Anesthetic Management of Emergency Insulinoma Resection: Case Report and Review of Literature.

Insulinoma, a neuroendocrine tumor originating from pancreatic islets, presents unique challenges in diagnosis and management. We present a case of a 73-year-old female with recurrent hypoglycemia leading to syncope, who underwent emergency pancreatectomy for a secreting insulinoma with multiple comorbidities. This case report aims to shed light on the complexities of insulinoma management and the importance of tailored perioperative strategies. The patient, presenting with severe hypoglycemia, was admitted for optimization. Preoperative assessment labeled her as ASA IVE and indicated a high risk of perioperative morbidity. General anesthesia, invasive monitoring, and epidural anesthesia were planned. Intraoperative glucose control was crucial, achieved with continuous blood glucose monitoring, octreotide administration, and insulin titration. The patient was extubated post-surgery, and pain was managed with epidural infusion. She was discharged on the 4th postoperative day with follow-up care. Insulinoma diagnosis relies on clinical, biochemical, and imaging tests, with 72-hour fasting as the gold standard. Localizing the tumor within the pancreas is essential for surgical success, often requiring invasive techniques. Surgical resection remains the definitive treatment, while medical management may be necessary in select cases. Anesthetic management should prioritize agents that minimize the cerebral metabolic rate for oxygen. Careful intraoperative glucose control and vigilant postoperative monitoring are essential. This case report highlights the intricate management of insulinoma, emphasizing tailored perioperative strategies that balance glucose regulation, anesthesia techniques, and postoperative care. However, the limited existing literature underscores the need for further research to refine anesthesia protocols, glucose control methods, and postoperative care, ultimately improving outcomes for patients with insulinoma.

A Mental Health Survey of Medical Professionals Working During the COVID-19 Pandemic at Shaukat Khanum Cancer Hospital, Lahore.

Introduction The last months of 2019 saw the emergence of a novel coronavirus, SARS-COV-2, capable of causing widespread disease in humans. The rapid spread of this new disease culminated in one of the biggest pandemics in known history. The far-reaching social, economical, and health effects of this pandemic are still unfolding on a global scale. Given the interconnectedness of social, environmental, and biological factors in manifesting psychiatric illnesses, it is fair to assume that the profound effects of this pandemic would likely increase the strain on mental healthcare systems.  The objective of this study was to assess the mental health burden amongst healthcare workers at Shaukat Khanum Memorial Cancer Hospital and Research Center (SKMCH & RC) at the start of the COVID-19 pandemic and to identify any differences in the mental health scores of anxiety, depression, and sleep disturbance for professionals directly involved in the care of COVID-19 patients as compared to those who were not. Material and methods This was an observational cross-sectional clinical study that used self-reported questionnaires after approval from the hospital's ethical board. The sample size was calculated based on a study published previously by Huang using a 23.04% incidence of anxiety in medical staff. Depression was quantified using the Patient Health Questionnaire-9 score (PHQ-9), anxiety by the Beck Anxiety Inventory, and sleep quality using the Pittsburgh Sleep Quality Index checklist (PSQI). A total of 221 healthcare workers who completed the questionnaires were included in the study and the results were analyzed using SPSS Statistics v. 23 (IBM Corp., Armonk, NY). Levene's test was used to assess the equality of variances, and an independent sample t-test and chi-square test were applied for the comparison of means. A one-way ANOVA test was used to compare means across more than two groups. Results Of the 221 healthcare workers recruited in the study, 57% were males, and 43% were females. Among the sample, 43% of participants were doctors, 27.1% were nurses, and others were technicians and medical assistants. It was observed that 50% of males and 36% of female healthcare workers experienced moderate to severe depression at the onset of the pandemic. Furthermore, 35% of males and 25% of females suffered from moderate to severe anxiety, and more than 80% of our study population reported poor quality of sleep. Conclusion The present study reported a high prevalence of anxiety levels, depressive symptoms, and poor sleep quality among the healthcare professionals working in SKMCH & RC Lahore during the COVID-19 pandemic irrespective of direct contact with COVID-19 patients in a healthcare setting.

HIV Transgenic Rats Demonstrate Impaired Sensorimotor Gating But Are Insensitive to Cannabinoid (Δ9-Tetrahydrocannabinol)-Induced Deficits.

BACKGROUND: HIV-associated neurocognitive disorder (HAND) is commonly observed in persons living with HIV (PWH) and is characterized by cognitive deficits implicating disruptions of fronto-striatal neurocircuitry. Such circuitry is also susceptible to alteration by cannabis and other drugs of abuse. PWH use cannabis at much higher rates than the general population, thus prioritizing the characterization of any interactions between HIV and cannabinoids on cognitively relevant systems. Prepulse inhibition (PPI) of the startle response, the process by which the motor response to a startling stimulus is attenuated by perception of a preceding non-startling stimulus, is an operational assay of fronto-striatal circuit integrity that is translatable across species. PPI is reduced in PWH. The HIV transgenic (HIVtg) rat model of HIV infection mimics numerous aspects of HAND, although to date the PPI deficit observed in PWH has yet to be fully recreated in animals. METHODS: PPI was measured in male and female HIVtg rats and wild-type controls following acute, nonconcurrent treatment with the primary constituents of cannabis: Δ 9-tetrahydrocannabinol (THC; 1 and 3 mg/kg, s.c.) and cannabidiol (1, 10, and 30 mg/kg, i.p.). RESULTS: HIVtg rats exhibited a significant PPI deficit relative to wild-type controls. THC reduced PPI in controls but not HIVtg rats. Cannabidiol exerted only minor, genotype-independent effects on PPI. CONCLUSIONS: HIVtg rats exhibit a relative insensitivity to the deleterious effects of THC on the fronto-striatal function reflected by PPI, which may partially explain the higher rates of cannabis use among PWH.

HIV Transgenic Rats Demonstrate Superior Task Acquisition and Intact Reversal Learning in the Within-Session Probabilistic Reversal Learning Task.

The HIV transgenic (HIVtg) rat is a commonly used animal model of chronic HIV infection that exhibits a wide range of cognitive deficits. To date, relatively little work has been conducted on these rats' capacity for reversal learning, an assay of executive function and cognitive flexibility used in humans. The present study sought to determine the impact of HIV genotype on probabilistic reversal learning, effortful motivation, and spontaneous locomotion/exploration in rats. Male (n = 8) and female (n = 8) HIVtg rats and wildtype (WT) controls were utilized. Cognitive flexibility was assessed via the Probabilistic Reversal Learning Task (PRLT), which reinforced responses to two stimuli on differential probabilistic schedules that periodically reversed. Effortful motivation and locomotor/exploratory behavior were assessed via the Progressive Ratio Breakpoint Task (PRBT) and the Behavioral Pattern Monitor (BPM), respectively. Regardless of sex, HIVtg rats required fewer trials to ascertain initial PRLT reward schedules than WT rats, and completed the same number of reversals. Secondary behaviors suggested that HIVtg PRLT performance was facilitated by a speed-accuracy tradeoff strategy. No main or interactive effects of genotype were observed in the PRBT or BPM. Relative to WT controls, HIVtg rats exhibited superior probabilistic reinforcement learning. Reversal learning was unaffected by HIV genotype, as was effortful motivation and exploratory behavior. These findings contrast with previous characterizations of the HIVtg rat, thus indicating a nuanced cognitive profile that is dependent upon such task specifications as within- versus between-session assessment and probabilistic versus deterministic reward schedules.

Investigation of the Structure-Activity Relationships of Psilocybin Analogues.

The 5-HT2A receptor is thought to be the primary target for psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) and other serotonergic hallucinogens (psychedelic drugs). Although a large amount of experimental work has been conducted to characterize the pharmacology of psilocybin and its dephosphorylated metabolite psilocin (4-hydroxy-N,N-dimethyltryptamine), there has been little systematic investigation of the structure-activity relationships (SAR) of 4-substituted tryptamine derivatives. In addition, structural analogs of psilocybin containing a 4-acetoxy group, such as 4-acetoxy-N,N-dimethyltryptamine (4-AcO-DMT), have appeared as new designer drugs, but almost nothing is known about their pharmacological effects. To address the gap of information, studies were conducted with 17 tryptamines containing a variety of symmetrical and asymmetrical N,N-dialkyl substituents and either a 4-hydroxy or 4-acetoxy group. Calcium mobilization assays were conducted to assess functional activity at human and mouse 5-HT2 subtypes. Head-twitch response (HTR) studies were conducted in C57BL/6J mice to assess 5-HT2A activation in vivo. All of the compounds acted as full or partial agonists at 5-HT2 subtypes, displaying similar potencies at 5-HT2A and 5-HT2B receptors, but some tryptamines with bulkier N-alkyl groups had lower potency at 5-HT2C receptors and higher 5-HT2B receptor efficacy. In addition, O-acetylation reduced the in vitro 5-HT2A potency of 4-hydroxy-N,N-dialkyltryptamines by about 10- to 20-fold but did not alter agonist efficacy. All of the compounds induce head twitches in mice, consistent with an LSD-like behavioral profile. In contrast to the functional data, acetylation of the 4-hydroxy group had little effect on HTR potency, suggesting that O-acetylated tryptamines may be deacetylated in vivo, acting as prodrugs. In summary, the tryptamine derivatives have psilocybin-like pharmacological properties, supporting their classification as psychedelic drugs.

The selective 5-HT2A receptor agonist 25CN-NBOH: Structure-activity relationship, in vivo pharmacology, and in vitro and ex vivo binding characteristics of [3H]25CN-NBOH.

The remarkable effects exhibited by classical psychedelics in recent clinical trials have spawned considerable interest in 5-HT2A receptor (5-HT2AR) activation as a treatment strategy for several psychiatric/cognitive disorders. In this study we have continued our development of 25CN-NBOH, one of the most 5-HT2AR-selective agonists reported to date, as a pharmacological tool for exploration of 5-HT2AR expression and functions. The importance of the 2' and 3' positions in 25CN-NBOH as structural hotspots for its 5-HT2AR activity was investigated by synthesis and pharmacological characterization of six novel analogs at 5-HT2AR and 5-HT2CR in binding and functional assays. While the 5-HT2AR activity of 25CN-NBOH was retained in 3'-methyl, 2',3'-chroman, 2',3'-dihydrofuran and 2',3'-furan analogs, the 3'-methoxy and 3'-ethyl analogs displayed substantially lower binding affinities and agonist potencies than 25CN-NBOH. Interestingly, the 2',3'-substitution pattern was also a key determinant of agonist efficacy, as all six analogs exhibited low-efficacy partial agonism or de facto antagonism at the 5-HT2AR in the functional assays. Systemic administration of 25CN-NBOH and its close structural analog 25CN-NBMD induced robust head-twitch response in mice, a well-established behavioural effect of 5-HT2AR activation in vivo, and 25CN-NBOH mediated robust reductions in the activity of mice in an anxiety-related marble burying assay, which supports the proposed beneficial effects of 5-HT2AR activation on disorders characterized by cognitive rigidity. Finally, tritiated 25CN-NBOH exhibited high 5-HT2AR binding affinity (KD ~1 nM) and selectivity against 5-HT2BR and 5-HT2CR in equilibrium and kinetic binding studies of the recombinant receptors, and in concordance [3H]25CN-NBOH displayed substantial specific, ketanserin-sensitive binding to cortex and small levels of binding to choroid plexus in rat brain slices in autoradiography studies. In conclusion, this work delineates the subtle molecular determinants of the 5-HT2AR activity in 25CN-NBOH, substantiates the potential in this compound and its analogs as tools for in vivo studies of the 5-HT2AR, and introduces a novel selective agonist radioligand as another potentially valuable tool for future explorations of this receptor.

Investigation of the 2,5-Dimethoxy Motif in Phenethylamine Serotonin 2A Receptor Agonists.

The 2,5-dimethoxyphenethylamine (2,5-PEA) scaffold is recognized as a motif conferring potent agonist activity at the serotonin 2A receptor (5-HT2AR). The 2,5-dimethoxy motif is present in several classical phenethylamine psychedelics such as 2,4,5- trimethoxyamphetamine (TMA-2), 2,5-dimethoxy-4-methylamphetamine (DOM), 2,5-dimethoxy-4-iodoamphetamine (DOI), 2,5- dimethoxy-4-bromoamphetamine (DOB), 2,5-dimethoxy-4-bromophenethylamine (2C-B), and 2,5-dimethoxy-4-iodophenethylamine (2C-I), and it has previously been suggested that this structural motif is essential for 5-HT2AR activation. In the present study, we present data that challenges this assumption. The 2- and 5-desmethoxy derivatives of 2C-B and DOB were synthesized, and their pharmacological profiles were evaluated in vitro at 5-HT2AR and 5-HT2CR in binding and functional assays and in vivo by assessing their induction of the head-twitch response in mice. Elimination of either the 2- or 5-methoxy group leads to a modest drop in binding affinity and functional potency at 5-HT2AR and 5-HT2CR, which was more pronounced upon removal of the 2-methoxy group. However, this trend was not mirrored in vivo, as removal of either methoxy group resulted in significant reduction in the ability of the compounds to induce the head-twitch response in mice. Thus, the 2,5-dimethoxyphenethylamine motif appears to be important for in vivo potency of phenethylamine 5-HT2AR agonists, but this does not correlate to the relative affinity and potency of the ligands at the recombinant 5-HT2AR.

Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species.

Serotonergic hallucinogens such as lysergic acid diethylamide (LSD) induce head twitches in rodents via 5-HT2A receptor activation. The goal of the present investigation was to determine whether a correlation exists between the potency of hallucinogens in the mouse head-twitch response (HTR) paradigm and their reported potencies in other species, specifically rats and humans. Dose-response experiments were conducted with phenylalkylamine and tryptamine hallucinogens in C57BL/6J mice, enlarging the available pool of HTR potency data to 41 total compounds. For agents where human data are available (n = 36), a strong positive correlation (r = 0.9448) was found between HTR potencies in mice and reported hallucinogenic potencies in humans. HTR potencies were also found to be correlated with published drug discrimination ED50 values for substitution in rats trained with either LSD (r = 0.9484, n = 16) or 2,5-dimethoxy-4-methylamphetamine (r = 0.9564, n = 21). All three of these behavioral effects (HTR in mice, hallucinogen discriminative stimulus effects in rats, and psychedelic effects in humans) have been linked to 5-HT2A receptor activation. We present evidence that hallucinogens induce these three effects with remarkably consistent potencies. In addition to having high construct validity, the HTR assay also appears to show significant predictive validity, confirming its translational relevance for predicting subjective potency of hallucinogens in humans. These findings support the use of the HTR paradigm as a preclinical model of hallucinogen psychopharmacology and in structure-activity relationship studies of hallucinogens. Future investigations with a larger number of test agents will evaluate whether the HTR assay can be used to predict the hallucinogenic potency of 5-HT2A agonists in humans. "This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.

Pharmacological and biotransformation studies of 1-acyl-substituted derivatives of d-lysergic acid diethylamide (LSD).

The ergoline d-lysergic acid diethylamide (LSD) is one of the most potent psychedelic drugs. 1-Acetyl-LSD (ALD-52), a derivative of LSD containing an acetyl group on the indole nitrogen, also produces psychedelic effects in humans and has about the same potency as LSD. Recently, several other 1-acyl-substitued LSD derivatives, including 1-propanoyl-LSD (1P-LSD) and 1-butanoyl-LSD (1B-LSD), have appeared as designer drugs. Although these compounds are assumed to act as prodrugs for LSD, studies have not specifically tested this prediction. The present investigation was conducted to address the gap of information about the pharmacological effects and mechanism-of-action of 1-acyl-substituted LSD derivatives. Competitive binding studies and calcium mobilization assays were performed to assess the interaction of ALD-52, 1P-LSD, and 1B-LSD with serotonin 5-HT2 receptor subtypes. A receptorome screening was performed with 1B-LSD to assess its binding to other potential targets. Head twitch response (HTR) studies were performed in C57BL/6J mice to assess in vivo activation of 5-HT2A (the receptor thought to be primarily responsible for hallucinogenesis). Finally, liquid chromatography/ion-trap mass spectrometry (LC/MS) was used to quantify plasma levels of LSD in Sprague-Dawley rats treated with ALD-52 and 1P-LSD. 1-Acyl-substitution reduced the affinity of LSD for most monoamine receptors, including 5-HT2A sites, by one to two orders of magnitude. Although LSD acts as an agonist at 5-HT2 subtypes, ALD-52, 1P-LSD and 1B-LSD have weak efficacy or act as antagonists in Ca2+-mobilization assays. Despite the detrimental effect of 1-acyl substitution on 5-HT2A affinity and efficacy, 1-acyl-substitued LSD derivatives induce head twitches in mice with relatively high potency. High levels of LSD were detected in the plasma of rats after subcutaneous administration of ALD-52 and 1P-LSD, demonstrating these compounds are rapidly and efficiently deacylated in vivo. These findings are consistent with the prediction that ALD-52, 1P-LSD and 1B-LSD serve as prodrugs for LSD. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.

Pharmacological characterizations of the 'legal high' fluorolintane and isomers.

1,2-Diarylethylamines represent a class of molecules that have shown potential in the treatment of pain, epilepsy, neurodegenerative disease and depression. Examples include lefetamine, remacemide, and lanicemine. Recently, several 1,2-diarylethylamines including the dissociatives diphenidine, methoxphenidine and ephenidine as well as the opioid MT-45, have appeared as 'research chemicals' or 'legal highs'. Due to their recent emergence little is known about their pharmacology. One of these, 1-[1-(2-fluorophenyl)-2-phenylethyl]pyrrolidine (fluorolintane, 2-F-DPPy), is available for purchase with purported dissociative effects intended to resemble phencyclidine (PCP) and ketamine. To better understand this emerging class, pharmacological investigations were undertaken for the first time on fluorolintane and its five aryl-fluorine-substituted isomers. In vitro binding studies revealed high affinity for N-methyl-D-aspartate (NMDA) receptors with fluorolintane (Ki = 87.92 nM) with lesser affinities for related compounds. Additional affinities were seen for all compounds at several sites including norepinephrine (NET), serotonin (SERT) and dopamine (DAT) transporters, and sigma receptors. Notably high affinities at DAT were observed, which were in most cases greater than NMDA receptor affinities. Additional functional and behavioral experiments show fluorolintane inhibited NMDA receptor-induced field excitatory postsynaptic potentials in rat hippocampal slices and inhibited long-term potentiation induced by theta-burst stimulation in rat hippocampal slices with potencies consistent with its NMDA receptor antagonism. Finally fluorolintane inhibited prepulse inhibition in rats, a measure of sensorimotor gating, with a median effective dose (ED50) of 13.3 mg/kg. These findings are consistent with anecdotal reports of dissociative effects of fluorolintane in humans.

Comparison of the behavioral effects of mescaline analogs using the head twitch response in mice.

BACKGROUND: In recent years, there has been increasing scientific interest in the effects and pharmacology of serotonergic hallucinogens. While a large amount of experimental work has been conducted to characterize the behavioral response to hallucinogens in rodents, there has been little systematic investigation of mescaline and its analogs. The hallucinogenic potency of mescaline is increased by α-methylation and by homologation of the 4-methoxy group but it not clear whether these structural modifications have similar effects on the activity of mescaline in rodent models. METHODS: In the present study, the head twitch response (HTR), a 5-HT2A receptor-mediated behavior induced by serotonergic hallucinogens, was used to assess the effects of mescaline and several analogs in C57BL/6J mice. HTR experiments were conducted with mescaline, escaline (4-ethoxy-3,5-dimethoxyphenylethylamine) and proscaline (3,5-dimethoxy-4-propoxyphenylethylamine), their α-methyl homologs TMA (3,4,5-trimethoxyamphetamine), 3C-E (4-ethoxy-3,5-dimethoxyamphetamine) and 3C-P (3,5-dimethoxy-4-propoxyamphetamine), and the 2,4,5-substituted regioisomers TMA-2 (2,4,5-trimethoxyamphetamine), MEM (4-ethoxy-2,5-dimethoxyamphetamine) and MPM (2,5-dimethoxy-4-propoxyamphetamine). RESULTS: TMA induced the HTR and was twice as potent as mescaline. For both mescaline and TMA, replacing the 4-methoxy substituent with an ethoxy or propoxy group increased potency in the HTR assay. By contrast, although TMA-2 also induced the HTR with twice the potency of mescaline, potency was not altered by homologation of the 4-alkoxy group in TMA-2. CONCLUSIONS: The potency relationships for these compounds in mice closely parallel the human hallucinogenic data. These findings are consistent with evidence that 2,4,5- and 3,4,5-substituted phenylalkylamine hallucinogens exhibit distinct structure-activity relationships. These results provide additional evidence that the HTR assay can be used to investigate the structure-activity relationships of serotonergic hallucinogens.

Pharmacological characterization of the LSD analog N-ethyl-N-cyclopropyl lysergamide (ECPLA).

RATIONALE: The lysergamide lysergic acid diethylamide (LSD) is a prototypical classical hallucinogen with remarkably high potency. LSD remains a popular recreational drug but is also becoming an important research tool for medical and neuroscience studies. Recently, several lysergamides that are close structural analogs of LSD have been sold as recreational drugs, which suggests that further studies are needed to explore the pharmacological properties of these compounds. OBJECTIVE: In this present investigation, another LSD congener, N-ethyl-N-cyclopropyl lysergamide (ECPLA), which to date has not been marketed as a recreational substance, was evaluated for its pharmacological features relative to those previously reported for LSD. The experiments focused on interactions with the 5-HT2A receptor, which is responsible for mediating the psychedelic effects of LSD and other hallucinogens. METHODS: Competitive binding assays were performed to measure the affinity of ECPLA for 27 monoamine receptors. The ability of ECPLA to activate human 5-HT2 receptor subtypes was assessed using calcium mobilization assays. Head twitch response (HTR) studies were conducted in C57BL/6J mice to determine whether ECPLA activates 5-HT2A receptors in vivo. Two other N-alkyl substituted lysergamides, N-methyl-N-isopropyl lysergamide (MIPLA) and N-methyl-N-propyl lysergamide (LAMPA), were also tested in the HTR paradigm for comparative purposes. RESULTS: ECPLA has high affinity for most serotonin receptors, α2-adrenoceptors, and D2-like dopamine receptors. Additionally, ECPLA was found to be a potent, highly efficacious 5-HT2A agonist for Gq-mediated calcium flux. Treatment with ECPLA induced head twitches in mice with a median effective dose (ED50) of 317.2 nmol/kg (IP), which is ~ 40% of the potency observed previously for LSD. LAMPA (ED50 = 358.3 nmol/kg) was virtually equipotent with ECPLA in the HTR paradigm whereas MIPLA (ED50 = 421.7 nmol/kg) was slightly less potent than ECPLA. CONCLUSIONS: These findings demonstrate that the pharmacological properties of ECPLA, MIPLA, and LAMPA are reminiscent of LSD and other lysergamide hallucinogens.

Comparison of the behavioral responses induced by phenylalkylamine hallucinogens and their tetrahydrobenzodifuran ("FLY") and benzodifuran ("DragonFLY") analogs.

In recent years, rigid analogs of phenylalkylamine hallucinogens have appeared as recreational drugs. Examples include 2-(8-bromo-2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b']difuran-4-yl)ethan-1-amine (2C-B-FLY) and 1-(8-bromobenzo[1,2-b;4,5-b']difuran-4-yl)-2-aminopropane (Bromo-DragonFLY, DOB-DFLY). Although some rigid compounds such as DOB-DFLY reportedly have higher potency than their non-rigid counterparts, it is not clear whether the same is true for 2C-B-FLY and other tetrahydrobenzodifurans. In the present study, the head twitch response (HTR), a 5-HT2A receptor-mediated behavior induced by serotonergic hallucinogens, was used to assess the effects of 2,5-dimethoxy-4-bromoamphetamine (DOB) and its α-desmethyl homologue 2,5-dimethoxy-4-bromophenethylamine (2C-B), as well as their benzodifuranyl and tetrahydrobenzodifuranyl analogs, in C57BL/6J mice. DOB (ED50 = 0.75 µmol/kg) and 2C-B (ED50 = 2.43 µmol/kg) induced the HTR. The benzodifurans DOB-DFLY (ED50 = 0.20 µmol/kg) and 2C-B-DFLY (ED50 = 1.07 µmol/kg) had significantly higher potency than DOB and 2C-B, respectively. The tetrahydrobenzodifurans DOB-FLY (ED50 = 0.67 µmol/kg) and 2C-B-FLY (ED50 = 1.79 µmol/kg), by contrast, were approximately equipotent with their non-rigid counterparts. Three novel tetrahydrobenzodifurans (2C-I-FLY, 2C-E-FLY and 2C-EF-FLY) were also active in the HTR assay but had relatively low potency. In summary, the in vivo potency of 2,5-dimethoxyphenylalkylamines is enhanced when the 2- and 5-methoxy groups are incorporated into aromatic furan rings, whereas potency is not altered if the methoxy groups are incorporated into dihydrofuran rings. The potency relationships for these compounds in mice closely parallel the human hallucinogenic data. The high potency of DOB-DFLY is probably linked to the presence of two structural features (a benzodifuran nucleus and an α-methyl group) known to enhance the potency of phenylalkylamine hallucinogens.

Correction to: Pharmacological characterization of the LSD analog N-ethyl-N-cyclopropyl lysergamide (ECPLA).

The author of this article wanted to change the Acknowledgments section to: These studies were supported by an award from NIDA (R01 DA041336), as well as by the Veteran's Administration VISN 22 Mental Illness Research, Education, and Clinical Center. Receptor binding and functional data were generously.

Chronic treatment with a metabotropic mGlu2/3 receptor agonist diminishes behavioral response to a phenethylamine hallucinogen.

BACKGROUND: There is evidence that mGlu2/3 receptors regulate 5-HT2A signaling, interactions that have been theorized to play a role in the antipsychotic-like effects of mGlu2/3 agonists as well as the hallucinogenic effects of 5-HT2A agonists. One approach to unraveling this interaction is through the chronic administration of agonists at the two receptors, which should influence the functional properties of the targeted receptor due to receptor downregulation or desensitization and thereby alter crosstalk between the two receptors. In this study, we investigated whether chronic treatment with the mGlu2/3 agonist LY379268 would alter the behavioral response to a phenethylamine hallucinogen, 25CN-NBOH, which acts as a selective 5-HT2A agonist. METHODS: We first conducted a dose response of 25CN-NBOH (0.1, 0.3, 1, 3, or 10 mg/kg) to confirm the effects on head-twitch response (HTR) and then blockade studies with either the M100907 (0.1 mg/kg) or SB242084 (0.1, 0.3, or 1 mg/kg) to determine the contribution of 5-HT2A and 5-HT2C to 25CN-NBOH-induced HTR, respectively. To determine whether an mGlu2/3 agonist could block 25CN-NBOH-induced HTR, mice were pretreated with vehicle or LY379268 (0.1, 1, or 10 mg/kg) prior to 25CN-NBOH, and HTR was assessed. The effects of chronic LY379268 on 5-HT2A agonist-induced HTR were evaluated by treating mice with either vehicle or LY379268 (10 mg/kg) for 21 days and measuring 25CN-NBOH-induced HTR 48 h after the final LY379268 treatment. The following day (72 h after the final LY379268 treatment), the ability of acute LY379268 to block PCP-induced locomotor activity was assessed. RESULTS: 25CN-NBOH dose-dependently increased the HTR, a 5-HT2A-mediated behavior, in mice. The selective 5-HT2A antagonist M100907 completely blocked the HTR induced by 25CN-NBOH, whereas the selective 5-HT2C antagonist SB242084 had no effect on the HTR. Administration of LY379268 (10 mg/kg SC) attenuated the HTR induced by 1 mg/kg 25CN-NBOH by ~ 50%. Chronic treatment (21 days) with LY379268 also attenuated the HTR response to 25CN-NBOH when tested 48 h after the last dose of LY379268. In locomotor tests, acute LY379268 significantly attenuated PCP-induced locomotor activity in the chronic vehicle treatment group; by contrast, there was only a trend for an overall interaction in the chronic LY379268 group, with LY379268 blocking the locomotor-stimulating effects of PCP only during the last 20 min. CONCLUSIONS: These data are consistent with a functional interaction between mGlu2/3 and 5-HT2A receptors, although the specific mechanism for the interaction is not known. These data support the hypothesis that mGlu2/3 receptors play a prominent role in modulating the behavioral response to 5-HT2A receptor activation.

HIV prevalence in blood donors and recipients in Pakistan: a meta-analysis and analysis of blood-bank data.

BACKGROUND: The first instances of HIV-antibody detection in donated blood in Pakistan were reported in 1988. Since then, documentation of HIV in blood donors and of rates of transmission via transfusion has been limited. Previously assumed to have a low prevalence, HIV is an increasing health concern in Pakistan. Since there is no national, centralized blood-banking system, there are no reliable data on which to base estimated risks of transfusion-associated HIV infection. This study was therefore conducted to estimate the prevalence of HIV in blood donors and recipients in Pakistan between 1988 and 2012. METHODS: Meta-analyses were undertaken of reported prevalences of HIV in blood donors and recipients published during 1988-2012. Papers were identified by searching PubMed, Google, CINAHL and PakMediNet and the websites of the World Health Organization, the national HIV/AIDS Surveillance Project and the National AIDS Control Programme of Pakistan. In addition, the 1998-2012 records of the Aga Khan University blood bank were analysed. RESULTS: The 254 abstracts identified at the preliminary search were reviewed and, after removal of duplications, case-reports, editorials and reviews, 32 papers were selected that met the inclusion criteria. All studies that reported on HIV antibodies in blood donors/recipients were included, irrespective of the methodology used. Since seroconversion had only been confirmed through supplemental testing in a few papers, the results were analysed separately for reports based on screening only and confirmed cases. A total of 142 of 2 023 379 blood donors and 4 of 3632 blood recipients were HIV positive, giving an overall pooled seroprevalence of 0.00111% in blood donors and 0.00325% in blood recipients. The annual prevalences of HIV in donors at the Aga Khan University blood banks were similar, ranging from 0.013% to 0.116%. CONCLUSION: Very few reports on HIV in blood donors in Pakistan could be retrieved, and the overall pooled prevalence is low. However, the limited data and confounding factors mean that that these results may significantly underestimate the true situation. It is recommended that a complete survey of blood banks should be conducted throughout the country, in order to provide a more reliable estimate of the risk of transfusion-associated HIV infection in Pakistan.