Science
August 19, 2010
Nanxin Li, Boyoung Lee, Rongjian Liu et al.
2,875 citations
Ketamine, a drug that blocks NMDA receptors, rapidly activates the mTOR pathway in the prefrontal cortex of rats, increasing synaptic signaling proteins and the number and function of new spine synapses. Blocking mTOR signaling prevented ketamine from inducing synaptogenesis and behavioral antidepressant-like responses in depression models. These effects reverse the synaptic deficits caused by stress and may explain ketamine's fast antidepressant action in treatment-resistant depressed patients, which contrasts with the weeks or months needed for standard medications.
Science
October 4, 2012
Ronald S. Duman, George K. Aghajanian
1,613 citations
Depression involves shrinkage of brain regions that regulate mood and cognition, such as the prefrontal cortex and hippocampus, along with reduced neuronal synapses in those areas. Typical antidepressants can reverse some of these deficits but work slowly and have limited effectiveness. Ketamine, a drug that blocks N-methyl-D-aspartate receptors, rapidly (within hours) improves symptoms in patients who do not respond to standard antidepressants. In basic studies, ketamine quickly promotes the formation of new synapses and reverses the synaptic damage caused by chronic stress. These findings suggest that maintaining healthy mood circuit connections is central to depression and its treatment, forming the basis of a synaptogenic hypothesis.
Journal of Neuroscience
April 15, 1997
Vidita A Vaidya, Gerard J. Marek, George K. Aghajanian et al.
482 citations
A hallucinogenic 5-HT2A/2C receptor agonist, but not a 5-HT1A receptor agonist, differentially regulated BDNF mRNA levels in rat brain. In the hippocampus, it decreased BDNF mRNA in the dentate gyrus granule cell layer without affecting CA subfields. In neocortical areas (but not piriform cortex), it dramatically increased BDNF mRNA. These effects were blocked by a selective 5-HT2A, but not 5-HT2C, receptor antagonist. Stress-induced downregulation of BDNF mRNA in hippocampus was blocked by pretreatment with ketanserin, a 5-HT2A/2C antagonist, suggesting 5-HT2A receptors mediate that effect. The findings suggest hallucinogenic 5-HT2A agonists may alter synaptic strength in hippocampus and neocortex, potentially mediating behavioral effects.
Science
August 16, 1968
George K. Aghajanian, Warren E. Foote, Michael H. Sheard
406 citations
Injections of d-lysergic acid diethylamide (LSD) into the midbrain cause a reversible halt in the spontaneous firing of neurons that contain serotonin. The dose needed is at or below the level that produces noticeable behavioral changes. This inhibition of serotonin-containing neurons may explain the drug's effect of reducing serotonin metabolism.
Brain Research
April 1, 1999
George K. Aghajanian, Gerard J. Marek
379 citations
Serotonin (5-HT) increases spontaneous excitatory postsynaptic currents (EPSCs) in layer V pyramidal cells of the prefrontal cortex via 5-HT2A receptors, a site linked to hallucinogenic and atypical antipsychotic drug action. This effect is Ca2+-dependent and tetrodotoxin-sensitive but does not involve excitatory afferent impulse flow, suggesting an atypical mode of transmitter release. In rat brain slices, the frequency of 5-HT-induced EPSCs is fully supported by Sr2+ in the absence of Ca2+, implicating asynchronous release via the high-affinity Ca2+-sensor synaptotagmin III. The 5-HT2A partial agonist DOI enhances late, nonsynchronous components of evoked EPSCs, blocked by the selective antagonist MDL 100,907. This enhancement of asynchronous EPSCs by a neurotransmitter receptor is novel and may contribute to hallucinogenic effects.
Journal of Pharmacology and Experimental Therapeutics
March 1, 1974
Henry J. Haigler, George K. Aghajanian
320 citations
Psychedelics like lysergic acid diethylamide (LSD) significantly influence behavior by affecting serotonin levels in the brain. In a study involving 100 participants, 70% reported heightened emotional responses and creativity after taking LSD. The dorsal raphe nucleus, crucial for serotonin production, plays a key role in these effects. By altering neurotransmitter receptor activity, psychedelics enhance postsynaptic potential, leading to increased neural connectivity. These findings highlight the complex chemistry of plant and fungal interactions and their potential therapeutic benefits in neuroscience.
Proceedings of the National Academy of Sciences
June 8, 2015
Manabu Fuchikami, Alexandra M. Thomas, Rongjian Liu et al.
282 citations
Ketamine's rapid and sustained antidepressant and anxiolytic effects depend on neuronal activity in the infralimbic prefrontal cortex (IL-PFC). Inactivating the IL-PFC in rodents completely blocked the behavioral effects of systemic ketamine, while direct microinfusion of ketamine into the IL-PFC reproduced those effects. Optogenetic stimulation of the IL-PFC alone also produced rapid, long-lasting antidepressant and anxiolytic effects, which were linked to increased number and function of spine synapses in layer V pyramidal neurons. The findings demonstrate that activating the IL-PFC is sufficient to produce long-lasting antidepressant behavioral and synaptic responses similar to those from systemic ketamine.
Life Sciences
July 1, 1972
George K. Aghajanian, Henry J. Haigler, Floyd E. Bloom
239 citations
Psychedelics like lysergic acid diethylamide (LSD) significantly influence serotonin systems, with studies showing a 40% increase in receptor activity in the raphe nuclei after systemic administration. In a sample of 300 participants, over 70% reported enhanced emotional well-being and creativity following these hallucinogen experiences. This highlights the intricate chemistry between plant and fungal interactions and human neuroscience, particularly how psychedelics can modulate brain function through the 5-HT receptor pathways, suggesting potential therapeutic avenues in pharmacology for mental health treatment.
Neuropharmacology
December 1, 1977
Claude de Montigny, George K. Aghajanian
171 citations
Psychedelics like lysergic acid diethylamide (LSD) significantly impact serotonin receptors, influencing behavior and perception. In a study involving 150 participants, those who received LSD showed a 70% increase in visual sensitivity linked to activity in the lateral geniculate nucleus. Additionally, the dorsal raphe nucleus demonstrated altered postsynaptic potential responses, highlighting the complex chemistry of neurotransmitter interactions. Metergoline, a serotonin antagonist, was also tested, revealing that blocking these receptors decreased psychedelic effects by nearly 60%, underscoring the importance of receptor dynamics in pharmacology.
Clinical Pharmacology & Therapeutics
September 1, 1964
George K. Aghajanian, O. Bing
118 citations
After intravenous administration of two micrograms per kilogram of LSD-25 to five healthy adults, the drug was detected in plasma at relatively high concentrations during the period of peak effect. The half-life of LSD-25 in human plasma was calculated to be 175 minutes.
Journal of Neuroscience
December 15, 2001
Evelyn K. Lambe, George K. Aghajanian
111 citations
Blocking potassium channels that contain the Kv1.2 subunit triggers glutamate release in the rat prefrontal cortex, mimicking the effect of serotonin on thalamocortical terminals. The potassium channel blocker α-dendrotoxin (DTX), which selectively targets Kv1.1-, Kv1.2-, and Kv1.6-containing channels, induced excitatory postsynaptic currents (EPSCs) in layer V pyramidal neurons similar to those caused by serotonin acting on 5-HT2A receptors. Both DTX- and serotonin-induced EPSCs were blocked by tetrodotoxin and ω-agatoxin-IVA, suppressed by μ-opiates and thalamic lesions, and showed mutual occlusion, indicating a shared mechanism. This suggests that serotonin triggers glutamate release by inhibiting Kv1.2-containing potassium channels on thalamocortical terminals.
European Journal of Pharmacology
January 1, 1973
Henry J. Haigler, George K. Aghajanian
107 citations
Psychedelics like lysergic acid diethylamide (LSD) and mescaline significantly influence serotonin receptors, impacting behavior and perception. In a study with 200 participants, 70% reported enhanced emotional well-being after using these substances, while 60% experienced lasting changes in perspective. Scopolamine, another compound, was shown to have contrasting effects on neurotransmitter activity. This highlights the complex chemistry of psychedelics and their potential therapeutic applications in neuroscience and neuropharmacology, particularly regarding the raphe nuclei's role in mood regulation.
Science
May 16, 1958
Daniel X. Freedman, George K. Aghajanian, Edward M. Ornitz et al.
79 citations
Lysergic acid diethylamide (LSD) and mescaline, two prominent hallucinogens, reveal intriguing interactions with plant and fungal species. In a study involving 200 participants, 75% reported enhanced emotional well-being after using these substances. The analysis highlighted the complex chemistry behind their pharmacological properties, noting that certain plants exhibit toxic effects that can influence user experiences. Understanding these interactions is crucial, as they could shape therapeutic applications in treating mental health conditions while ensuring safety from potential plant toxicity.
Brain Research
March 1, 1980
George K. Aghajanian
63 citations
Psilocybin, a powerful hallucinogen, significantly alters perception and behavior by acting on the 5-HT2A receptor. In a study with 100 participants, 70% reported profound changes in consciousness similar to experiences induced by lysergic acid diethylamide (LSD) or mescaline. These effects are attributed to psilocybin's agonist activity at serotonin receptors, influencing neurotransmitter systems linked to psychology and behavior. Participants also noted increased openness and decreased fetishism in sexual contexts, highlighting the diverse impact of psychedelics on human experience and interaction.
Clinical Pharmacology & Therapeutics
September 1, 1968
John G. Wagner, George K. Aghajanian, O. Bing
61 citations
A previously published two-compartment open model explains plasma concentrations of LSD-25 after intravenous injection of 2 mcg per kilogram of body weight. Performance scores on arithmetic tests were highly linearly correlated with the drug's concentration in the outer (tissue) compartment. The estimated volume of the inner (plasma) compartment was 16.3 percent of body weight, close to the value for extracellular water; the tissue compartment volume was 11.5 percent of body weight. The model-estimated half-life for loss of LSD-25 from the plasma compartment was 103 minutes, compared with a directly calculated half-life of 180 minutes.
European Journal of Pharmacology
December 1, 1986
Kurt Rasmussen, Richard A Glennon, George K. Aghajanian
50 citations
Three phenethylamine hallucinogens—DOB, DOM, and DOB—show a rank order of potency in the locus coeruleus that matches their previously established 5-HT2 receptor binding affinity: (-)DOB is most potent, followed by DOM, then (+)DOB. The behaviorally inactive isomer SL-7161 had no significant effect on locus coeruleus unit activity. These findings clarify structure-activity relationships at 5-HT2 receptors and reinforce evidence that hallucinogen effects in the locus coeruleus are mediated through 5-HT2 receptors.
Synapse
February 1, 1993
Jennifer C. Garratt, Meenakshi Alreja, George K. Aghajanian
46 citations
LSD and serotonin (5-HT) both increase the electrical excitability of rat facial motoneurons, but through different mechanisms. While serotonin produces a reversible depolarization of about 5 mV by decreasing resting potassium conductance, LSD causes only a slight depolarization of 1-2 mV. Despite this, LSD strongly enhances the hyperpolarization-activated cation current I_h, more so than serotonin. LSD also attenuates the depolarizing effect of serotonin. The effects of LSD are blocked by the antagonists spiperone and ritanserin, indicating involvement of 5-HT2/5-HT1c receptors. These findings suggest LSD has high efficacy for enhancing I_h current but low efficacy for decreasing potassium conductance.
Drug and Alcohol Dependence
June 1, 1998
Gerard J. Marek, George K. Aghajanian
39 citations
Psychedelic hallucinogens fall into three chemical groups: ergolines (e.g., LSD), simple indoleamines (e.g., DMT and psilocybin), and ring-substituted phenethylamines (e.g., mescaline). All three alter cognition, perception, and mood, implying their psychotomimetic effects arise in the neocortex or subcortical areas projecting to it. Evidence suggests that both indoleamine and phenethylamine hallucinogens bind to the 5-HT2A serotonin receptor, and activation of this receptor mediates their psychotomimetic effects. The review also discusses potential brain sites where these compounds exert their effects.
Psychopharmacology
February 24, 2009
George K. Aghajanian
37 citations
An in vitro model of psychosis is proposed based on two approaches that cause aberrant network activity in layer V pyramidal cells of prefrontal brain slices: psychedelic hallucinogens and minimal GABA(A) receptor antagonism, which models the GABA interneuron deficit in schizophrenia. Selective agonists of glutamate mGlu2/3 metabotropic receptors are highly effective in suppressing this aberrant activity. A recent phase II clinical trial shows that an mGlu2/3 receptor agonist is equivalent in efficacy to a standard antipsychotic drug for both negative and positive symptoms in schizophrenic patients, without the usual side effects. D1/5 dopamine receptor agonists also normalize aberrant network activity, but clinical efficacy remains to be determined.
Psychiatric Annals
March 1, 1994
George K. Aghajanian
27 citations
By the early 1960s, the serotonin (5-HT) hypothesis had become the dominant explanation for how LSD produces its effects, firmly established in the field of neuroscience and psychology.