Background
‘Piperazine-containing party pills’ were marketed and sold as legal alternatives to methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA) until 2008 in New Zealand. The major ...constituents of these ‘pills’ were benzylphenylpiperazine (BZP) and trifluoromethylphenylpiperazine (TFMPP). Despite their popularity, there is a paucity of knowledge about their central effects in humans. This study investigated their effects on human neural processing using electroencephalographic techniques.
Methods
A randomised, double-blind, placebo-controlled study investigated the effects of an acute dose of these compounds on the interhemispheric transfer of information (IHTT) using the Poffenberger task. Reaction time data were also collected. Healthy, right-handed males were given an oral dose of either BZP (
n
= 13) (200 mg), TFMPP (
n
= 15) (60 mg), a combination of BZP + TFMPP (
n
= 15) (100 mg/30 mg), dexamphetamine (
n
= 16) (20 mg), or placebo (
n
= 23) and tested both before and 120 min after drug administration.
Results
A mixed factorial repeated measures analysis of variance of absolute N160 latency and contrast analysis revealed that only TFMPP (
F
(1,77)
= 17.30,
p
≤ 0.001) significantly reduced the absolute N160 latency. Analysis of the IHTT revealed that only TFMPP (
F
(1,77)
= 5.266,
p
≤ 0.02) significantly reduced the IHTT, while BZP, BZP + TFMPP and dexamphetamine had no effect. Contrast analysis revealed that both TFMPP (
F
(1,77)
= 17.30,
p
≤ 0.001) and placebo (
F
(1,77)
= 15.08,
p
≤ 0.001) preserved the laterality of information transfer from one hemisphere to the other. Reaction time (
p
> 0.05) was not significantly affected by any of the drug treatments.
Conclusions
The usual directional asymmetry (i.e. faster R-to-L transfer relative to L-to-R) observed in healthy control group was absent following the administration of either BZP, BZP + TFMPP or dexamphetamine. Surprisingly, lateralised hemispheric function was not affected by TFMPP. Our findings highlight how the administration of BZP, TFMPP and BZP + TFMPP leads to changes in the pattern of information transfer.
Methadone maintenance treatment (MMT) has been used as a treatment for opiate dependence since the mid-1960s. Evidence suggests that methadone binds to mu opiate receptors as do other opiates and ...induces changes in neurophysiological function. However, little is known, about how neural activity within the higher frequency gamma band (>30 Hz) while at rest changes in those stabilized on MMT despite its association with the excitation-inhibition balance within pyramidal-interneuron networks. Our study investigated differences in resting gamma power (37-41 Hz) between patients undergoing MMT for opiate dependence, illicit opiate users, and healthy controls subjects. Electroencephalographic data were recorded from 26 sites according to the international 10-20 system. Compared with the healthy controls subjects, people either undergoing MMT (mean difference MD = 0.32, 95% CI = 0.09-0.55, P < .01) or currently using illicit opiates (MD = 0.31, 95% CI = 0.06-0.56, P = .01) exhibited significant increased gamma power. The sLORETA (standardized low-resolution electromagnetic tomography) between-group comparison revealed dysfunctional neuronal activity in the occipital, parietal, and frontal lobes in the patients undergoing MMT. A more severe profile of dysfunction was observed in those using illicit opiates. Our findings suggest that long-term exposure to opioids is associated with disrupted resting state network, which may be reduced after MMT.
BackgroundMost uveal melanoma (UM) patients will develop metastatic disease to the liver. No effective therapies are currently available to treat metastatic UM (mUM). B7-H3/CD276 is an immune ...checkpoint molecule expressed in many tumors and notably, expressed at high levels in mUM. Here we investigated the preclinical efficacy of a Chimeric Antigen Receptor (CAR) T cell-based immunotherapy targeting B7-H3. Our B7-H3-specific CAR construct includes an inducible caspase 9 (iC9) suicide gene controlled by the chemical induced of dimerization AP1903 in case of an adverse reaction. This mechanism allows rapid and conditional elimination of iC9.B7-H3 CAR T cells.MethodsB7-H3 expression on human UM tissue samples and cell lines was assessed by immunohistochemistry and flow cytometry. iC9.B7-H3 CAR T cells were generated from healthy donors’ peripheral blood mononuclear cells by transduction with a retroviral vector encoding a B7-H3-specifc CAR comprised of iC9 suicide gene and CD28 costimulatory domain. Antitumor activity of iC9.B7-H3 CAR T cells was tested in vitro with UM cell lines, mUM patient-derived organotypic tumor spheroids (PDOTS), and NSG mice.ResultsHigh surface expression of B7-H3 was observed on human mUM tissue samples (n=6). Tested specimens demonstrated 50–100% (n=4) and 26–50% (n=2) of positively stained cells, with most (5/6) displaying moderate-strong intensity and only 1 demonstrating weak intensity of expression. Homogeneous B7-H3 expression was confirmed on primary and metastatic UM cell lines (n=6, 97 ± 6%). iC9.B7-H3 CAR T cells demonstrated specific and potent antitumor activity against UM cells at high and low E:T ratios (tumor killing: 90±5% at 1:1, 43±5% at 1:16), and complete eradication of B7-H3-expressing PDOTS. iC9.B7-H3 CAR T cells demonstrated robust expansion in vivo resulting in complete and sustainable eradication of UM liver metastases for over 120 days. Administration of AP1903 rapidly eliminated iC9.B7-H3 CAR T cells demonstrating the functionality of the iC9 safety-switch.ConclusionsOur study identified B7-H3 as a novel target for CAR T cell-based immunotherapy in mUM and demonstrates the preclinical efficacy of iC9.B7-H3 CAR T cells. Our findings strongly support the rationale for the design of a Phase I clinical trial to treat patients with mUM.Ethics ApprovalFormalin-fixed paraffin-embedded tissue samples derived from surgically removed metastatic lesions of UM patients were collected under an Institutional Review Board (IRB) approved protocol and kindly provided by the Dr. G. Boland BioBank at Massachusetts General Hospital (MGH). Fresh mUM tumor samples from deidentified UM patients were obtained under Dana-Farber/Harvard Cancer Center IRB-approved protocols.
Structural modifications of the left-hand side of compound 1 were identified which retained or improved potent binding to Bcl-2 and Bcl-xL in in vitro biochemical assays and had strong activity in an ...RS4;11 apoptotic cellular assay. For example, sulfoxide diastereomer 13 maintained good binding affinity and comparable cellular potency to 1 while improving aqueous solubility. The corresponding diastereomer (14) was significantly less potent in the cell, and docking studies suggest that this is due to a stereochemical preference for the RS versus SS sulfoxide. Appending a dimethylaminoethoxy side chain (27) adjacent to the benzylic position of the biphenyl moiety of 1 improved cellular activity by approximately three-fold, and this activity was corroborated in cell lines overexpressing Bcl-2 and Bcl-xL.
Background: Long-Term Potentiation (LTP) is recognised as a core neuronal process underlying long-term memory. However, a direct relationship between LTP and human memory performance is yet to be ...demonstrated. The first aim of the current study was thus to assess the relationship between LTP and human long-term memory performance. With this also comes an opportunity to explore factors thought to mediate the relationship between LTP and long-term memory. The second aim of the current study was to explore the relationship between LTP and memory in groups differing with respect to BDNF Val66Met; a single nucleotide polymorphism implicated in memory function. Methods: Participants were split into three genotype groups (Val/Val, Val/Met, Met/Met) and were presented with both an EEG paradigm for inducing LTP-like enhancements of the visually-evoked response, and a test of visual memory. Results: The magnitude of LTP 40 minutes after induction was predictive of long-term memory performance. Additionally, the BDNF Met allele was associated with both reduced LTP and reduced memory performance. Conclusions: The current study not only presents the first evidence for a relationship between sensory LTP and human memory performance, but also demonstrates how targeting this relationship can provide insight into factors implicated in variation in human memory performance. It is anticipated that this will be of utility to future clinical studies of disrupted memory function.
Rationale
A novel group of designer drugs containing benzylpiperazine (BZP) and/or trifluoromethylphenylpiperazine (TFMPP) have been available worldwide for more than a decade; however, their effects ...on human brain function have not been extensively described.
Objectives
In a double-blind, placebo-controlled crossover study, the acute effects of BZP and TFMPP (alone and in combination) on the neural networks involved in executive function were investigated using an event-related Stroop functional magnetic resonance imaging (fMRI) paradigm.
Methods
Thirteen healthy participants aged 18–40 years undertook the Stroop task 90 min after taking an oral dose of either BZP (200 mg), TFMPP (either 50 or 60 mg), BZP + TFMPP (100 + 30 mg) or placebo. A change in activity in neural regions reflects an increase in local demand for oxygen, due to an increase in neuronal activity.
Results
Relative to placebo, an increase in neural activation was observed in the dorsal striatum following BZP, and in the thalamus following TFMPP, when performing the Stroop task.
Conclusion
These data suggest that additional compensatory resources were recruited to maintain performance during the Stroop task. When BZP and TFMPP were administered together, both the dorsal striatum and thalamus were activated. However, the combination of BZP/TFMPP attenuated activation in the caudate, possibly due to TFMPP’s indirect effects on dopamine release via 5HT
2C
receptors.
Methamphetamine (MA) is a potent psychostimulant drug whose abuse has become a global epidemic in recent years. Firstly, this review article briefly discusses the epidemiology and clinical ...pharmacology of methamphetamine dependence. Secondly, the article reviews relevant animal literature modeling methamphetamine dependence and discusses possible mechanisms of methamphetamine-induced neurotoxicity. Thirdly, it provides a critical review of functional and structural neuroimaging studies in human MA abusers; including positron emission tomography (PET) and functional and structural magnetic resonance imaging (MRI). The effect of abstinence from methamphetamine, both short- and long-term within the context of these studies is also reviewed.
The selective serotonin reuptake inhibitor fluoxetine significantly enhances adult visual cortex plasticity within the rat. This effect is related to decreased gamma-aminobutyric acid (GABA) mediated ...inhibition and identifies fluoxetine as a potential agent for enhancing plasticity in the adult human brain. We tested the hypothesis that fluoxetine would enhance visual perceptual learning of a motion direction discrimination (MDD) task in humans. We also investigated (1) the effect of fluoxetine on visual and motor cortex excitability and (2) the impact of increased GABA mediated inhibition following a single dose of triazolam on post-training MDD task performance. Within a double blind, placebo controlled design, 20 healthy adult participants completed a 19-day course of fluoxetine (
= 10, 20 mg per day) or placebo (
= 10). Participants were trained on the MDD task over the final 5 days of fluoxetine administration. Accuracy for the trained MDD stimulus and an untrained MDD stimulus configuration was assessed before and after training, after triazolam and 1 week after triazolam. Motor and visual cortex excitability were measured using transcranial magnetic stimulation. Fluoxetine did not enhance the magnitude or rate of perceptual learning and full transfer of learning to the untrained stimulus was observed for both groups. After training was complete, trazolam had no effect on trained task performance but significantly impaired untrained task performance. No consistent effects of fluoxetine on cortical excitability were observed. The results do not support the hypothesis that fluoxetine can enhance learning in humans. However, the specific effect of triazolam on MDD task performance for the untrained stimulus suggests that learning and learning transfer rely on dissociable neural mechanisms.
Abstract Objective Central melanocortin pathways are well-established regulators of energy balance. However, scant data exist about the role of systemic melanocortin peptides. We set out to determine ...if peripheral α-melanocyte stimulating hormone (α-MSH) plays a role in glucose homeostasis and tested the hypothesis that the pituitary is able to sense a physiological increase in circulating glucose and responds by secreting α-MSH. Methods We established glucose-stimulated α-MSH secretion using humans, non-human primates, and mouse models. Continuous α-MSH infusions were performed during glucose tolerance tests and hyperinsulinemic-euglycemic clamps to evaluate the systemic effect of α-MSH in glucose regulation. Complementary ex vivo and in vitro techniques were employed to delineate the direct action of α-MSH via the melanocortin 5 receptor (MC5R)–PKA axis in skeletal muscles. Combined treatment of non-selective/selective phosphodiesterase inhibitor and α-MSH was adopted to restore glucose tolerance in obese mice. Results Here we demonstrate that pituitary secretion of α-MSH is increased by glucose. Peripheral α-MSH increases temperature in skeletal muscles, acts directly on soleus and gastrocnemius muscles to significantly increase glucose uptake, and enhances whole-body glucose clearance via the activation of muscle MC5R and protein kinase A. These actions are absent in obese mice, accompanied by a blunting of α-MSH-induced cAMP levels in skeletal muscles of obese mice. Both selective and non-selective phosphodiesterase inhibition restores α-MSH induced skeletal muscle glucose uptake and improves glucose disposal in obese mice. Conclusion These data describe a novel endocrine circuit that modulates glucose homeostasis by pituitary α-MSH, which increases muscle glucose uptake and thermogenesis through the activation of a MC5R-PKA-pathway, which is disrupted in obesity.
Background
“Party pills” containing benzylpiperazine (BZP) used to be widely and legally available as recreational drugs in New Zealand. There are only two published trials on human subjects (1973), ...which suggested that 100 mg of BZP produced subjective and physiological effects similar to 10 mg of dexamphetamine. The purpose of this study is to further investigate the subjective and physiological responses to BZP in females.
Methods/study design
In a randomised, double blind, placebo-controlled study, the subjective and physiological effects of BZP were investigated in 27 healthy, right-handed non-smoking females (mean age 22 ± 3 years). Two groups were tested before and approximately 120 minutes after administration of a single oral dose of either 200 mg BZP (
n
= 14) or placebo (
n
= 13). Participants were required to comment on the subjective effects of BZP using three rating scales—the Addiction Centre for Research Inventory, the Profile of Mood States and the Visual Analogue Scale. Participants’ blood pressure, heart rate and temperature were also measured.
Results/findings
Statistical analysis using a split-plot analysis of variance and
t
tests revealed that BZP significantly increases blood pressure and heart rate (
p
< 0.05) Likewise, the subjective reports revealed that BZP has significant stimulant effects, increases euphoria and dysphoria and increases sociability and drug liking (
p
< 0.05).
Discussion/interpretation
Physiological and subjective data reflected a clear similarity between the effects of BZP and those of other commonly known stimulants such as amphetamine and 3,4-methylenedioxymethamphetamine.
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