. , 2002, Brain research. Cognitive brain research.

[109]  J. Mayhew,et al.  How Visual Stimuli Activate Dopaminergic Neurons at Short Latency , 2005, Science.

[110]  Stefan Gazdzinski,et al.  MRSI and DTI: a multimodal approach for improved detection of white matter abnormalities in alcohol and nicotine dependence , 2009, NMR in biomedicine.

[111]  J. Changeux,et al.  X-ray structures of general anaesthetics bound to a pentameric ligand-gated ion channel , 2011, Nature.

[112]  G. Tononi,et al.  Breakdown in cortical effective connectivity during midazolam-induced loss of consciousness , 2010, Proceedings of the National Academy of Sciences.

[113]  A. Damasio,et al.  Emotion, decision making and the orbitofrontal cortex. , 2000, Cerebral cortex.