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Neuroscience

Serotonergic Hallucinogen-Induced Visual Perceptual Alterations

November 30, 2016 / DMT, LSD, Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Publications / By / ,

Abstract

Serotonergic hallucinogens, such as lysergic acid diethylamide (LSD), psilocybin, and N,N-dimethyltryptamine (DMT), are famous for their capacity to temporally and profoundly alter an individual’s visual experiences. These visual alterations show consistent attributes despite large inter- and intra-individual variances. Many reports document a common perception of colors as more saturated, with increased brightness and contrast in the environment (“Visual Intensifications”). Environmental objects might be altered in size (“Visual illusions”) or take on a modified and special meaning for the subject (“Altered self-reference”). Subjects may perceive light flashes or geometrical figures containing recurrent patterns (“Elementary imagery and hallucinations”) influenced by auditory stimuli (“Audiovisual synesthesia”), or they may envision images of people, animals, or landscapes (“Complex imagery and hallucinations”) without any physical stimuli supporting their percepts. This wide assortment of visual phenomena suggests that one single neuropsychopharmacological mechanism is unlikely to explain such vast phenomenological diversity. Starting with mechanisms that act at the cellular level, the key role of 5-HT2A receptor activation and the subsequent increased cortical excitation will be considered. Next, it will be shown that area specific anatomical and dynamical features link increased excitation to the specific visual contents of hallucinations. The decrease of alpha oscillations by hallucinogens will then be introduced as a systemic mechanism for amplifying internal-driven excitation that overwhelms stimulus-induced excitations. Finally, the hallucinogen-induced parallel decrease of the N170 visual evoked potential and increased medial P1 potential will be discussed as key mechanisms for inducing a dysbalance between global integration and early visual gain that may explain several hallucinogen-induced visual experiences, including visual hallucinations, illusions, and intensifications.

Kometer, M., & Vollenweider, F. X. (2016). Serotonergic Hallucinogen-Induced Visual Perceptual Alterations. 10.1007/7854_2016_461
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Ketamine’s Mechanisms of Rapid Antidepressant Activity: Evidence from Preclinical Studies

November 30, 2016 / Depressive Disorders, Ketamine, Neuroscience, Papers, Psychology, Publications / By / ,

Abstract

Enthusiasm over the growing series of reports describing ketamine’s rapid onset of robust antidepressant activity in clinical trials has ignited a large number of back-translational efforts attempting to employ rodent models to better characterize the antidepressant properties of the drug and to improve our understanding of its underlying mechanisms of antidepressant action. On balance, these preclinical studies have yielded fairly consistent findings demonstrating that ketamine has a broad range of behavioral effects consistent with antidepressant activity in a variety of rodent models. Many of these studies further suggest that ketamine’s effects are unique from other classic antidepressant drugs in producing more durable effects in some models and more rapidly reversing the behavioral effects of chronic stressor exposure in other models. The preclinical studies are also beginning to elucidate the drug’s mechanisms of antidepressant activity, with the majority of recent studies suggesting that increased levels of regional alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) receptor activation and brain-derived neurotrophic factor (BDNF) expression, as well as enhanced synaptic plasticity, are critical components of the response. However, there remain several points of disagreement and inconsistency in the preclinical literature that require additional investigation, including the effectiveness of other NMDA receptor-targeting drugs and the specific targets of ketamine’s proximal effects. This chapter provides an overview and critical review of this preclinical literature. It is anticipated that a more complete understanding of ketamine’s mechanisms of antidepressant action will allow for a safer and more efficient use of ketamine in the clinical setting and afford us new opportunities for novel drug development.

Hermes, G., & Sanacora, G. (2016). Ketamine’s Mechanisms of Rapid Antidepressant Activity: Evidence from Preclinical Studies. In Ketamine for Treatment-Resistant Depression (pp. 73-98). Springer International Publishing. 10.1007/978-3-319-42925-0_6

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Integrative analysis of sex differences in the rapid antidepressant effects of ketamine in preclinical models for individualized clinical outcomes

November 26, 2016 / Depressive Disorders, Ketamine, Neuroscience, Papers, Psychology, Publications / By / , ,

Abstract

In major depressive disorder, women exhibit higher lifetime prevalence and different antidepressant response rates than men, which illustrates the importance of examining individual differences in the pathophysiology of depression and therapeutic response. In recent years, the consideration of sex in related preclinical research has thus gained interest — particularly in light of novel evidence for rapid-acting antidepressants. Notably, the literature recently revealed a higher sensitivity of females to the antidepressant effects of the N-methyl-d-aspartate receptor antagonist ketamine, in both baseline and preclinical conditions. Combined with its fast-acting and relatively sustained properties, this evidence highlights ketamine as a particularly interesting therapeutic alternative for this sensitive population, and supports the value in considering sex as a critical factor for improved individualized therapeutic strategies.

Saland, S. K., Duclot, F., & Kabbaj, M. (2017). Integrative analysis of sex differences in the rapid antidepressant effects of ketamine in preclinical models for individualized clinical outcomes. Current Opinion in Behavioral Sciences, 14, 19-26. 10.1016/j.cobeha.2016.11.002
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d-Lysergic Acid Diethylamide (LSD) as a Model of Psychosis: Mechanism of Action and Pharmacology

November 23, 2016 / LSD, Neuroscience, Papers, Psychology, Psychotic Disorders, Publications / By / , , ,

Abstract

d-Lysergic Acid Diethylamide (LSD) is known for its hallucinogenic properties and psychotic-like symptoms, especially at high doses. It is indeed used as a pharmacological model of psychosis in preclinical research. The goal of this review was to understand the mechanism of action of psychotic-like effects of LSD. We searched Pubmed, Web of Science, Scopus, Google Scholar and articles’ reference lists for preclinical studies regarding the mechanism of action involved in the psychotic-like effects induced by LSD. LSD’s mechanism of action is pleiotropic, primarily mediated by the serotonergic system in the Dorsal Raphe, binding the 5-HT2Areceptor as a partial agonist and 5-HT1A as an agonist. LSD also modulates the Ventral Tegmental Area, at higher doses, by stimulating dopamine D2, Trace Amine Associate receptor 1 (TAAR1) and 5-HT2A. More studies clarifying the mechanism of action of the psychotic-like symptoms or psychosis induced by LSD in humans are needed. LSD’s effects are mediated by a pleiotropic mechanism involving serotonergic, dopaminergic, and glutamatergic neurotransmission. Thus, the LSD-induced psychosis is a useful model to test the therapeutic efficacy of potential novel antipsychotic drugs, particularly drugs with dual serotonergic and dopaminergic (DA) mechanism or acting on TAAR1 receptors.

De Gregorio, D., Comai, S., Posa, L., & Gobbi, G. (2016). d-Lysergic Acid Diethylamide (LSD) as a Model of Psychosis: Mechanism of Action and Pharmacology. International Journal of Molecular Sciences, 17(11), 1953. 10.3390/ijms17111953
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Risks Associated with Misuse of Ketamine as a Rapid-Acting Antidepressant

November 22, 2016 / Depressive Disorders, Ketamine, Neuroscience, Papers, Psychology, Publications / By / , , , , ,

Abstract

Major depression is a serious psychiatric disorder and remains a leading cause of disability worldwide. Conventional antidepressants take at least several weeks to achieve a therapeutic response and this lag period has hindered their ability to attain beneficial effects in depressed individuals at high risk of suicide. The non-competitive N-methyl-D-aspartate glutamate receptor antagonist ketamine has been shown to have rapid antidepressant effects in both rodents and humans. The emergence of ketamine as a fast-acting antidepressant provides promising new insights into the development of a rapid treatment response in patients with clinical depression. However, its safety and toxicity remain a concern. In this review, we focus on the limitations of ketamine, including neurotoxicity, cognitive dysfunction, adverse events associated with mental status, psychotomimetic effects, cardiovascular events, and uropathic effects. Studies have shown that its safety and tolerability profiles are generally good at low doses and with short-term treatment in depressed patients. The adverse events associated with ketamine usually occur with very high doses that are administered for prolonged periods of time and can be relieved by cessation. The antidepressant actions of its two enantiomers, S-ketamine (esketamine) and R-ketamine, are also discussed. R-ketamine has greater antidepressant actions than S-ketamine, without ketamine-related side-effects. Future treatment strategies should consider using R-ketamine for the treatment of depressed patients to decrease the risk of adverse events associated with long-term ketamine use.

Zhu, W., Ding, Z., Zhang, Y., Shi, J., Hashimoto, K., & Lu, L. (2016). Risks associated with misuse of ketamine as a rapid-acting antidepressant. Neuroscience Bulletin, 32(6), 557-564. 10.1007/s12264-016-0081-2

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Case series: Antidepressant effects of low-affinity and low-trapping NMDA receptor antagonists did not predict response to ketamine in seven subjects

November 21, 2016 / Depressive Disorders, Ketamine, Neuroscience, Papers, Psychology, Publications / By / , , , ,

Abstract

Ketamine’s antidepressant effects have variously been attributed to its wide-acting N-methyl-D-aspartate (NMDA) antagonism, its high-affinity for the NMDA receptor (Sanacora et al., 2008), and its trapping mechanism of blockade (Autry et al., 2011; Duman et al., 2016; Zarate et al., 2013). Several novel agents are being developed and tested that attempt to maintain ketamine’s antidepressant efficacy while minimizing its side effects, particularly its psychotomimetic properties and abuse potential.

Lepow, L., Luckenbaugh, D. A., Park, L., Henter, I. D., & Zarate, C. A. (2017). Case series: Antidepressant effects of low-affinity and low-trapping NMDA receptor antagonists did not predict response to ketamine in seven subjects. Journal of psychiatric research, 86, 55-57. 10.1016/j.jpsychires.2016.10.023
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Biosynthesis of the psychotropic plant diterpene salvinorin A: Discovery and characterization of the Salvia divinorum clerodienyl diphosphate synthase

November 19, 2016 / Neuroscience, Papers, Pharmacology & Chemistry, Publications, Salvia / Salvinorin A, Substance Use Disorder / By / , , , , , ,

Abstract

Salvia divinorum commonly known as diviner’s sage, is an ethnomedicinal plant of the mint family (Lamiaceae). S. divinorum is rich in clerodane-type diterpenoids, which accumulate predominantly in leaf glandular trichomes. The main bioactive metabolite, salvinorin A, is the first non-nitrogenous natural compound known to function as an opioid-receptor agonist, and is undergoing clinical trials for potential use in treating neuropsychiatric diseases and drug addictions. We report here the discovery and functional characterization of two S. divinorumditerpene synthases (diTPSs), the ent-copalyl diphosphate (ent-CPP) synthase SdCPS1, and the clerodienyl diphosphate (CLPP) synthase SdCPS2. Mining of leaf- and trichome-specific transcriptomes revealed five diTPSs, two of which are class II diTPSs (SdCPS1-2) and three are class I enzymes (SdKSL1-3). Of the class II diTPSs, transient expression in Nicotiana benthamianaidentified SdCPS1 as an ent-CPP synthase, which is prevalent in roots and, together with SdKSL1, exhibits a possible dual role in general and specialized metabolism. In vivo co-expression and in vitro assays combined with NMR analysis identified SdCPS2 as a CLPP synthase. A role of SdCPS2 in catalyzing the committed step in salvinorin A biosynthesis is supported by its biochemical function, trichome-specific expression and absence of additional class II diTPSs in S. divinorum. Structure-guided mutagenesis revealed four catalytic residues that enabled the re-programming of SdCPS2 activity to afford four distinct products, thus advancing our understanding of how neo-functionalization events have shaped the array of different class II diTPS functions in plants, and may promote synthetic biology platforms for a broader spectrum of diterpenoid bioproducts.

Pelot, K. A., Mitchell, R., Kwon, M., Hagelthorn, D. M., Wardman, J. F., Chiang, A., … & Zerbe, P. (2016). Biosynthesis of the psychotropic plant diterpene salvinorin A: Discovery and characterization of the Salvia divinorum clerodienyl diphosphate synthase. The Plant Journal. 10.1111/tpj.13427
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The serotonin 5-HT2C receptor and the non-addictive nature of classic hallucinogens

November 15, 2016 / LSD, Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Publications, Substance Use Disorder / By / ,

Abstract

Classic hallucinogens share pharmacology as serotonin 5-HT2A, 5-HT2B, and 5-HT2Creceptor agonists. Unique among most other Schedule 1 drugs, they are generally non-addictive and can be effective tools in the treatment of addiction. Mechanisms underlying these attributes are largely unknown. However, many preclinical studies show that 5-HT2C agonists counteract the addictive effects of drugs from several classes, suggesting this pharmacological property of classic hallucinogens may be significant. Drawing from a comprehensive analysis of preclinical behavior, neuroanatomy, and neurochemistry studies, this review builds rationale for this hypothesis, and also proposes a testable, neurobiological framework. 5-HT2C agonists work, in part, by modulating dopamine neuron activity in the ventral tegmental area—nucleus accumbens (NAc) reward pathway. We argue that activation of 5-HT2Creceptors on NAc shell, GABAergic, medium spiny neurons inhibits potassium Kv1.x channels, thereby enhancing inhibitory activity via intrinsic mechanisms. Together with experiments that show that addictive drugs, such as cocaine, potentiate Kv1.x channels, thereby suppressing NAc shell GABAergic activity, this hypothesis provides a mechanism by which classic hallucinogen-mediated stimulation of 5-HT2C receptors could thwart addiction. It also provides a potential reason for the non-addictive nature of classic hallucinogens.

Canal, C. E., & Murnane, K. S. (2016). The serotonin 5-HT2C receptor and the non-addictive nature of classic hallucinogens. Journal of Psychopharmacology, 0269881116677104.
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Ketamine: NMDA Receptors and Beyond

November 2, 2016 / Depressive Disorders, Ketamine, Neuroscience, Papers, Psychology, Psychotic Disorders / By / , ,

Abstract

Human studies examining the effects of the dissociative anesthetic ketamine as a model for psychosis and as a rapidly acting antidepressant have spurred great interest in understanding ketamine’s actions at molecular, cellular, and network levels. Although ketamine has unequivocal uncompetitive inhibitory effects on N-methyl-d-aspartate receptors (NMDARs) and may preferentially alter the function of NMDARs on interneurons, recent work has questioned whether block of NMDARs is critical for its mood enhancing actions. In this viewpoint, we examine the evolving literature on ketamine supporting NMDARs as important triggers for certain psychiatric effects and the possibility that the antidepressant trigger is unrelated to NMDARs. The rapidly evolving story of ketamine offers great hope for untangling and treating the biology of both depressive and psychotic illnesses.
Zorumski, C. F., Izumi, Y., & Mennerick, S. (2016). Ketamine: NMDA receptors and beyond. Journal of Neuroscience, 36(44), 11158-11164. 10.1523/JNEUROSCI.1547-16.2016
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MOLECULAR DOCKING STUDIES ON THE THERAPEUTIC TARGETS OF ALZHEIMER DISEASE (ACHE AND BCHE) USING NATURAL BIOACTIVE ALKALOIDS

November 1, 2016 / Ayahuasca, Neuroscience, Papers, Psychiatry & Medicine, Publications / By / ,

Abstract

Alzheimer’s disease (AD), a progressive neurodegenerative disorder with many cognitive and neuropsychiatric symptoms, is biochemically characterized by a significant decrease in the brain neurotransmitter Acetylcholine (ACh). In the present insilico study, six plant bioactive compounds namely Harmol, Vasicine, Harmaline, Harmine, Harmane and Harmalol (from P. Nigellastrum Bunge) were analyzed for their inhibitory role on AChE (Acetylcholinesterase) and BChE (Butyrylcholinesterase) activity by applying the molecular docking studies. Other parameters viz. determination of molecular interaction-based binding affinity values, protein-ligand interactions, Lipinski rule of five, functional properties and biological activities for the above compounds were also calculated by employing the appropriate bioinformatics tools. The results of docking analysis clearly showed that Harmalol has highest binding affinity with AChE (-8.6 kcal/mole) and BChE (-8.0 kcal/mole) but it does not qualified the enzyme inhibitory activity, since it was exerted, and also has least percentage activity on AD and neurodegenerative disease. Whereas, the Harmine has been second qualified binding affinity (-8.4 kcal/mol) and first in other parameters when compared with Harmalol. Hence, we are concluding that Harmine is the best compound for further studies to treat AD.

Jyothi, P., & Yellamma, K. (2016). MOLECULAR DOCKING STUDIES ON THE THERAPEUTIC TARGETS OF ALZHEIMER DISEASE (AChE AND BChE) USING NATURAL BIOACTIVE ALKALOIDS. International Journal of Pharmacy and Pharmaceutical Sciences, 8(12).
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