The impact of spike timing precision and spike emission reliability on decoding accuracy.

Precisely timed and reliably emitted spikes are hypothesized to serve multiple functions, including improving the accuracy and reproducibility of encoding stimuli, memories, or behaviours across trials. When these spikes occur as a repeating sequence, they can be used to encode and decode a potential time series. Here, we show both analytically and in simulations that the error incurred in approximating a time series with precisely timed and reliably emitted spikes decreases linearly with the number of neurons or spikes used in the decoding. This was verified numerically with synthetically generated patterns of spikes. Further, we found that if spikes were imprecise in their timing, or unreliable in their emission, the error incurred in decoding with these spikes would be sub-linear. However, if the spike precision or spike reliability increased with network size, the error incurred in decoding a time-series with sequences of spikes would maintain a linear decrease with network size. The spike precision had to increase linearly with network size, while the probability of spike failure had to decrease with the square-root of the network size. Finally, we identified a candidate circuit to test this scaling relationship: the repeating sequences of spikes with sub-millisecond precision in area HVC (proper name) of the zebra finch. This scaling relationship can be tested using both neural data and song-spectrogram-based recordings while taking advantage of the natural fluctuation in HVC network size due to neurogenesis.

Kainate receptor channel opening and gating mechanism.

Kainate receptors, a subclass of ionotropic glutamate receptors, are tetrameric ligand-gated ion channels that mediate excitatory neurotransmission1-4. Kainate receptors modulate neuronal circuits and synaptic plasticity during the development and function of the central nervous system and are implicated in various neurological and psychiatric diseases, including epilepsy, depression, schizophrenia, anxiety and autism5-11. Although structures of kainate receptor domains and subunit assemblies are available12-18, the mechanism of kainate receptor gating remains poorly understood. Here we present cryo-electron microscopy structures of the kainate receptor GluK2 in the presence of the agonist glutamate and the positive allosteric modulators lectin concanavalin A and BPAM344. Concanavalin A and BPAM344 inhibit kainate receptor desensitization and prolong activation by acting as a spacer between the amino-terminal and ligand-binding domains and a stabilizer of the ligand-binding domain dimer interface, respectively. Channel opening involves the kinking of all four pore-forming M3 helices. Our structures reveal the molecular basis of kainate receptor gating, which could guide the development of drugs for treatment of neurological disorders.

Management of Hyperhemolysis in ß-thalassemia With Multiple Immunosuppressives, Including Complement Blockade.

Hyperhemolysis is a life-threatening condition of exaggerated hemolysis of red blood cells which occurs in patients receiving chronic transfusion therapy. We present a 19-year-old male with the ß-thalassemia major with an episode of hyperhemolysis. Hemolysis was initially unresponsive to immunosuppression but responded after the addition of eculizumab. Several weeks after stabilization, hemolysis returned; which was also managed with immunosuppression and eculizumab. Hyperhemolysis presents significant challenges in ß-thalassemia due to the underlying dysfunctional erythropoiesis and transfusion dependence. Aggressive immunosuppression combined with eculizumab successfully slowed the hemolysis and allowed for the resumption of transfusions.

In Cocaine Dependence, Neural Prediction Errors During Loss Avoidance Are Increased With Cocaine Deprivation and Predict Drug Use.

BACKGROUND: In substance-dependent individuals, drug deprivation and drug use trigger divergent behavioral responses to environmental cues. These divergent responses are consonant with data showing that short- and long-term adaptations in dopamine signaling are similarly sensitive to state of drug use. The literature suggests a drug state-dependent role of learning in maintaining substance use; evidence linking dopamine to both reinforcement learning and addiction provides a framework to test this possibility. METHODS: In a randomized crossover design, 22 participants with current cocaine use disorder completed a probabilistic loss-learning task during functional magnetic resonance imaging while on and off cocaine (44 sessions). Another 54 participants without Axis I psychopathology served as a secondary reference group. Within-drug state and paired-subjects' learning effects were assessed with computational model-derived individual learning parameters. Model-based neuroimaging analyses evaluated effects of drug use state on neural learning signals. Relationships among model-derived behavioral learning rates (α+, α-), neural prediction error signals (δ+, δ-), cocaine use, and desire to use were assessed. RESULTS: During cocaine deprivation, cocaine-dependent individuals exhibited heightened positive learning rates (α+), heightened neural positive prediction error (δ+) responses, and heightened association of α+ with neural δ+ responses. The deprivation-enhanced neural learning signals were specific to successful loss avoidance, comparable to participants without psychiatric conditions, and mediated a relationship between chronicity of drug use and desire to use cocaine. CONCLUSIONS: Neurocomputational learning signals are sensitive to drug use status and suggest that heightened reinforcement by successful avoidance of negative outcomes may contribute to drug seeking during deprivation. More generally, attention to drug use state is important for delineating substrates of addiction.

Neutronic performance characteristics of different LEU fuels in a proposed NIST research reactor.

As a potential replacement for the National Bureau Standards Reactor (NBSR) at the U.S. National Institute of Standards and Technology (NIST), a conceptual design of a new reactor with a horizontally-split core has recently been studied using low-enriched uranium (LEU) silicide dispersion (U3Si2/Al) fuel. In this paper, the neutronics calculations of the proposed NIST reactor with other two low-enriched U-Mo fuels (U-10Mo monolithic fuel and U-7Mo/Al dispersion fuel) were performed, and the results were compared to that of the U3Si2/Al fuel, with the objective of identifying the best fuel candidate for the reactor cycle length and maximum cold neutron production. To make consistent comparisons, fuel inventories for multi-cycle equilibrium cores were produced for each fuel based on a 30 d reactor cycle at 20 MW thermal power. With its very high uranium density, the potential to load more uranium in the core with U-10Mo monolithic fuel was explored with test cases using an alternate fuel management scheme, a higher power level (30 MW), or a longer cycle (45 d). The research results indicate similar neutronics performance characteristics of the three LEU fuel options in the proposed NIST reactor with the same power level. However, the ability to load more fuel in the reactor with the U-10Mo option allows additional flexibility in the reactor design and could lead to other optimizations that maximize cold neutron production.

FAAH variant Pro129Thr modulates subjective effects produced by cocaine administration.

BACKGROUND AND OBJECTIVES: The endogenous cannabinoid anandamide (AEA), an agonist at type-1 cannabinoid (CB1) receptors, is metabolized by fatty acid amide hydrolase (FAAH). The common variant rs324420 C->A within the FAAH gene on chromosome 1 codes for a missense substitution (Pro129Thr), resulting in decreased FAAH activity and increased endocannabinoid potentiation. This FAAH variant has been linked to alterations in mood and stress reactivity, as well as being independently linked to increased risk for addiction. We hypothesized that cocaine use disordered (CUD) participants with the FAAH Pro129 Thr variant would exhibit a distinct profile of cocaine-induced subjective effects in the laboratory. METHODS: A total of 70 CUD participants received intravenous doses of saline (placebo, 0 mg) and cocaine (20, 40 mg) in a lab-controlled setting and rated 10 subjective effect measures prior to and following saline and cocaine administration, using a Visual Analog Scale (VAS). RESULTS: The variant allele was associated with increased cocaine-induced subjective ratings for "Drug Effect," "High," and "Depressed." The prevalence of the variant allele A and the AA genotypes were greater in our CUD group than in the general population (A allele: 47% vs. 34%; AA genotype: 30% vs. 13%; p < .05). Finally, the reported amount and frequency of tobacco and cocaine use was higher in subjects with the AC/AA allele. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: These results add to existing evidence that this variant of the FAAH genotype may be over-represented among those who have CUD, and this over-representation may result from greater subjective responses to cocaine administration. (Am J Addict 2018;27:567-573).

Comparison of three measurement models of discounting among individuals with methamphetamine use disorder.

BACKGROUND AND OBJECTIVES: Delay discounting is associated with numerous clinically significant aspects of substance use disorders (SUDs). Recent studies have demonstrated that different models for assessing discounting may result in disparate conclusions. The current study compared two discounting tasks: money now versus money later (M-M) and methamphetamine now versus money later (MA-M) among non-treatment seeking individuals (N = 59) with methamphetamine use disorder (MAUD). Results from each task were assessed using three different models for assessing delay discounting. METHODS: Discounting data were fit to three models of discounting, log k using Mazur's hyperbolic formula, area under the curve (AUC), and an alternative AUC model in which the delay values have been log transformed (AUClog). RESULTS: For both discounting tasks, the distribution of model-related outcomes were normally distributed when using log k and AUClog, but skewed for AUC. Discounting in the MA-M task was significantly greater compared to the M-M task when using log k and AUClog but not AUC. CONCLUSION: To our knowledge, the current study is the first to report significantly greater discounting in a MA-M relative to M-M discounting task among individuals with MAUD, an outcome consistent with other psychomotor stimulants and drugs of abuse. SCIENTIFIC SIGNIFICANCE: The differential results observed across the three discounting models reaffirm potential issues with AUC noted in recent studies and highlight that researchers must be cautious when deciding on their final model of discounting. (Am J Addict 2018;XX:1-8).

Exenatide once weekly for smoking cessation: study protocol for a randomized clinical trial.

BACKGROUND: Cigarette smoking is the greatest preventable cause of morbidity and premature mortality in the United States. Approved pharmacological treatments for smoking cessation are marginally effective, underscoring the need for improved pharmacotherapies. A novel approach might use glucagon-like peptide-1 (GLP-1) agonists, which reduce alcohol and drug use in preclinical studies. GLP-1 is produced in the intestinal L-cells and in the hindbrain. The peptide maintains glucose homeostasis and reduces food intake. Several GLP-1 agonists are used clinically to treat type 2 diabetes and obesity, but none have been tested in humans to reduce smoking. AIMS: We will examine whether extended-release exenatide reduces smoking, craving, and withdrawal symptoms, as well as cue-induced craving for cigarettes. METHODS: We will enroll prediabetic and/or overweight treatment seeking smokers (n = 90) into a double-blind, placebo-controlled, randomized clinical trial. Participants will be randomized in a 1:1 ratio to receive exenatide or placebo. All participants will receive transdermal nicotine replacement therapy (NRT) and behavioral counseling. Abstinence from smoking (verified via expired CO level of ≤5 ppm), craving (Questionnaire of Smoking Urges score), and withdrawal symptoms (Wisconsin Scale of Withdrawal Symptoms score) will be assessed weekly during 6 weeks of treatment and at 1 and 4 weeks posttreatment. Cue-induced craving for cigarettes will be assessed at baseline and at 3 weeks of treatment following virtual reality exposure. EXPECTED OUTCOMES: We hypothesize that exenatide will increase the number of participants able to achieve complete smoking abstinence above that achieved via standard NRT and that exenatide will reduce craving and withdrawal symptoms, as well as cue-induced craving for cigarettes.

Cystic Fibrosis Foundation Pulmonary Guidelines. Use of Cystic Fibrosis Transmembrane Conductance Regulator Modulator Therapy in Patients with Cystic Fibrosis.

RATIONALE: Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators are a new class of medications targeting the underlying defect in CF. Ivacaftor (IVA) and IVA combined with lumacaftor (LUM; IVA/LUM) have been approved by the U.S. Food and Drug Administration (FDA) for use in patients with CF. However, the FDA label for these medications encompasses patient groups that were not studied as part of the drug approval process. CF clinicians, patients, and their families have recognized a need for recommendations to guide the use of these medications. OBJECTIVE: Develop evidence-based guidelines for CFTR modulator therapy in patients with CF. METHODS: A multidisciplinary committee of CF caregivers and patient representatives was assembled. A methodologist, an epidemiologist, a medical librarian, and a biostatistician were recruited to assist with the literature search, evidence grading, and generation of recommendations. The committee developed clinical questions using the Patient-Intervention-Comparison-Outcome format. A systematic review was conducted to find relevant publications. The evidence was then evaluated using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach, and recommendations were made based on this analysis. RESULTS: For adults and children aged 6 years and older with CF due to gating mutations other than G551D or R117H, the guideline panel made a conditional recommendation for treatment with IVA. For those with the R117H mutation, the guideline panel made a conditional recommendation for treatment with IVA for 1) adults aged 18 years or older, and 2) children aged 6-17 years with a forced expiratory volume in 1 second (FEV1) less than 90% predicted. For those with the R117H mutation, the guideline panel made a conditional recommendation against treatment with IVA for 1) children aged 12-17 years with an FEV1 greater than 90% predicted, and 2) children less than 6 years of age. Among those with two copies of F508del, the guideline panel made a strong recommendation for treatment with IVA/LUM for adults and children aged 12 years and older with an FEV1 less than 90% predicted; and made a conditional recommendation for treatment with IVA/LUM for 1) adults and children aged 12 years or older with an FEV1 greater than 90% predicted, and 2) children aged 6-11 years. CONCLUSIONS: Using the GRADE approach, we have made recommendations for the use of CFTR modulators in patients with CF. These recommendations will be of help to CF clinicians, patients, and their families in guiding decisions regarding use of these medications.

Guanfacine Attenuates Adverse Effects of Dronabinol (THC) on Working Memory in Adolescent-Onset Heavy Cannabis Users: A Pilot Study.

The cannabinoid-1 receptor (CB1R) agonist Δ9-tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, adversely effects working memory performance in humans. The α2A-adrenoceptor (AR) agonist guanfacine improves working memory performance in humans. The authors aimed to determine the effects of short-term (6 days) treatment with guanfacine on adverse cognitive effects produced by THC. Employing a double-blind, placebo-controlled crossover design, the cognitive, subjective, and cardiovascular effects produced by oral THC (20 mg) administration were determined twice in the same cannabis users: once after treatment with placebo and once after treatment with guanfacine (3 mg/day). Compared with performance at baseline, THC negatively affected accuracy on spatial working memory trials while participants were maintained on placebo (p=0.012) but not guanfacine (p=0.497); compared with placebo, accuracy was significantly (p=0.003, Cohen's d=-0.640) improved while individuals were treated with guanfacine. Similarly, compared with baseline, THC increased omission errors on an attentional task while participants were maintained on placebo (p=0.017) but not on guanfacine (p=0.709); compared with placebo, there were significantly (p=0.034, Cohen's d=0.838) fewer omissions while individuals were maintained on guanfacine. Although THC increased visual analog scores of subjective effects and heart rate, these increases were similar during treatment with placebo and guanfacine. THC did not significantly affect performance of a recognition memory task or blood pressure while individuals were maintained on either treatment. Although preliminary, these results suggest that guanfacine warrants further testing as a potential treatment for cannabis-induced cognitive deficits.

A COMPARISON OF MAZUR'S k AND AREA UNDER THE CURVE FOR DESCRIBING STEEP DISCOUNTERS.

Delay discounting describes how a reward loses value as a function of increasing delay to its receipt and has been reliably associated with a variety of vulnerable populations including those with substance use disorders (SUDs). Two commonly used models to assess delay discounting in the field of SUDs include log k derived from Mazur's hyperbolic equation and area under the curve (AUC). In the current study, we compared log k with AUC on delay discounting data obtained from non-treatment seeking, cocaine- and methamphetamine-dependent volunteers. We specifically chose this population in order to obtain a distribution of relatively steep discounters. The results show that the relationship between AUC and log k is better described by a quadratic rather than a linear function. In other words, changes in discounting, as measured by AUC and log k, are reflected differently across a range of obtained responses. Additionally, the distribution of AUC values was skewed, which appears to be more likely among populations exhibiting greater discounting. Finally, closer examination of indifference points revealed that AUC was almost perfectly predicted by the area from the two longest delays, with relatively less input from shorter delays. Given these results, researchers should exercise additional caution when deciding which method to assess discounting data and how final results are to be interpreted, particularly when dealing with relatively high rates of discounting. High rates of discounting are likely in populations with impulsive disorders such as those with SUDs.

The limited impact that cocaine use patterns have on neurocognitive functioning in individuals with cocaine use disorder.

It is well-documented in the literature that cocaine use is associated with neurocognitive impairment. The manner in which patterns of cocaine use, such as years of use, recent use over the past month, and daily amount of cocaine use, moderate neurocognition has been studied in a relatively piecemeal manner. Hence, the purpose of the study was to evaluate whether cocaine use patterns modulate neurocognition in individuals with cocaine use disorder. Cocaine users who were cocaine-negative ( n=125) were divided into tertiles based on cocaine use patterns and the performances of the highest and lowest groups were compared on the following cognitive measures: Continuous Performance Task-II, n-back, and Hopkins Verbal Learning Task-Revised. Participants with cocaine use disorder who used for more years (25.2±0.6 versus 10.1±0.6 years; mean±standard error of the mean) and who had more recent cocaine use over the past month (26.3±0.5 versus 6.0±0.6 days) did not differ significantly on any of the neurocognitive variables when compared to those with use patterns of shorter duration and less frequency (all p's >0.05). Lastly, participants reporting the greatest amount daily cocaine use (1.8±0.0 g) demonstrated better performance on an auditory working memory task when compared to those with the lowest daily use (0.7±0.0 g; p=0.04). While one might expect that individuals who used greater amounts of cocaine over longer periods of time would demonstrate relatively poorer performance on measures of neurocognition, particularly in the initial phase of abstinence, our findings did not confirm this. While speculative, a potential explanation for these findings is that after an individual uses cocaine for a certain number of years, or uses a specific amount over time, then the deleterious effects of cocaine on neurocognition stabilizes, and increased duration of cocaine use does not further exacerbate those impairments.

Genetic moderation of cocaine subjective effects by variation in the TPH1, TPH2, and SLC6A4 serotonin genes.

OBJECTIVE: This study investigated variants of tryptophan hydroxylase (TPH)1, TPH2, and SLC6A4 in the moderation of the subjective effects of cocaine. METHODS: Non-treatment-seeking cocaine-dependent individuals (N=66) were intravenously administered saline and cocaine (40 mg) in a randomized order. Participants self-reported subjective effects of cocaine using a visual analog scale starting before administration of saline or cocaine (-15 min) to up to 20 min after infusion. Self-report ratings on the visual analog scale ranged from 0 (no effect) to 100 (greatest effect). Participants were genotyped for the TPH1 rs1799913, TPH2 rs4290270, and SLC6A4 5-HTTLPR variants. Repeated-measures analysis of covariance was used to examine changes in subjective effect scores over time while controlling for population structure. RESULTS: Participants carrying the TPH1 rs1799913 A allele reported greater subjective response to cocaine for 'stimulated' and 'access' relative to the CC genotype group. Those carrying the TPH2 rs4290270 A allele reported higher 'good effect' and lower 'depressed' effect relative to the TT genotype group. Those carrying the SLC6A4 5-HTTLPR S' allele reported greater 'desire' and 'access' compared with the L'L' genotype group. CONCLUSION: These findings indicate that TPH1, TPH2, and SLC6A4 variants moderate the subjective effects of cocaine in non-treatment-seeking cocaine-dependent participants.

Electrocardiographic characteristics in individuals with cocaine use disorder.

BACKGROUND AND OBJECTIVES: Chronic cocaine use has been linked to several abnormalities in cardiac functioning. The objective of this study was to further characterize baseline heart rate and electrocardiograph (ECG) profiles of individuals with cocaine use disorder (CUD) by evaluating demographic and drug use variables that may impact cardiovascular profiles. METHODS: Participants with CUD (n = 335, primarily African-American males) provided demographic and drug use data and ECG profiles (eg, heart rate, PR Interval, QRS, and QTc) were obtained via 12-lead ECG. RESULTS: Forty-eight percent and ten percent of cocaine users met criteria for sinus bradycardia (heart rate ≤60) and severe bradycardia (heart rate ≤50), respectively. Females had significantly higher heart rate (p = .020, d = .30) and QTc (p < .001, d = .75) and significantly lower QRS (p = .002, d = .42) in comparison to males. Those who were cocaine positive had higher QTc (p = .025, d = .26) with a higher prevalence of bradycardia (chi-square = 3.91, p = .048) than those who were negative. Cocaine users who also used alcohol had significantly lower PR Interval (p = .003, d = .36), QRS (p = .014, d = .29), and QTc (p = .037, d = .25) than those who denied alcohol use. CONCLUSIONS: These findings characterize the baseline heart rate and ECG profiles of individuals with CUD, confirm previous reports of cocaine-induced alterations in cardiovascular function, and demonstrate factors impacting cardiovascular profiles. SCIENTIFIC SIGNIFICANCE: While exploratory, these results suggest the presence of bradycardia may serve as a useful biomarker for initiating therapy for individuals with CUD and averting potential adverse cardiovascular events. Future prospective studies are needed to assess this possibility. (Am J Addict 2017;26:221-227).

The relationship between premorbid IQ and neurocognitive functioning in individuals with cocaine use disorders.

OBJECTIVE: To determine whether premorbid IQ mediates performance on neurocognitive tests in individuals diagnosed with cocaine use disorder (CUD). METHOD: Recently abstinent cocaine users (N = 113) completed measures sensitive to the effects of cocaine on cognition: Conners' Continuous Performance Task-II (CPT-II), n-back working memory test, and Hopkins Verbal Learning Task-Revised (HVLT-R). Premorbid IQ was calculated using the Oklahoma Premorbid Intelligence Estimate, which integrates scores from the Wechsler Adult Intelligence Scale-III and demographic variables. Participants were grouped according to their premorbid IQ using commonly accepted classifications of ability level (above average [>110], average [90-109], and below average [<90]) and comparisons in neurocognitive performance were performed using one-way analysis of variance. RESULTS: Significant differences were detected between groups on the HVLT-R including Trial 1 (p = .002), total word recall across the 3 list-learning trials (p < .001), and recall following a delay (p < .001). Significant differences were also detected on the N-back, including auditory and visual accuracy (p = .022 and p < .001, respectively) and mean and maximum block length (p < .001). Although significant differences were observed between the above average and average groups (mean effect size = .418 [Cohen's d]), the magnitude of group differences was greatest between the average and below average groups (mean effect size = .716). CONCLUSIONS: These results raise questions as to whether the neurocognitive impairment observed in individuals diagnosed with CUD predated the onset of cocaine use or whether the impairments were caused by cocaine use. Because these impairments are potential risk factors for poor treatment outcomes, it is important to consider the need to modify treatment programs to account for lower premorbid IQ. (PsycINFO Database Record

Treadmill exercise improves fitness and reduces craving and use of cocaine in individuals with concurrent cocaine and tobacco-use disorder.

Exercise may be a useful treatment for substance use disorders. Participants (N=24) included treatment-seeking individuals with concurrent cocaine and tobacco-use disorder (cigarette smokers). Participants were randomized to either running or walking (30min per session, 3 times per week) or sitting (control condition) for 4 consecutive weeks. Several metrics indicated significant differences among runners, walkers, and sitters during sessions, including mean distance covered and calories burned. In addition, remote physiological monitoring showed that the groups differed significantly according to mean maximum heart rate (HR), respiration, and locomotor activity. Across the 4-week study, exercise improved fitness measures including significantly decreasing resting HR. Though not statistically significant, exercise improved abstinence from cocaine and increased self-reports of no cocaine use in last 24h. In general, reductions in tobacco use and craving were not as robust. To our knowledge, this is the first study to evaluate the effects of a multi-week exercise program in individuals with concurrent cocaine and tobacco-use disorder. The data clearly show significant improvements in basic fitness measures and several indices reveal that exercise improved both self-report and biochemically verified reports of cocaine abstinence. Taken together, the data from this study provide preliminary evidence for the efficacy of exercise for improving fitness and reducing cocaine use.

The α-1 adrenoceptor (ADRA1A) genotype moderates the magnitude of acute cocaine-induced subjective effects in cocaine-dependent individuals.

OBJECTIVES: We examined whether a functional variant of the ADRA1A gene moderated cocaine-induced subjective effects in a group of cocaine-dependent individuals. METHODS: This study was a within-participant, double-blind, placebo-controlled inpatient human laboratory evaluation of 65 nontreatment-seeking, cocaine-dependent [Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV)] individuals aged 18-55 years. Participants received both placebo (saline, IV) and cocaine (40 mg, IV), and subjective responses were assessed 15 min before receiving an infusion and at 5 min intervals for the subsequent 20 min. The rs1048101 variant of the α1A-adrenoceptor (ADRA1A) gene was genotyped and it was evaluated whether the Cys to Arg substitution at codon 347 in exon 2 (Cys347Arg) moderated the magnitude of the subjective effects produced by cocaine. RESULTS: Thirty (46%) participants were found to have the major allele CC genotype and 35 (44%) carried at least one minor T-allele of rs1048101 (TT or TC genotype). Individuals with the CC genotype showed greater responses for 'desire' (P<0.0001), 'high' (P<0.0001), 'any drug effect' (P<0.0001), 'like cocaine' (P<0.0001), and 'likely to use cocaine if given access' (P<0.05) with experiment-wise significance. CONCLUSION: This study indicates that the ADRA1A genotype could be used to identify individuals for whom acute cocaine exposure may be more rewarding and by inference may result in greater difficulty in establishing and/or maintaining abstinence from cocaine.

Cocaine cardiovascular effects and pharmacokinetics after treatment with the acetylcholinesterase inhibitor donepezil.

BACKGROUND: In rodents, cholinesterase inhibitors can cause sustained decreases in the reinforcing effects of cocaine. Nonetheless, cocaine is metabolized by butyrylcholinesterase (BuChE), raising concerns that cholinesterase inhibition could increase its peripheral concentrations, perhaps augmenting toxicity. Although donepezil is approved for use in patients and selective for inhibiting acetylcholinesterase over BuChE, no studies have reported cocaine bioavailability in human subjects receiving donepezil. METHODS: Twelve cocaine-dependent veterans received three days of treatment with either oral placebo or 5 mg daily of donepezil, followed by cross-over to the opposite treatment. During both oral treatments, double-blind intravenous cocaine was administered at .0, .18, and .36 mg/kg in a laboratory setting, followed by determinations of heart rate, blood pressure, and plasma concentrations of cocaine and major metabolites. RESULTS: Intravenous cocaine produced dose-related increases in systolic blood pressure that were most pronounced over the initial 30 minutes after treatment. Oral donepezil attenuated drug-induced elevations of systolic blood pressure following low-dose cocaine (.18 mg/kg). No significant difference in blood pressure following treatment with placebo or donepezil after high-dose cocaine (.36 mg/kg). Peak values of blood pressure and heart rate were unaffected by donepezil. Plasma concentrations of cocaine and metabolites did not differ in donepezil- and placebo-treated participants. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: We conclude that donepezil can attenuate drug-induced increases in systolic blood pressure following low-dose cocaine, but does not otherwise modify the cardiovascular effects of intravenous cocaine. Clinically significant changes in cocaine bioavailability and cardiovascular effects do not occur following this dose of donepezil. (Am J Addict 2016;25:392-399).

Doxazosin XL reduces symptoms of posttraumatic stress disorder in veterans with PTSD: a pilot clinical trial.

BACKGROUND: Serotonin and norepinephrine reuptake inhibitors are effective first-line agents for the treatment of posttraumatic stress disorder (PTSD), but treatment is associated with a range of side effects that limit treatment adherence. Prazosin, an α1-noradrenergic antagonist with a half-life of roughly 2-3 hours, has shown promise in the treatment of sleep disturbance and nightmares. Doxazosin extended release (XL) is also an α1-noradrenergic antagonist but with a half-life of approximately 15-19 hours. METHODS: We conducted a double-blind, placebo-controlled, within-subjects trial to characterize the impact of doxazosin XL on PTSD symptoms. Participants (N = 8) were diagnosed using DSM-IV criteria. They completed the study twice, once during treatment with doxazosin XL and once during treatment with matched placebo, with a 2-week washout separating the 2 episodes. Doxazosin XL was titrated from 4 mg/d to 16 mg/d over 12 days. After 4 days of treatment at 16 mg/d or the equivalent number of placebo capsules, PTSD symptoms were assessed using the Clinician-Administered PTSD Scale (CAPS17) and the PTSD Checklist-Military version (PCL-M). Repeated measures analysis of variance were used to evaluate effects of treatment, time, and treatment × time. This study was run from November 20, 2013, to June 31, 2014. RESULTS: Doxazosin XL treatment was associated with a nonsignificant treatment × time reduction in ratings on the CAPS hyperarousal subscale (P < .10) (but not on the CAPS Total score) and with significant treatment × time reductions in PCL-M ratings (P = .002). CONCLUSIONS: Doxazosin XL may be an effective alternative to prazosin for the treatment of some PTSD symptoms. TRIAL REGISTRATION: ClinicalTrials.gov Identifier:NCT02308202.