Cocaine-like discriminative stimulus effects of alpha-pyrrolidinovalerophenone, methcathinone and their 3,4-methylenedioxy or 4-methyl analogs in rhesus monkeys.

Synthetic cathinones are beta-ketone amphetamine analogs that have emerged as a heterogeneous class of abused compounds that function as either monoamine transporter substrates or inhibitors. Pre-clinical drug discrimination procedures are useful for interrogating structure-activity relationships of abuse-related drug effects; however, in vivo structure-activity relationship comparisons between synthetic cathinones with different mechanisms of action are lacking. The aim of the present study was to determine whether the cocaine-like discriminative stimulus effects of the monoamine transporter inhibitor alpha-pyrrolidinovalerophenone (alpha-PVP) and the monoamine transporter substrate methcathinone were differentially sensitive to 3,4-methylenedioxy and 4-methyl substitutions. Male rhesus monkeys (n = 4) were trained to discriminate intramuscular cocaine (0.32 mg/kg) from saline in a two-key food-reinforced discrimination procedure. Potency and timecourse of cocaine-like discriminative stimulus effects were determined for (±)-alpha-PVP, (±)-methcathinone and their 3,4-methylenedioxy or 4-methyl analogs. Alpha-PVP and methcathinone produced dose- and time-dependent cocaine-like effects. A 3,4-methylenedioxy addition to either alpha-PVP or methcathinone (methylone) did not alter the potency or efficacy to produce cocaine-like effects, but did prolong the time course. A 4-methyl addition to alpha-PVP (pyrovalerone) did not alter the potency or efficacy to produce cocaine-like effects, but did prolong the time course. In contrast, addition of a 4-methyl moiety to methcathinone (4MMC; mephedrone) significantly attenuated efficacy to produce cocaine-like effects. Overall, these results suggest different structural requirements for cocaine-like discriminative stimulus effects of monoamine transporter inhibitor and substrate synthetic cathinone analogs. Given that 4MMC is more hydrophobic than MDMC, these results suggest that hydrophobicity may be an important determinant for limiting monoamine transporter substrate abuse-related behavioral effects.

Methamphetamine-like discriminative stimulus effects of bupropion and its two hydroxy metabolites in male rhesus monkeys.

The dopamine transporter (DAT) inhibitor and nicotinic acetylcholine (nACh) receptor antagonist bupropion is being investigated as a candidate 'agonist' medication for methamphetamine addiction. In addition to its complex pharmacology, bupropion also has two distinct pharmacologically active metabolites. However, the mechanism by which bupropion produces methamphetamine-like 'agonist' effects remains unknown. The aim of the present study was to determine the role of DAT inhibition, nACh receptor antagonism, and the hydroxybupropion metabolites in the methamphetamine-like discriminative stimulus effects of bupropion in rhesus monkeys. In addition, varenicline, a partial agonist at the nACh receptor, and risperidone, a dopamine antagonist, were tested as controls. Monkeys (n=4) were trained to discriminate 0.18 mg/kg intramuscular methamphetamine from saline in a two-key food-reinforced discrimination procedure. The potency and time course of methamphetamine-like discriminative stimulus effects were determined for all compounds. Bupropion, methylphenidate, and 2S,3S-hydroxybupropion produced full, at least 90%, methamphetamine-like effects. 2R,3R-Hydroxybupropion, mecamylamine, and nicotine also produced full methamphetamine-like effects, but drug potency was more variable between monkeys. Varenicline produced partial methamphetamine-like effects, whereas risperidone did not. Overall, these results suggest DAT inhibition as the major mechanism of the methamphetamine-like 'agonist' effects of bupropion, although nACh receptor antagonism appeared, at least partially, to contribute. Furthermore, the contribution of the 2S,3S-hydroxybupropion metabolite could not be completely ruled out.

Tolerance and cross-tolerance to head twitch behavior elicited by phenethylamine- and tryptamine-derived hallucinogens in mice.

The serotonin 5-hydroxytryptamine 2A (5-HT2A) receptor is a potential therapeutic target to a host of neuropsychiatric conditions, but agonist actions at this site are linked to abuse-related hallucinogenic effects that may limit therapeutic efficacy of chronic drug administration. Tolerance to some effects of hallucinogens has been observed in humans and laboratory animals, but the understanding of tolerance and cross-tolerance between distinct structural classes of hallucinogens is limited. Here, we used the drug-elicited head twitch response (HTR) in mice to assess the development of tolerance and cross-tolerance with two phenethylamine-derived [DOI (2,5-dimethoxy-4-iodoamphetamine) and 2C-T-7 (2,5-dimethoxy-4-propylthiophenethylamine)] and two tryptamine-derived [DPT (N,N-dipropyltryptamine) and DIPT (N,N-diisopropyltryptamine)] drugs with agonist affinity for 5-HT2A receptors. Tolerance developed to HTR elicited by daily DOI or 2C-T-7, but not to HTR elicited by DPT or DIPT. DOI-elicited tolerance was not surmountable with dose, and a similar insurmountable cross-tolerance was evident when DOI-tolerant mice were tested with various doses of 2C-T-7 or DPT. These studies suggest that the use of phenethylamine-derived hallucinogens as therapeutic agents may be limited not only by their abuse potential, but also by the rapid development of tolerance that would likely be maintained even if a patient were switched to a different 5-HT2A agonist medication from a distinct structural class. However, these experiments also imply that tryptamine-derived hallucinogens might have a reduced potential for tolerance development, compared with phenethylamine-derived 5-HT2A agonists, and might therefore be more suitable for chronic administration in a therapeutic context.

Increased Risk of Cryptogenic Stroke Associated with Patent Foramen Ovale in Young Adults.

Ischemic stroke is defined as a reduction in blood flow to brain tissue that results in the deterioration and death of neurons in a matter of minutes. While often seen in older patients with a history of atherosclerosis of the major arteries, a subset of ischemic strokes occur in younger individuals with minimal to no prior risk factors. Further evaluation of these unknown, or cryptogenic, strokes has yielded positive findings of a patent foramen ovale (PFO) in a concerning number of cases. Cryptogenic strokes attributable to PFO present an important clinical occurrence because they do not fit the typical template regarding those most at risk for such acutely devastating outcomes, making their identification uniquely important for both immediate and long-term patient care.  A 20-year-old Hispanic female presented to the emergency department for evaluation of neurological symptoms indicating obstruction of a major cerebral vessel. After being placed on stroke alert and found to have an embolus occluding the left middle cerebral artery (MCA) via non-contrast computed tomography (CT), tissue plasminogen activator (tPA) was administered, and mechanical thrombectomy was performed to restore blood flow. Following stabilization, further testing done on the patient revealed a substantial PFO that likely allowed for the crossing of an embolus from venous blood returning to the heart directly into the arterial circulation. The patient opted for cardiac monitor placement and has remained asymptomatic to this point while awaiting surgical repair. This case demonstrates an unusual presentation of ischemic stroke in a young individual with no reported risk factors and highlights the importance of screening for large PFO in patients prior to a serious cerebrovascular accident. It is our hope that highlighting this case may heighten awareness of this condition and allow for timely recognition from medical personnel who may encounter this same medical emergency in the future.

Advanced Filtration Membranes for the Removal of Perfluoroalkyl Species from Water.

Perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) are two perfluoroalkyl substances that have been shown to result in several adverse health effects, including birth defects, kidney/testicular cancer, as well as liver and thyroid damage. The surfactant nature of PFOS and PFOA in water makes these compounds extremely difficult to remove from drinking water. In this paper, an efficient method to remove PFOS and PFOA from drinking water using linear fluorinated silane-functionalized aluminum oxide hydroxide (γ-AlOOH) nanowhiskers was developed. Filters functionalized with linear fluorinated silanes containing 13-17 fluorine atoms were able to remove >90% of the PFOS/PFOA at a very high flux of 1223 L/m2·h. However, due to the hydrophobicity of these linear fluorinated silanes, high pressure drop was also noted across the membrane thickness during the filtration process. To reduce the back-pressure drop, linear fluorinated silanes with appended hydrophilic poly(ethylene glycol) units were synthesized, and it was further demonstrated that the new hydrophilic linear fluorinated silane dramatically reduced the pressure drop of the γ-AlOOH filter while maintaining 99.9% PFOS and PFOA reduction. Adsorption tests were performed to understand the removal mechanism.

Vortioxetine Differentially Modulates MK-801-Induced Changes in Visual Signal Detection Task Performance and Locomotor Activity.

Attention impairment is a common feature of Major Depressive Disorder (MDD), and MDD-associated cognitive dysfunction may play an important role in determining functional status among this patient population. Vortioxetine is a multimodal antidepressant that may improve some aspects of cognitive function in MDD patients, and may indirectly increase glutamate neurotransmission in brain regions classically associated with attention function. Previous non-clinical research suggests that vortioxetine has limited effects on attention. This laboratory previously found that vortioxetine did not improve attention function in animals impaired by acute scopolamine administration, using the visual signal detection task (VSDT). However, vortioxetine has limited effects on acetylcholinergic neurotransmission, and thus it is possible that attention impaired by other mechanisms would be attenuated by vortioxetine. This study sought to investigate whether acute vortioxetine administration can attenuate VSDT impairments and hyperlocomotion induced by the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801. We found that acute vortioxetine administration had no effect on VSDT performance on its own, but potentiated MK-801-induced VSDT impairments. Furthermore, vortioxetine had no effect on locomotor activity on its own, and did not alter MK-801-induced hyperlocomotion. We further investigated whether vortioxetine's effect on MK-801 could be driven by a kinetic interaction, but found that plasma and brain exposure for vortioxetine and MK-801 were similar whether administered alone or in combination. Thus, it appears that vortioxetine selectively potentiates MK-801-induced impairments in attention without altering its effects on locomotion, and further that this interaction must be pharmacodynamic in nature. A theoretical mechanism for this interaction is discussed.

Cocaine-like discriminative stimulus effects of amphetamine, cathinone, methamphetamine, and their 3,4-methylenedioxy analogs in male rhesus monkeys.

RATIONALE: Synthetic cathinones have emerged as the newest class of abused monoamine transporter substrates. Structurally, these compounds are all beta-ketone amphetamine (cathinone) analogs. Whether synthetic cathinone analogs produce differential behavioral effects from their amphetamine analog counterparts has not been systematically examined. Preclinical drug discrimination procedures have been useful for determining the structure activity relationships (SARs) of abused drugs; however, direct comparisons between amphetamine and cathinone analogs are lacking and, in particular, in non-human primate models. OBJECTIVES: The study aim was to determine the potency and time course of (±)-amphetamine, (±)-cathinone, and (±)-methamphetamine and their 3,4-methylenedioxy analogs (±)-MDA, (±)-MDC, and (±)-MDMA, respectively, to produce cocaine-like discriminative stimulus effects. If cathinone analogs have similar behavioral pharmacological properties to their amphetamine counterparts, then we would predict similar potencies and efficacies to produce cocaine-like discriminative stimulus effects. METHODS: Male rhesus monkeys (n = 4) were trained to discriminate intramuscular cocaine (0.32 mg/kg) from saline in a two-key food-reinforced discrimination procedure. RESULTS: Racemic amphetamine, cathinone, and methamphetamine produced dose-dependent and full substitution, ≥90 % cocaine-appropriate responding, in all monkeys. Addition of 3,4-methylenedioxy moiety attenuated both the potency and efficacy of amphetamine (MDA), cathinone (MDC), and methamphetamine (MDMA) to produce full cocaine-like effects. Moreover, the cocaine-like effects of amphetamine and cathinone were attenuated to a greater extent than those of methamphetamine or previously published methcathinone (Smith et al. 2016). CONCLUSION: The presence of an N-methyl group blunted both the potency and the efficacy shift of the 3,4-methylenedioxy addition for both amphetamine and cathinone analogs.

Relationship between discriminative stimulus effects and plasma methamphetamine and amphetamine levels of intramuscular methamphetamine in male rhesus monkeys.

Methamphetamine is a globally abused drug that is metabolized to amphetamine, which also produces abuse-related behavioral effects. However, the contributing role of methamphetamine metabolism to amphetamine in methamphetamine's abuse-related subjective effects is unknown. This preclinical study was designed to determine 1) the relationship between plasma methamphetamine levels and methamphetamine discriminative stimulus effects and 2) the contribution of the methamphetamine metabolite amphetamine in the discriminative stimulus effects of methamphetamine in rhesus monkeys. Adult male rhesus monkeys (n=3) were trained to discriminate 0.18mg/kg intramuscular (+)-methamphetamine from saline in a two-key food-reinforced discrimination procedure. Time course of saline, (+)-methamphetamine (0.032-0.32mg/kg), and (+)-amphetamine (0.032-0.32mg/kg) discriminative stimulus effects were determined. Parallel pharmacokinetic studies were conducted in the same monkeys to determine plasma methamphetamine and amphetamine levels after methamphetamine administration and amphetamine levels after amphetamine administration for correlation with behavior in the discrimination procedure. Both methamphetamine and amphetamine produced full, ≥90%, methamphetamine-like discriminative stimulus effects. Amphetamine displayed a slightly, but significantly, longer duration of action than methamphetamine in the discrimination procedure. Both methamphetamine and amphetamine behavioral effects were related to methamphetamine and amphetamine plasma levels by a clockwise hysteresis loop indicating acute tolerance had developed to the discriminative stimulus effects. Furthermore, amphetamine levels after methamphetamine administration were absent when methamphetamine stimulus effects were greatest and peaked when methamphetamine discriminative stimulus effects returned to saline-like levels. Overall, these results demonstrate the methamphetamine metabolite amphetamine does not contribute to methamphetamine's abuse-related subjective effects.

Hallucinogen-like effects of 2-([2-(4-cyano-2,5-dimethoxyphenyl) ethylamino]methyl)phenol (25CN-NBOH), a novel N-benzylphenethylamine with 100-fold selectivity for 5-HT2A receptors, in mice.

RATIONALE: 2-([2-(4-cyano-2,5-dimethoxyphenyl)ethylamino]methyl)phenol (25CN-NBOH) is structurally similar to N-benzyl substituted phenethylamine hallucinogens currently emerging as drugs of abuse. 25CN-NBOH exhibits dramatic selectivity for 5-HT2A receptors in vitro, but has not been behaviorally characterized. OBJECTIVE: 25CN-NBOH was compared to the traditional phenethylamine hallucinogen R(-)-2,5-dimethoxy-4-iodoamphetamine (DOI) using mouse models of drug-elicited head twitch behavior and drug discrimination. METHODS: Drug-elicited head twitches were quantified for 10 min following administration of various doses of either DOI or 25CN-NBOH, with and without pretreatments of 0.01 mg/kg 5-HT2A antagonist M100907 or 3.0 mg/kg 5-HT2C antagonist RS102221. The capacity of 25CN-NBOH to attenuate DOI-elicited head twitch was also investigated. Mice were trained to discriminate DOI or M100907 from saline, and 25CN-NBOH was tested for generalization. RESULTS: 25CN-NBOH induced a head twitch response in the mouse that was lower in magnitude than that of DOI, blocked by M100907, but not altered by RS102221. DOI-elicited head twitch was dose-dependently attenuated by 25CN-NBOH pretreatment. 25CN-NBOH produced an intermediate degree of generalization (55 %) for the DOI training dose, and these interoceptive effects were attenuated by M100907. Finally, 25CN-NBOH did not generalize to M100907 at any dose, but ketanserin fully substituted in these animals. CONCLUSIONS: 25CN-NBOH was behaviorally active, but less effective than DOI in two mouse models of hallucinogenic effects. The effectiveness with which M100907 antagonized the behavioral actions of 25CN-NBOH strongly suggests that the 5-HT2A receptor is an important site of agonist action for this compound in vivo.

Treatment of the psychotic patient who is violent.

Aggression among patients with serious mental illness occurs relatively infrequently, but it is a significant concern for patients, relatives, mental health professionals, and the public. Recognition of this risk and providing access and continuity of appropriate psychiatric care should be major clinical and administrative objectives in the management of violence in psychotic patients. To date, pharmacologic approaches have been unclear and inconsistent. At present, typical antipsychotics continue to have a primary role in acute management and in long-term management, in which noncompliance necessitates the use of long-acting depot neuroleptic preparations. Atypical antipsychotics in acute and long-acting intramuscular forms doubtless will influence and expand the choice for acute management of hostile psychotic patients and the long-term management of poorly compliant patients who are at risk to become violent on relapse. Persistent aggression should be managed by atypical antipsychotics with a preferential indication for clozapine, for which the most data on efficacy are available. The role of adjunctive medications is presently unclear. A major focus of care should be to refine legal processes and to conduct intervention studies aimed at enhancing treatment compliance. Violence risk reduction is not only crucial from a societal perspective, but also it is a humanitarian necessity to alleviate the burden and stigma for patients with serious mental illness.

Insight into illness and attitudes toward medications among inpatients with schizophrenia.

This study assessed symptoms, severity of illness functional level, insight into illness, and attitudes toward medication in a sample of psychiatric patients who were newly admitted to a state hospital. The patients were evaluated before and after treatment with atypical, conventional, or mixed (atypical plus conventional) antipsychotic medication regimens with the Brief Psychiatric Rating Scale (BPRS), the Clinical Global Impression, the Global Assessment of Functioning, the Scale to Assess Unawareness of Mental Disorder, and the Drug Attitude Inventory. Overall, the patients showed significant improvement in symptoms, severity of illness, functional level, and insight into their illness during the course of hospitalization. Their attitudes toward medications changed minimally during treatment. Only the patients who were treated with conventional antipsychotics showed significant improvement in their attitudes toward medication. However, the change was not large enough to differentiate the conventional antipsychotic treatment group from the other treatment groups.

The prevalence of chest compression leaning during in-hospital cardiopulmonary resuscitation.

OBJECTIVE: Successful resuscitation from cardiac arrest requires the delivery of high-quality chest compressions, encompassing parameters such as adequate rate, depth, and full recoil between compressions. The lack of compression recoil ("leaning" or "incomplete recoil") has been shown to adversely affect hemodynamics in experimental arrest models, but the prevalence of leaning during actual resuscitation is poorly understood. We hypothesized that leaning varies across resuscitation events, possibly due to rescuer and/or patient characteristics and may worsen over time from rescuer fatigue during continuous chest compressions. METHODS: This was an observational clinical cohort study at one academic medical center. Data were collected from adult in-hospital and Emergency Department arrest events using monitor/defibrillators that record chest compression characteristics and provide real-time feedback. RESULTS: We analyzed 112,569 chest compressions from 108 arrest episodes from 5/2007 to 2/2009. Leaning was present in 98/108 (91%) cases; 12% of all compressions exhibited leaning. Leaning varied widely across cases: 41/108 (38%) of arrest episodes exhibited <5% leaning yet 20/108 (19%) demonstrated >20% compression leaning. When evaluating blocks of continuous compressions (>120 s), only 4/33 (12%) had an increase in leaning over time and 29/33 (88%) showed a decrease (p<0.001). CONCLUSIONS: Chest compression leaning was common during resuscitation care and exhibited a wide distribution, with most leaning within a subset of resuscitations. Leaning decreased over time during continuous chest compression blocks, suggesting that either leaning may not be a function of rescuer fatiguing, or that it may have been mitigated by automated feedback provided during resuscitation episodes.

Pharmacotherapy of delusional disorders in the context of offending and the potential for compulsory treatment.

Delusional disorder is an uncommon mental illness with an estimated prevalence of 0.03%. Its low prevalence has likely contributed to the paucity of research interest in this area, leading to substantial gaps in knowledge concerning its treatment and management. In the absence of a robust literature, most clinicians rely on their experience and guidelines for treating schizophrenia when treating patients with delusional disorder. This article reviews the available literature that is specific to the treatment of delusional disorder. In addition, it focuses on specific forensic and medicolegal aspects of managing patients with delusional disorder.