Inhibition of the Amygdala: Key to Pathological States?

Abstract: The amygdala plays an important role in associating sensory stimuli with aversive or appetitive outcomes. Conditioning procedures potentiate inputs to the amygdala, which facilitate emotional responses via subcortical and cortical outputs. Powerful inhibitory circuits exist that control expression of conditioned responses in the amygdala, including inhibition from prefrontal cortex. Deficient inhibitory tone in the amygdala could lead to overexpression of conditioned responses, producing pathological states such as anxiety disorders and drug‐seeking behavior. Support for this comes from several lines of animal research: (1) GABA antagonist‐induced priming of anxiety states, (2) extinction of conditioned fear, (3) modulation of inhibitory avoidance memory, and (4) cue‐induced reinstatement of drug seeking. Cue‐induced craving in humans is associated with feelings of fear and autonomic arousal, suggesting a link between fear and addiction in the amygdala. Future therapies aimed at increasing inhibitory tone in the amygdala, either locally or via the prefrontal cortex, may prevent anxiety disorders and addiction relapse. Novel neuropeptides, which can either excite or inhibit specific components of anxiety responses, offer promise in this regard.

[1]  R. Pitman Overview of Biological Themes in PTSD a , 1997, Annals of the New York Academy of Sciences.

[2]  C. A. Morgan,et al.  Role of norepinephrine in the pathophysiology and treatment of posttraumatic stress disorder , 1999, Biological Psychiatry.

[3]  Hisao Nishijo,et al.  Neuronal responses of the rat amygdala during extinction and reassociation learning in elementary and configural associative tasks , 2002, The European journal of neuroscience.

[4]  Joseph E LeDoux Emotion Circuits in the Brain , 2000 .

[5]  Jeffrey W Grimm,et al.  Dissociation of Primary and Secondary Reward-Relevant Limbic Nuclei in an Animal Model of Relapse , 2000, Neuropsychopharmacology.

[6]  R. See,et al.  Lesions of the basolateral amygdala abolish the ability of drug associated cues to reinstate responding during withdrawal from self-administered cocaine , 1997, Behavioural Brain Research.

[7]  Stephen Maren,et al.  Auditory fear conditioning increases CS‐elicited spike firing in lateral amygdala neurons even after extensive overtraining , 2000, The European journal of neuroscience.

[8]  Joseph E LeDoux,et al.  Fear conditioning induces associative long-term potentiation in the amygdala , 1997, Nature.

[9]  S. Hyman Brain neurocircuitry of anxiety and fear: implications for clinical research and practice. , 1998, Biological psychiatry.

[10]  A. Shekhar,et al.  Excitatory amino acid receptor antagonists block the cardiovascular and anxiety responses elicited by gamma-aminobutyric acidA receptor blockade in the basolateral amygdala of rats. , 1997, The Journal of pharmacology and experimental therapeutics.

[11]  S. Rauch,et al.  An fMRI study of anterior cingulate function in posttraumatic stress disorder , 2001, Biological Psychiatry.

[12]  M. McKERNAN,et al.  Fear conditioning induces a lasting potentiation of synaptic currents in vitro , 1997, Nature.

[13]  M. Fendt,et al.  The neuroanatomical and neurochemical basis of conditioned fear , 1999, Neuroscience & Biobehavioral Reviews.

[14]  Joseph E. LeDoux,et al.  Extinction of emotional learning: Contribution of medial prefrontal cortex , 1993, Neuroscience Letters.

[15]  M. Reivich,et al.  Limbic activation during cue-induced cocaine craving. , 1999, The American journal of psychiatry.

[16]  T. Ono,et al.  Neuronal responsiveness to various sensory stimuli, and associative learning in the rat amygdala , 1995, Neuroscience.

[17]  R Bandler,et al.  Orbitomedial prefrontal cortical projections to distinct longitudinal columns of the periaqueductal gray in the rat , 2000, The Journal of comparative neurology.

[18]  J. D. McGaugh Memory--a century of consolidation. , 2000, Science.

[19]  Joseph E LeDoux,et al.  Different lateral amygdala outputs mediate reactions and actions elicited by a fear-arousing stimulus , 2000, Nature Neuroscience.

[20]  A. Shekhar,et al.  Role of corticotropin-releasing factor and urocortin within the basolateral amygdala of rats in anxiety and panic responses , 1999, Behavioural Brain Research.

[21]  G. Quirk,et al.  The Role of Ventromedial Prefrontal Cortex in the Recovery of Extinguished Fear , 2000, The Journal of Neuroscience.

[22]  Joseph E LeDoux,et al.  Fear conditioning enhances short-latency auditory responses of lateral amygdala neurons: Parallel recordings in the freely behaving rat , 1995, Neuron.

[23]  J M Gorman,et al.  Neuroanatomical hypothesis of panic disorder, revised. , 2000, The American journal of psychiatry.

[24]  S. Morzorati,et al.  Priming of experimental anxiety by repeated subthreshold GABA blockade in the rat amygdala , 1995, Brain Research.

[25]  Theresa M. Desrochers,et al.  Two different lateral amygdala cell populations contribute to the initiation and storage of memory , 2001, Nature Neuroscience.

[26]  A. Shekhar,et al.  Sodium lactate elicits anxiety in rats after repeated GABA receptor blockade in the basolateral amygdala. , 2000, European journal of pharmacology.

[27]  R. Roth,et al.  The role of mesoprefrontal dopamine neurons in the acquisition and expression of conditioned fear in the rat , 1999, Neuroscience.

[28]  T. Robbins,et al.  Different types of fear-conditioned behaviour mediated by separate nuclei within amygdala , 1997, Nature.

[29]  J. D. McGaugh,et al.  Role of adrenal stress hormones in forming lasting memories in the brain , 2002, Current Opinion in Neurobiology.

[30]  G. Quirk,et al.  Neurons in medial prefrontal cortex signal memory for fear extinction , 2002, Nature.

[31]  J L McGaugh,et al.  Amygdala activity at encoding correlated with long-term, free recall of emotional information. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[32]  J. Anthony,et al.  Epidemiologic evidence on cocaine use and panic attacks. , 1989, American journal of epidemiology.

[33]  J. Metcalfe,et al.  Neural Systems and Cue-Induced Cocaine Craving , 2002, Neuropsychopharmacology.

[34]  S. Mineka,et al.  Fears, phobias, and preparedness: toward an evolved module of fear and fear learning. , 2001, Psychological review.

[35]  D. Gehlert,et al.  Astressin, a corticotropin releasing factor antagonist, reverses the anxiogenic effects of urocortin when administered into the basolateral amygdala , 2000, Brain Research.

[36]  J. Stewart,et al.  Pathways to relapse: the neurobiology of drug- and stress-induced relapse to drug-taking. , 2000, Journal of psychiatry & neuroscience : JPN.

[37]  A. Shekhar,et al.  Excitatory amino acid receptors in the basolateral amygdala regulate anxiety responses in the social interaction test , 1997, Brain Research.

[38]  S. Mineka,et al.  A modern learning theory perspective on the etiology of panic disorder. , 2001, Psychological review.

[39]  Jeffrey W Grimm,et al.  Dopamine, but not glutamate, receptor blockade in the basolateral amygdala attenuates conditioned reward in a rat model of relapse to cocaine-seeking behavior , 2001, Psychopharmacology.

[40]  D. Paré,et al.  Neuronal Correlates of Fear in the Lateral Amygdala: Multiple Extracellular Recordings in Conscious Cats , 2000, The Journal of Neuroscience.

[41]  Jeffrey P. Pascoe,et al.  Electrophysiological characteristics of amygdaloid central nucleus neurons during Pavlovian fear conditioning in the rabbit , 1985, Behavioural Brain Research.

[42]  F. Mascagni,et al.  Projections of the medial and lateral prefrontal cortices to the amygdala: a Phaseolus vulgaris leucoagglutinin study in the rat , 1996, Neuroscience.

[43]  Marzia Martina,et al.  An Inhibitory Interface Gates Impulse Traffic between the Input and Output Stations of the Amygdala , 1999, The Journal of Neuroscience.

[44]  Anthony A Grace,et al.  Cellular Mechanisms of Infralimbic and Prelimbic Prefrontal Cortical Inhibition and Dopaminergic Modulation of Basolateral Amygdala Neurons In Vivo , 2002, The Journal of Neuroscience.

[45]  Joseph E LeDoux,et al.  Inhibition of the mesoamygdala dopaminergic pathway impairs the retrieval of conditioned fear associations. , 1999, Behavioral neuroscience.

[46]  M. Kuhar,et al.  Benzodiazepine receptors: localization in rat amygdala , 1983, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[47]  Lawrence H Staib,et al.  Neural correlates of exposure to traumatic pictures and sound in Vietnam combat veterans with and without posttraumatic stress disorder: a positron emission tomography study , 1999, Biological Psychiatry.

[48]  D. Gehlert,et al.  Amygdalar neuropeptide Y Y1 receptors mediate the anxiolytic-like actions of neuropeptide Y in the social interaction test. , 1999, European journal of pharmacology.

[49]  J. D. McGaugh,et al.  Amygdala modulation of hippocampal-dependent and caudate nucleus-dependent memory processes. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[50]  Joseph A Maldjian,et al.  Decreased gray matter concentration in the insular, orbitofrontal, cingulate, and temporal cortices of cocaine patients , 2002, Biological Psychiatry.

[51]  D. Smiley,et al.  Neuropeptide Y-Y2 receptors mediate anxiety in the amygdala , 2002, Pharmacology Biochemistry and Behavior.

[52]  P. Holland,et al.  Amygdala circuitry in attentional and representational processes , 1999, Trends in Cognitive Sciences.

[53]  S. Erb,et al.  A role for the CRF-containing pathway from central nucleus of the amygdala to bed nucleus of the stria terminalis in the stress-induced reinstatement of cocaine seeking in rats , 2001, Psychopharmacology.

[54]  James L. McGaugh,et al.  β-Adrenergic activation and memory for emotional events , 1994, Nature.

[55]  Joseph E LeDoux,et al.  Indelibility of Subcortical Emotional Memories , 1989, Journal of Cognitive Neuroscience.

[56]  A. Shekhar,et al.  Regulation of anxiety by GABAA receptors in the rat amygdala , 1995, Pharmacology Biochemistry and Behavior.

[57]  S. O'Malley,et al.  Psychological stress, drug-related cues and cocaine craving , 2000, Psychopharmacology.