George K. Aghajanian - The Consciousness Library

Optogenetic stimulation of infralimbic PFC reproduces ketamine’s rapid and sustained antidepressant actions

Proceedings of the National Academy of Sciences June 8, 2015 Manabu Fuchikami, Alexandra M. Thomas, Rongjian Liu et al. 282 citations

Ketamine produces rapid and sustained antidepressant actions in depressed patients, but the precise cellular mechanisms underlying these effects have not been identified. Here we determined if modulation of neuronal activity in the infralimbic prefrontal cortex (IL-PFC) underlies the antidepressant and anxiolytic actions of ketamine. We found that neuronal inactivation of the IL-PFC completely...

DOI: 10.1073/pnas.1414728112 Full text Ketamine Optogenetics Antidepressant Anxiolytic +6

Synaptic Dysfunction in Depression: Potential Therapeutic Targets

Science October 4, 2012 Ronald S. Duman, George K. Aghajanian 1,613 citations

Basic and clinical studies demonstrate that depression is associated with reduced size of brain regions that regulate mood and cognition, including the prefrontal cortex and the hippocampus, and decreased neuronal synapses in these areas. Antidepressants can block or reverse these neuronal deficits, although typical antidepressants have limited efficacy and delayed response times of weeks to...

DOI: 10.1126/science.1222939

Signaling pathways underlying the rapid antidepressant actions of ketamine.

Neuropharmacology January 2012 Ronald S Duman, Nanxin Li, Rong-Jian Liu et al.

Currently available medications have significant limitations, most notably low response rate and time lag for treatment response. Recent clinical studies have demonstrated that ketamine, an NMDA receptor antagonist produces a rapid antidepressant response (within hours) and is effective in treatment resistant depressed patients. Molecular and cellular studies in rodent models demonstrate that...

DOI: 10.1016/j.neuropharm.2011.08.044 Full text

Glutamate NMDA receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure

Biological Psychiatry February 3, 2011 Nanxin Li, Rong-Jian Liu, J. Dwyer et al.

Background Despite widely reported clinical and preclinical studies of rapid antidepressant actions of glutamate N-methyl-D-aspartic acid (NMDA) receptor antagonists, there has been very little work examining the effects of these drugs in stress models of depression that require chronic administration of antidepressants, or the molecular mechanisms that could account for the rapid responses....

DOI: 10.1016/j.biopsych.2010.12.015 Full text

mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists

Science August 19, 2010 Nanxin Li, Boyoung Lee, Rongjian Liu et al. 2,875 citations

The rapid antidepressant response after ketamine administration in treatment-resistant depressed patients suggests a possible new approach for treating mood disorders compared to the weeks or months required for standard medications. However, the mechanisms underlying this action of ketamine [a glutamate N-methyl-D-aspartic acid (NMDA) receptor antagonist] have not been identified. We observed...

DOI: 10.1126/science.1190287 Full text Ketamine Antidepressant Prefrontal cortex Pi3k/akt/mtor pathway +7

Modeling “psychosis” in vitro by inducing disordered neuronal network activity in cortical brain slices

Psychopharmacology February 24, 2009 George K. Aghajanian 37 citations

INTRODUCTION: Dysregulation of neuronal networks has been suggested to underlie the cognitive and perceptual abnormalities observed schizophrenia. DISCUSSIONS: An in vitro model of psychosis is proposed based on the two different approaches to cause aberrant network activity in layer V pyramidal cells of prefrontal brain slices: (1) psychedelic hallucinogens such as lysergic acid diethylamide...

DOI: 10.1007/s00213-009-1484-9 Full text Glutamatergic Psychosis Schizophrenia object-oriented programming Glutamate receptor +4

Prefrontal cortical network activity: Opposite effects of psychedelic hallucinogens and D1/D5 dopamine receptor activation

Neuroscience February 10, 2007 Evelyn K. Lambe, George K. Aghajanian 35 citations

The fine-tuning of network activity provides a modulating influence on how information is processed and interpreted in the brain. Here, we use brain slices of rat prefrontal cortex to study how recurrent network activity is affected by neuromodulators known to alter normal cortical function. We previously determined that glutamate spillover and stimulation of extrasynaptic N-methyl-d-aspartic...

DOI: 10.1016/j.neuroscience.2006.12.048 Full text Nmda receptor Glutamate receptor Dopamine Adenylyl cyclase +6

The Role of Kv1.2-Containing Potassium Channels in Serotonin-Induced Glutamate Release from Thalamocortical Terminals in Rat Frontal Cortex

Journal of Neuroscience December 15, 2001 Evelyn K. Lambe, George K. Aghajanian 111 citations

Serotonin 5-HT 2A receptors have been implicated in psychiatric illness and the psychotomimetic effects of hallucinogens. In brain slices, focal stimulation of 5-HT 2A receptors in rat prefrontal cortex results in dramatically increased glutamate release onto layer V pyramidal neurons, as measured by an increase in “spontaneous” (nonelectrically evoked) EPSCs. This glutamate release is blocked...

DOI: 10.1523/jneurosci.21-24-09955.2001 Full text Glutamate receptor Potassium channel Channel blocker Tetrodotoxin +2

Serotonin model of schizophrenia: emerging role of glutamate mechanisms.

Brain research. Brain research reviews March 2000 G K Aghajanian, G J Marek

The serotonin (5-HT) hypothesis of schizophrenia arose from early studies on interactions between the hallucinogenic drug LSD (D-lysergic acid diethylamide) and 5-HT in peripheral systems. More recent studies have shown that the two major classes of psychedelic hallucinogens, the indoleamines (e.g., LSD) and phenethylamines (e.g. , mescaline), produce their central effects through a common...

DOI: 10.1016/s0165-0173(99)00046-6 Full text

Serotonin and hallucinogens.

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology August 1999 G K Aghajanian, G J Marek

This brief review traces the serotonin (5-HT) hypothesis of the action of hallucinogenic drugs from the early 1950s to the present day. There is now converging evidence from biochemical, electrophysiological, and behavioral studies that the two major classes of psychedelic hallucinogens, the indoleamines (e.g., LSD) and the phenethylamines (e.g., mescaline), have a common site of action as...

DOI: 10.1016/s0893-133x(98)00135-3 Full text

Serotonin, via 5-HT2A receptors, increases EPSCs in layer V pyramidal cells of prefrontal cortex by an asynchronous mode of glutamate release

Brain Research April 1, 1999 George K. Aghajanian, Gerard J. Marek 379 citations

Previously, serotonin (5-HT) was found to induce a marked increase in glutamatergic spontaneous excitatory postsynaptic currents (EPSCs) in apical dendrites of layer V pyramidal cells of prefrontal cortex; this effect was mediated by 5-HT2A receptors, a proposed site of action of hallucinogenic and atypical antipsychotic drugs. Unexpectedly, although the effect of 5-HT was Ca2+-dependent and...

DOI: 10.1016/s0006-8993(99)01224-x Excitatory postsynaptic potential Glutamatergic Neurotransmission Inhibitory postsynaptic potential +2

Indoleamine and the phenethylamine hallucinogens: mechanisms of psychotomimetic action

Drug and Alcohol Dependence June 1, 1998 Gerard J. Marek, George K. Aghajanian 39 citations

The psychedelic hallucinogens are comprised of three different groups of compounds according to Ž . Ž . their chemical structure Fig. 1 : 1 the ergolines Ž which contain an indole moiety e.g. lysergic acid . Ž . diethylamide, LSD ; 2 simple indoleamine hallucinoŽ gens e.g. N,N-dimethyltryptamine, DMT and psilocy. bin which share an indoleamine structure with the Ž endogenous neurotransmitter...

DOI: 10.1016/s0376-8716(98)00076-3 Psilocybin Mescaline Psychotomimetic Hallucinogen +4

5-HT2AReceptor-Mediated Regulation of Brain-Derived Neurotrophic Factor mRNA in the Hippocampus and the Neocortex

Journal of Neuroscience April 15, 1997 Vidita A Vaidya, Gerard J. Marek, George K. Aghajanian et al. 482 citations

The influence of 5-HT receptor agonists on the expression of BDNF in brain was determined. Administration of a hallucinogenic 5-HT2A /2C receptor agonist, but not a 5-HT1A receptor agonist, resulted in a significant but differential regulation of BDNF mRNA levels in hippocampus and neocortex. In the hippocampus, the 5-HT2A /2C receptor agonist significantly decreased BDNF mRNA expression in the...

DOI: 10.1523/jneurosci.17-08-02785.1997 Full text Neocortex Hippocampus Brain-derived neurotrophic factor Neurotrophic factors +2

Serotonin and the Action of LSD in the Brain

Psychiatric Annals March 1, 1994 George K. Aghajanian 27 citations

By the early 1960s the 5-HT hypothesis of the action of LSD had become firmly established in the field.

DOI: 10.3928/0048-5713-19940301-09 Serotonin Action physics Receptor

LSD has high efficacy relative to serotonin in enhancing the cationic current Ih: Intracellular studies in rat facial motoneurons

Synapse February 1, 1993 Jennifer C. Garratt, Meenakshi Alreja, George K. Aghajanian 46 citations

Abstract The effects of LSD (d‐lysergic acid diethylamide) on rat facial motoneurons were compared to those of 5‐hydroxytryptamine (5‐HT) in brain slices by means of current clamp and single‐electrode voltage‐clamp recordings. As previously reported, 5‐HT, in part by decreasing a resting potassium conductance, produced a reversible depolarization (∼5 mV), an increase in input resistance, and an...

DOI: 10.1002/syn.890130205 Serotonin Ritanserin Spiperone Depolarization +10

Phenethylamine hallucinogens in the locus coeruleus: potency of action correlates with rank order of 5-HT2 binding affinity

European Journal of Pharmacology December 1, 1986 Kurt Rasmussen, Richard A Glennon, George K. Aghajanian 50 citations

The rank order of potency for the physiological effects of three phenethylamine hallucinogens in the locus coeruleus (LC) was identical to that previously shown for their 5-HT2 binding affinity [-) DOB greater than DOM greater than ( + )DOB). The behaviorally inactive positional isomer of DOB, SL-7161, did not significantly affect LC unit activity. These results offer insight into...

DOI: 10.1016/0014-2999(86)90014-2 Serotonin Phenethylamine Hallucinogen Locus coeruleus +8

Intracellular studies on the effects of systemic administration of serotonin agonists on rat facial motoneurons.

European Journal of Pharmacology February 26, 1982 C P Vandermaelen, G K Aghajanian 37 citations

Intracellular recordings were made from facial motoneurons of anesthetized rats during systemic administration of 5-methoxy-N,-N-dimethyltryptamine (5-MeODMT) and p-chloroamphetamine (PCA), drugs which elicit the behavioral serotonin syndrome. Both drugs caused a slow depolarization, increased input resistance, and increased excitability of facial motoneurons. These changes are identical to...

DOI: 10.1016/0014-2999(82)90242-4 Full text

Effects of chlorimipramine and lysergic acid diethylamide on efflux of precursor-formed 3-H-serotonin: correlations with serotonergic impulse flow.

Journal of Pharmacology and Experimental Therapeutics June 1, 1975 D. Gallager, G. Aghajanian 83 citations

The effects of d-lysergic acid diethylamide (LSD) and chlorimipramine (CIMI) on the firing rate of serotonergic (5-HT) neurons and on the in vivo efflux of 5-HT were investigated in parallel. A cerebroventricular perfusing technique was used to measure the efflux of 3-H-5-HT formed in vivo from 3-H-tryptophan. Impulse flow in serotonergic neurons was monitored by single unit recording from...

DOI: 10.1016/s0022-3565(25)30200-4

Correlation of performance test scores with “tissue concentration” of lysergic acid diethylamide in human subiects

Clinical Pharmacology & Therapeutics September 1, 1968 John G. Wagner, George K. Aghajanian, O. Bing 61 citations

Previously published plasma concentrations of LSD‐25, observed following intravenous iniection of 2 mcg. per kilogram of LSD‐25, have been found to be explained by the two‐compartment open model. Performance scores on arithmetic tests were shown to be highly linearly correlated with the concentration in the “tissue” (outer) compartment. The estimated volume of the plasma (inner) compartment was...

DOI: 10.1002/cpt196895635 Lysergic acid diethylamide Compartment ship Body weight Extracellular fluid +3

Lysergic Acid Diethylamide: Sensitive Neuronal Units in the Midbrain Raphe

Science August 16, 1968 George K. Aghajanian, Warren E. Foote, Michael H. Sheard 406 citations

Units in areas of the midbrain rich in neurons containing serotonin respond to parenteral injections of d-lysergic acid diethylamide by a reversible cessation of spontaneous activity. The dose required is at or below threshold for gross behavioral effects. An inhibition of neurons containing serotonin after administration of d-lysergic acid diethylamide could account for the decreased...

DOI: 10.1126/science.161.3842.706 Lysergic acid diethylamide Serotonin Serotonergic Midbrain +7

Persistence of lysergic acid diethylamide in the plasma of human subjects

Clinical Pharmacology & Therapeutics September 1, 1964 George K. Aghajanian, O. Bing 118 citations

Two micrograms per kilogram of LSD‐25 was administered intravenously to five normal human subjects. The concentration of drug in plasma was determined serially over the subsequent 8 hours. LSD‐25 was found to be present in human plasma in relatively large quantities during the period of peak effect. The half‐life of LSD‐25 in human plasma was calculated to be 175 minutes.

DOI: 10.1002/cpt196455611 Lysergic acid diethylamide Human plasma Persistence discontinuity Plasma levels +5

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