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Neuroscience

Effects of LSD on grooming behavior in serotonin transporter heterozygous (Sert+/−) mice

September 1, 2015 / LSD, Neuroscience, Papers, Psychology, Publications / By / , ,

Abstract

Serotonin (5-HT) plays a crucial role in the brain, modulating mood, cognition and reward. The serotonin transporter (SERT) is responsible for the reuptake of 5-HT from the synaptic cleft and regulates serotonin signaling in the brain. In humans, SERT genetic variance is linked to the pathogenesis of various psychiatric disorders, including anxiety, autism spectrum disorders (ASD) and obsessive–compulsive disorder (OCD). Rodent self-grooming is a complex, evolutionarily conserved patterned behavior relevant to stress, ASD and OCD. Genetic ablation of mouse Sert causes various behavioral deficits, including increased anxiety and grooming behavior. The hallucinogenic drug lysergic acid diethylamide (LSD) is a potent serotonergic agonist known to modulate human and animal behavior. Here, we examined heterozygous Sert+/− mouse behavior following acute administration of LSD (0.32 mg/kg). Overall, Sert+/− mice displayed a longer duration of self-grooming behavior regardless of LSD treatment. In contrast, LSD increased serotonin-sensitive behaviors, such as head twitching, tremors and backwards gait behaviors in both Sert+/+ and Sert+/− mice. There were no significant interactions between LSD treatment and Sert gene dosage in any of the behavioral domains measured. These results suggest that Sert+/− mice may respond to the behavioral effects of LSD in a similar manner to wild-type mice.

Kyzar, E. J., Stewart, A. M., & Kalueff, A. V. (2016). Effects of LSD on grooming behavior in serotonin transporter heterozygous (Sert+/−) mice. Behavioural brain research, 296, 47-52. http://dx.doi.org/10.1016/j.bbr.2015.08.018
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The mixed serotonin receptor agonist psilocybin reduces threat-induced modulation of amygdala connectivity

August 22, 2015 / Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Publications / By / , , , , ,

Abstract

Stimulation of serotonergic neurotransmission by psilocybin has been shown to shift emotional biases away from negative towards positive stimuli. We have recently shown that reduced amygdala activity during threat processing might underlie psilocybin’s effect on emotional processing. However, it is still not known whether psilocybin modulates bottom-up or top-down connectivity within the visual-limbic-prefrontal network underlying threat processing. We therefore analyzed our previous fMRI data using dynamic causal modeling and used Bayesian model selection to infer how psilocybin modulated effective connectivity within the visual–limbic–prefrontal network during threat processing. First, both placebo and psilocybin data were best explained by a model in which threat affect modulated bidirectional connections between the primary visual cortex, amygdala, and lateral prefrontal cortex. Second, psilocybin decreased the threat-induced modulation of top-down connectivity from the amygdala to primary visual cortex, speaking to a neural mechanism that might underlie putative shifts towards positive affect states after psilocybin administration. These findings may have important implications for the treatment of mood and anxiety disorders.

Kraehenmann, R., Schmidt, A., Friston, K., Preller, K. H., Seifritz, E., & Vollenweider, F. X. (2015). The mixed serotonin receptor agonist psilocybin reduces threat-induced modulation of amygdala connectivity. NeuroImage: Clinical. https://dx.doi.org/10.1016/j.nicl.2015.08.009
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Noribogaine is a G-Protein Biased κ-Opioid Receptor Agonist

August 21, 2015 / Iboga / Ibogaine, Neuroscience, Papers, Psychology, Publications, Substance Use Disorder / By / , , , , , ,

Abstract

Noribogaine is the long-lived human metabolite of the anti-addictive substance ibogaine. Noribogaine efficaciously reaches the brain with concentrations up to 20 μM after acute therapeutic dose of 40 mg/kg ibogaine in animals. Noribogaine displays atypical opioid-like components in vivo, anti-addictive effects and potent modulatory properties of the tolerance to opiates for which the mode of action remained uncharacterized thus far. Our binding experiments and computational simulations indicates that noribogaine may bind to the orthosteric morphinan binding site of the opioid receptors. Functional activities of noribogaine at G-protein and non G-protein pathways of the mu and kappa opioid receptors were characterized. Noribogaine was a weak mu antagonist with a functional inhibition constants (Ke) of 20 μM at the G-protein and β-arrestin signaling pathways. Conversely, noribogaine was a G-protein biased kappa agonist 75% as efficacious as dynorphin A at stimulating GDP-GTP exchange (EC50 = 9 μM) but only 12% as efficacious at recruiting β-arrestin, which could contribute to the lack of dysphoric effects of noribogaine. In turn, noribogaine functionally inhibited dynorphin-induced kappa β-arrestin recruitment and was more potent than its G-protein agonistic activity with an IC50 of 1 μM. This biased agonist/antagonist pharmacology is unique to noribogaine in comparison to various other ligands including ibogaine, 18-MC, nalmefene, and 6’-GNTI. We predict noribogaine to promote certain analgesic effects as well as anti-addictive effects at effective concentrations >1 μM in the brain. Because elevated levels of dynorphins are commonly observed and correlated with anxiety, dysphoric effects, and decreased dopaminergic tone, a therapeutically relevant functional inhibition bias to endogenously released dynorphins by noribogaine might be worthy of consideration for treating anxiety and substance related disorders.

Maillet, E. L., Milon, N., Heghinian, M. D., Fishback, J., Schürer, S. C., Garamszegi, N., & Mash, D. C. (2015). Noribogaine is a G-Protein Biased κ-Opioid Receptor Agonist. Neuropharmacology. https://dx.doi.org/10.1016/j.neuropharm.2015.08.032
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5-HT2A and mGlu2/3 receptor interactions: on their relevance to cognitive function and psychosis

August 19, 2015 / Neuroscience, Papers, Psychology, Psychotic Disorders, Publications / By / ,

Abstract

Serotonin [fusion_builder_container hundred_percent=”yes” overflow=”visible”][fusion_builder_row][fusion_builder_column type=”1_1″ background_position=”left top” background_color=”” border_size=”” border_color=”” border_style=”solid” spacing=”yes” background_image=”” background_repeat=”no-repeat” padding=”” margin_top=”0px” margin_bottom=”0px” class=”” id=”” animation_type=”” animation_speed=”0.3″ animation_direction=”left” hide_on_mobile=”no” center_content=”no” min_height=”none”][5-hydroxytryptamine (5-HT)] and glutamate have both been implicated in the pathophysiology of neuropsychiatric disorders but also in the mechanism of antipsychotic and hallucinogenic drug actions. Furthermore, close antagonistic interactions between 5-HT2A and metabotropic glutamate (mGlu)2/3 receptors have been established over the last decades on the basis of numerous electrophysiological, biochemical, and behavioral studies. Besides synaptic mechanisms, more recent findings suggested that heterodimeric 5-HT2A-mGlu2 receptor complexes in the prefrontal cortex may account for the functional crosstalk between these two receptor subtypes. In this review, we focus on in-vitro and in-vivo studies documenting the important relationship between 5-HT2A and mGlu2/3 receptors, with relevance to both normal behavioral function and psychosis.

Wischhof, L., & Koch, M. (2015). 5-HT2A and mGlu2/3 receptor interactions: on their relevance to cognitive function and psychosis. Behavioural pharmacology. https://dx.doi.org/10.1097/FBP.0000000000000183
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Psilocybin-induced spiritual experiences and insightfulness are associated with synchronization of neuronal oscillations

August 1, 2015 / Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Publications / By / , , ,

Abstract

Rationale

During the last years, considerable progress has been made toward understanding the neuronal basis of consciousness by using sophisticated behavioral tasks, brain-imaging techniques, and various psychoactive drugs. Nevertheless, the neuronal mechanisms underlying some of the most intriguing states of consciousness, including spiritual experiences, remain unknown.

Objectives

To elucidate state of consciousness-related neuronal mechanisms, human subjects were given psilocybin, a naturally occurring serotonergic agonist and hallucinogen that has been used for centuries to induce spiritual experiences in religious and medical rituals.

Methods

In this double-blind, placebo-controlled study, 50 healthy human volunteers received a moderate dose of psilocybin, while high-density electroencephalogram (EEG) recordings were taken during eyes-open and eyes-closed resting states. The current source density and the lagged phase synchronization of neuronal oscillations across distributed brain regions were computed and correlated with psilocybin-induced altered states of consciousness.

Results

Psilocybin decreased the current source density of neuronal oscillations at 1.5–20 Hz within a neural network comprising the anterior and posterior cingulate cortices and the parahippocampal regions. Most intriguingly, the intensity levels of psilocybin-induced spiritual experience and insightfulness correlated with the lagged phase synchronization of delta oscillations (1.5–4 Hz) between the retrosplenial cortex, the parahippocampus, and the lateral orbitofrontal area.

Conclusions

These results provide systematic evidence for the direct association of a specific spatiotemporal neuronal mechanism with spiritual experiences and enhanced insight into life and existence. The identified mechanism may constitute a pathway for modulating mental health, as spiritual experiences can promote sustained well-being and psychological resilience.

Kometer, M., Pokorny, T., Seifritz, E., & Vollenweider, F. X. (2015). Psilocybin-induced spiritual experiences and insightfulness are associated with synchronization of neuronal oscillations. Psychopharmacology, 1-14. https://dx.doi.org/10.1007/s00213-015-4026-7

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Psychopharmacological Agents and Suicide Risk Reduction: Ketamine and Other Approaches

August 1, 2015 / Depressive Disorders, Ketamine, Neuroscience, Papers, Psychology, Publications / By / , ,

Abstract

Suicide is a major global public health problem and the leading cause of injury mortality in the USA. Suicide is a complex phenomenon involving several systems and neurobiological pathways, with interacting genetic and environmental mechanisms. The literature on the neurobiology and pharmacotherapy of suicide has been limited. To date, no medications have proven efficacious for treating acute suicidal crises. There is an emerging literature supporting a rapid anti-suicidal effect of ketamine, a non-competitive N-methyl-d-aspartate (NMDA) glutamate receptor antagonist, among depressed patients with suicidal ideation. Potential ketamine’s anti-suicidal effect mechanisms are linked to interruption of the kynurenine pathway and modulating pro-inflammatory cytokines exacerbation. However, available data are not sufficient for its routine integration in clinical practice, and larger and replicated randomized control studies are needed.

Al Jurdi, R. K., Swann, A., & Mathew, S. J. (2015). Psychopharmacological Agents and Suicide Risk Reduction: Ketamine and Other Approaches. Current psychiatry reports, 17(10), 1-10. https://dx.doi.org/10.1007/s11920-015-0614-9

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5-HTTLPR Genotype Moderates the Effects of Past Ecstasy Use on Verbal Memory Performance in Adolescent and Emerging Adults: A Pilot Study

July 31, 2015 / MDMA, Neuroscience, Papers, Publications / By / , , , ,

Abstract

OBJECTIVE: Ecstasy use is associated with memory deficits. Serotonin transporter gene (5-HTTLPR) polymorphisms have been linked with memory function in healthy samples. The present pilot study investigated the influence of 5-HTTLPR polymorphisms on memory performance in ecstasy users, marijuana-using controls, and non-drug-using controls, after a minimum of 7 days of abstinence.

METHOD: Data were collected from 116 young adults (18-25 years-old), including 45 controls, 42 marijuana users, and 29 ecstasy users, and were balanced for 5-HTTLPR genotype. Participants were abstinent seven days prior to completing memory testing. Three MANCOVAs and one ANCOVA were run to examine whether drug group, 5-HTTLPR genotype, and their interactions predicted verbal and visual memory after controlling for gender, past year alcohol use, other drug use, and nicotine cotinine levels.

RESULTS: MANCOVA and ANCOVA analysis revealed a significant interaction between drug group and genotype (p = .03) such that ecstasy users with the L/L genotype performed significantly worse on CVLT-2 total recall (p = .05), short (p = .008) and long delay free recall (p = .01), and recognition (p = .006), with the reverse pattern found in controls. Ecstasy did not significantly predict visual memory. 5-HTTLPR genotype significantly predicted memory for faces (p = .02); short allele carriers performed better than those with L/L genotype.

CONCLUSIONS: 5-HTTLPR genotype moderated the effects of ecstasy on verbal memory, with L/L carriers performing worse compared to controls. Future research should continue to examine individual differences in ecstasy’s impact on neurocognitive performance as well as relationships with neuronal structure. Additional screening and prevention efforts focused on adolescents and emerging adults are necessary to prevent ecstasy consumption.

Wright, N. E., Strong, J. A., Gilbart, E. R., Shollenbarger, S. G., & Lisdahl, K. M. (2015). 5-HTTLPR Genotype Moderates the Effects of Past Ecstasy Use on Verbal Memory Performance in Adolescent and Emerging Adults: A Pilot Study. PloS one, 10(7), e0134708. http://dx.doi.org/10.1371/journal.pone.0134708

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Developmental outcomes of 3,4-methylenedioxymethamphetamine (ecstasy)-exposed infants in the UK

July 28, 2015 / MDMA, Neuroscience, Papers, Publications / By / , , , , , ,

Abstract

OBJECTIVE: This paper aims to review findings from a longitudinal study of prenatal methylenedioxymethamphetamine (MDMA, “ecstasy”) on infant development.

METHODS: In a prospective, longitudinal cohort design, we followed 28 MDMA-exposed and 68 non-MDMA-exposed infants from birth to 2 years of age. Women recruited voluntarily into a study of recreational drug use during pregnancy were interviewed to obtain type, frequency, and amount of recreational drug use. Their children were followed for a 2-year period after birth. A large number of drug and environmental covariates were controlled. Infants were seen at 1, 4, 12, 18, and 24 months using standardized normative tests of mental and motor development.

RESULTS: There were no differences between MDMA-exposed and non-MDMA-exposed infants at birth except that MDMA-exposed infants were more likely to be male. Motor delays were evident in MDMA infants at each age and amount of MDMA exposure predicted motor deficits at 12 months in a dose-dependent fashion.

CONCLUSIONS: Prenatal MDMA exposure is related to fine and gross motor delays in the first 2 years of life. Follow-up studies are needed to determine long-term effects.

Singer, L. T., Moore, D. G., Min, M. O., Goodwin, J., Turner, J. J., Fulton, S., & Parrott, A. C. (2015). Developmental outcomes of 3, 4‐methylenedioxymethamphetamine (ecstasy)‐exposed infants in the UK. Human Psychopharmacology: Clinical and Experimental, 30(4), 290-294. http://dx.doi.org/0.1002/hup.2459

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Antidepressant mechanism of ketamine: perspective from preclinical studies

July 21, 2015 / Depressive Disorders, Ketamine, Neuroscience, Papers, Psychiatry & Medicine, Psychology, Publications / By / , , ,

Abstract

A debilitating mental disorder, major depressive disorder is a leading cause of global disease burden. Existing antidepressant drugs are not adequate for the majority of depressed patients, and large clinical studies have demonstrated their limited efficacy and slow response onset. Growing evidence of low-dose ketamine’s rapid and potent antidepressant effects offers strong potential for future antidepressant agents. However, ketamine has considerable drawbacks such as its abuse potential, psychomimetic effects, and increased oxidative stress in the brain, thus limiting its widespread clinical use. To develop superior antidepressant drugs, it is crucial to better understand ketamine’s antidepressant mechanism of action. Recent preclinical studies indicate that ketamine’s antidepressant mechanism involves mammalian target of rapamycin pathway activation and subsequent synaptogenesis in the prefrontal cortex, as well as glycogen synthase kinase-3 beta (GSK-3β) inactivation. Adjunct GSK-3β inhibitors, such as lithium, can enhance ketamine’s efficacy by augmenting and prolonging its antidepressant effects. Given the potential for depressive relapses, lithium in addition to ketamine is a promising solution for this clinical issue.

Scheuing, L., Chiu, C. T., Liao, H. M., & Chuang, D. M. (2015). Antidepressant mechanism of ketamine: perspective from preclinical studies. Frontiers in Neuroscience, 9. http://dx.doi.org/10.3389/fnins.2015.00249
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Acute ketamine challenge increases resting state prefrontal-hippocampal connectivity in both humans and rats.

July 18, 2015 / Ketamine, Neuroscience, Papers, Psychology, Psychotic Disorders, Publications / By / , , , , , ,

Abstract

RATIONALE:

Aberrant prefrontal-hippocampal (PFC-HC) connectivity is disrupted in several psychiatric and at-risk conditions. Advances in rodent functional imaging have opened the possibility that this phenotype could serve as a translational imaging marker for psychiatric research. Recent evidence from functional magnetic resonance imaging (fMRI) studies has indicated an increase in PFC-HC coupling during working-memory tasks in both schizophrenic patients and at-risk populations, in contrast to a decrease in resting-state PFC-HC connectivity. Acute ketamine challenge is widely used in both humans and rats as a pharmacological model to study the mechanisms of N-methyl-D-aspartate (NMDA) receptor hypofunction in the context of psychiatric disorders.

OBJECTIVES:

We aimed to establish whether acute ketamine challenge has consistent effects in rats and humans by investigating resting-state fMRI PFC-HC connectivity and thus to corroborate its potential utility as a translational probe.

METHODS:

Twenty-four healthy human subjects (12 females, mean age 25 years) received intravenous doses of either saline (placebo) or ketamine (0.5 mg/kg body weight). Eighteen Sprague-Dawley male rats received either saline or ketamine (25 mg/kg). Resting-state fMRI measurements took place after injections, and the data were analyzed for PFC-HC functional connectivity.

RESULTS:

In both species, ketamine induced a robust increase in PFC-HC coupling, in contrast to findings in chronic schizophrenia.

CONCLUSIONS:

This translational comparison demonstrates a cross-species consistency in pharmacological effect and elucidates ketamine-induced alterations in PFC-HC coupling, a phenotype often disrupted in pathological conditions, which may give clue to understanding of psychiatric disorders and their onset, and help in the development of new treatments.

Grimm, O., Gass, N., Weber-Fahr, W., Sartorius, A., Schenker, E., Spedding, M., … & Meyer-Lindenberg, A. (2015). Acute ketamine challenge increases resting state prefrontal-hippocampal connectivity in both humans and rats. Psychopharmacology, 1-11.
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