Tryptophan depletion disinhibits punishment but not reward prediction: implications for resilience

Rationale  

We have previously shown that tryptophan depletion enhances punishment but not reward prediction (Cools et al. in Neuropsychopharmacology 33:2291–2299, 2008b). This provided evidence for a valence-specific role of serotonin (which declines under depleted tryptophan) in aversive processing. Recent theoretical (Dayan and Huys in PLoS Comput Biol 4:e4, 2008) and experimental (Crockett et al. in J Neurosci 29:11993–11999, 2009) approaches have, however, further specified this role by showing that serotonin is critical for punishment-induced inhibition.     

Modulation of the GSTT1 activity by the GSTM1 phenotype in a sample of Italian farm-workers

Glutathione S-transferase (GST) isozymes catalyze nucleophilic attack by reduced Glutathione (GSH) on a variety of electrophilic compounds and play a central role in biotransformation of xenobiotics (Hayes et al., Annu Rev Pharmacol Toxicol 45:51–88, 2005). We performed a case–control study to evaluate the GSTM1 and GSTT1 polymorphisms and to investigate if exposure to pesticides conditions the GSTT1 activity level in 115 healthy controls and 90 farm-workers exposed to pesticides. Polymorphisms were investigated using a GSTM1 or a GSTT1-specific PCR. Enzyme activity was measured by means of DCM as co-substrate, as described by Bruhn et al. (Biochem Pharmacol 56:1189–1193, 1998). There was no significant difference between the farm-workers and the healthy controls regarding the distribution of various alleles of the GSTM1 and GSTT1 genes and the GSTT1 enzyme activity. In farm-workers, the GSTM1 null genotype was associated with a significant increase of GSTT1 activity, suggesting a regulative mechanism common to GSTM1 and GSTT1 enzymes after exposure to xenobiotics.     

Threshold of toxicological concern values for non-genotoxic effects in industrial chemicals: re-evaluation of the Cramer classification

The TTC concept employs available data from animal testing to derive a distribution of NOAELs. Taking a probabilistic view, the 5th percentile of the distribution is taken as a threshold value for toxicity. In this paper, we use 824 NOAELs from repeated dose toxicity studies of industrial chemicals to re-evaluate the currently employed TTC values, which have been derived for substances grouped according to the Cramer scheme (Cramer et al. in Food Cosm Toxicol 16:255–276, 1978) by Munro et al. (Food Chem Toxicol 34:829–867, 1996) and refined by Kroes and Kozianowski (Toxicol Lett 127:43–46, 2002), Kroes et al. 2000. In our data set, consisting of 756 NOAELs from 28-day repeated dose testing and 57 NOAELs from 90-days repeated dose testing, the experimental NOAEL had to be extrapolated to chronic TTC using regulatory accepted extrapolation factors. The TTC values derived from our data set were higher than the currently used TTC values confirming the safety of the latter. We analysed the prediction of the Cramer classification by comparing the classification by this tool with the guidance values for classification according to the Globally Harmonised System of classification and labelling of the United Nations (GHS). Nearly 90% of the chemicals were in Cramer class 3 and assumed as highly toxic compared to 22% according to the GHS. The Cramer classification does underestimate the toxicity of chemicals only in 4.6% of the cases. Hence, from a regulatory perspective, the Cramer classification scheme might be applied as it overestimates hazard of a chemical.     

Correlation of aqueous and lipid solubilities with flux for prodrugs of 5-fluorouracil, theophylline, and 6-mercaptopurine: A Potts-Guy approach

The Potts and Guy equation that has been used to predict permeability coefficients for molecules being delivered from aqueous vehicles has been transformed to accommodate lipid vehicles that are less polar than skin, and polar vehicles that are less polar than water. Solubilities in pH 4.0 aqueous buffer (SAQ), solubilities in isopropyl myristate (SIPM), and molecular weights (MW) of prodrugs of 5-fluorouracil (5-FU), theophylline (Th), and 6-mercaptopurine (6-MP) have been regressed against their fluxes from suspensions in IPM (JM). Seven series (n = 39) of alkylcarbonyloxymethyl (ACOM), alkyloxycarbonyl (AOC), alkylcarbonyl (AC), and alkylaminocarbonyl (AAC) prodrugs were used to determine the best fit to the transformed Potts and Guy equation (eq 6): log JM = x + y log SIPM + (1 - y)log SAQ - z MW. The estimated values for x, y, and z were -0. 193, +0.525, and +0.00364, respectively, with r 2 = 0.945 for n = 39. Inclusion of a miscellaneous series comprised of the parent drugs and a branched alkyl chain prodrug gave an equally good fit only if 6-MP was excluded from the analysis. The best performer (largest JM) in each series was usually correctly identified. The values for x, y, and z were consistent with values obtained by Potts and Guy, but the inclusion of the (l - y)log SAQ term in eq 6 and the value for y, shows that water solubility is almost as important as lipid solubility in predicting flux. There were no significant changes in predicted log JM or xi for each series if their log JM or xi were calculated using y and z coefficients obtained for solutions to eq 6 from which the data for the series had been excluded. This suggests that the data from all the series is homogeneous. Data from Kasting, Smith, and Cooper for SIPM, SPG, and MW of unrelated molecules were regressed against their fluxes from propylene glycol (PG) using eq 7: log JM = x + y log SIPM + (1 - y) log SPG - z MW. The estimated values for x, y, and z were -1.673, +0.599, and +0.00595, respectively, with r 2 = 0.852 for n = 28. These values for x, y, and z are also consistent with those previously reported by Potts and Guy, and, together with the results for fluxes from IPM, show the general utility of the transformed Potts and Guy equation in predicting flux from vehicles other than water and in showing the importance of solubility in a polar solvent as well as a nonpolar solvent in predicting flux.     

Nicotine withdrawal and reward responsivity in a card-sorting task

Rationale  Animal studies have demonstrated decreased reward responsivity during nicotine withdrawal (e.g., Epping-Jordan et al., Nature 393:76–79, 1998) and the Card Arranging Reward Responsivity Objective Test (CARROT) has recently been used to study the effect of nicotine withdrawal on reward responsivity in humans (e.g., Al-Adawi and Powell, Addiction 92:1773–1782, 1997; Powell et al., Biol Psychiatry 51:151–163, 2002). We investigated a suggestion that nicotine withdrawal may have additional reward-related effects apart from the reward responsivity effects already observed. Objective  The objective of this study was to determine whether or not nicotine withdrawal results in slower improvements in performance on a card-sorting task over a series of trials. Method  We carried out two experiments using a modified version of the CARROT, the mCARROT, to compare the performance of human participants in nicotine withdrawal with those who were satiated. Results  Although withdrawal produced no direct effect on the mCARROT measure of reward responsivity, the overall sorting rate was lower, and the increase in sorting rate across successive trials was slower during nicotine withdrawal than during satiation. Conclusions  These data indicate that nicotine withdrawal impacted on task performance independently of the introduction of a performance contingent reward, suggesting a novel reward-related effect of nicotine withdrawal.     

Synthesis of piperazino and morpholino derivatives of aryloxypropane with potential analgesic and possible antimigraine activities

Abstract  

Modeling studies demonstrate that aryl piperazines (I), aryloxyalkylamines (II), phenylalkykamines (III) and indolylalkylamines (VI) may interact at 5-HT receptors in a similar manner. Examination of these structures (I–VI) reveals that all possess an aromatic moiety and terminal amine binding sites (Glennon et al., J Med Chem 32(8):1921–1926, 1989). In the present investigation a new series of aryloxyalkylamines (4, 5, 8, and 9) was designed and synthesized, in which the aromatic moiety is a phenyl group substituted at the 2,3-, 2,4-, 2,5-, or 2,6-positions by halogens and the terminal amine is N-methylpiperazine, or morpholine. In addition, the alkyl side chain is ethyl, or substituted ethyl at the α- or β-carbon by a methyl group. The length of the alkyl chain that separates the terminal amine from the ether oxygen atom of the aryloxy group is of major importance, and two-carbon chain appears optimal. The structures of the new compounds were assessed by microanalyses, IR, and NMR. The analgesic activity of selected compounds was performed on experimental animals and proved to be in the range of 85–100% relative to aspirin.     

Nicotine does not enhance basic semantic priming

Rationale  

Utilising a cognitively demanding strategy-based priming paradigm, we recently observed that acute transdermal nicotine selectively influenced controlled semantic processing but not related-word links within semantic memory per se as reported by Holmes et al. (Int J Neuropsychopharmacol 11:389–399, 2008).     

Meta-analysis of the acute effects of nicotine and smoking on human performance

Rationale and objective  

Empirical studies indicate that nicotine enhances some aspects of attention and cognition, suggesting a role in the maintenance of tobacco dependence. The purpose of this review was to update the literature since our previous review (Heishman et al. Exp Clin Psychopharmacol 2:345–395, 1994) and to determine which aspects of human performance were most sensitive to the effects of nicotine and smoking.     

Rhesus Macaque Model of Chronic Opiate Dependence and Neuro-AIDS: Longitudinal Assessment of Auditory Brainstem Responses and Visual Evoked Potentials

Our work characterizes the effects of opiate (morphine) dependence on auditory brainstem and visual evoked responses in a rhesus macaque model of neuro-AIDS utilizing a chronic continuous drug delivery paradigm. The goal of this study was to clarify whether morphine is protective, or if it exacerbates simian immunodeficiency virus (SIV)-related systemic and neurological disease. Our model employs a macrophage tropic CD4/CCR5 coreceptor virus, SIV_mac239 (R71/E17), which crosses the blood-brain barrier shortly after inoculation and closely mimics the natural disease course of human immunodeficiency virus infection. The cohort was divided into three groups: morphine only, SIV only, and SIV + morphine. Evoked potential (EP) abnormalities in subclinically infected macaques were evident as early as 8 weeks postinoculation. Prolongations in EP latencies were observed in SIV-infected macaques across all modalities. Animals with the highest cerebrospinal fluid viral loads and clinical disease showed more abnormalities than those with subclinical disease, confirming our previous work (Raymond et al., J Neurovirol 4:512–520, 1998; J Neurovirol 5:217–231, 1999; AIDS Res Hum Retroviruses 16:1163–1173, 2000). Although some differences were observed in auditory and visual evoked potentials in morphine-treated compared to morphine-untreated SIV-infected animals, the effects were relatively small and not consistent across evoked potential type. However, morphine-treated animals with subclinical disease had a clear tendency toward higher virus loads in peripheral and central nervous system tissues (Marcario et al., J Neuroimmune Pharmacol 3:12–25, 2008) suggesting that if had been possible to follow all animals to end-stage disease, a clearer pattern of evoked potential abnormality might have emerged. This work was supported by NIH grants DA12827, HD02528, and COBRE P20RR16443. Meeting presentations: Psychoneuroimmunology Research Society, May 2007; USA-Caribbean Conference: HIV/AIDS and Drug Abuse, Dec 2006; Society on NeuroImmune Pharmacology, April 2006 and April 2005; Association for Research in Otolaryngology 29th MidWinter Meeting, Feb. 2006; Society for Neuroscience, Oct. 2004.     

Non-toxic inhibition of HIV-1 replication with silver–copper nanoparticles

Cu and Ag–Cu mixed alloy nanoparticles displayed significant inhibition to HIV-1 replication with limited toxicity to human cells at relatively low concentrations of metal. A previous study (Elechiguerra et al. in J Nanobiotechnol 3:6–16, 2005) suggested a size-specific Ag nanoparticle can be tailored to block or damage the glycoprotein (gp) 120/gp41 spike or, more specifically, the invariant epitope at the gp120 binding site. Two different protocols were employed to test whether nanoparticles block entry of HIV-1, and in both instances the nanoparticles acted at some point other than initial binding. This work shows that Ag, Cu, and Ag–Cu mixed alloy metals display a chemically dependent inactivation of the target virus.     

Placebo analgesia affects the behavioral despair tests and hormonal secretions in mice

Rationale  

The placebo effect is a fascinating yet puzzling phenomenon, which has challenged investigators over the past 50 years. In previous studies, the investigators only focused on the placebo effect obtained within a single domain, and pain is the field in which most of the placebo research has been performed. However, recent research by our laboratory (Zhang and Luo in Psychophysiology 46:626–634, 2009; Zhang et al. 2011) showed that, in human subjects, the placebo effect can be transferred from one domain to the other, namely from pain to emotion.     

Obesity and knee osteoarthritis

Background  

The association between obesity and knee osteoarthritis, and specifically the role of obesity as a risk factor for knee osteoarthritis has been well documented. A systematic review and meta-analysis by Blagojevic et al. in Osteoarthr Cartil 18(1):24–33, (2010) examined 36 papers reporting on BMI and found that all studies demonstrated obesity and being overweight to be risk factors for knee osteoarthritis. The effect size for obesity as a risk factor for knee OA was reported to be I ² = 97%, and the random effects pooled odds ratio for obesity compared to normal weight was 2.63 with a 95% CI of 2.28–3.05.     

Detection of reciprocal quantitative trait loci for acute ethanol withdrawal and ethanol consumption in heterogeneous stock mice

Rationale  Previous studies have suggested that there is an inverse genetic relationship between ethanol consumption (two-bottle choice, continuous access) and ethanol withdrawal (e.g., Metten et al., Behav Brain Res 95:113–122, 1998a). Objectives  The current study used short-term selective breeding from heterogeneous stock (HS) animals to examine this relationship. The primary goal of the current study was to determine if reciprocal quantitative trait loci (QTLs) could be found in the selectively bred lines. The advantage of detecting QTLs in HS animals is that it is possible to extract a haplotype signature for the QTL, which in turn can be used to narrow the number of candidate genes generated from gene expression and sequence databases (see, e.g., Hitzemann et al., Mamm Genome 14:733–747, 2003). Results  Seven reciprocal QTLs were detected on chromosomes (Chr) 1 (two), 3, 6, 11, 16, and 17 that exceeded the nominal LOD threshold of 10; genetic drift, which occurs during selection, dramatically increases the LOD threshold. The proximal Chr 1 QTL was examined in some detail. The haplotype structure of the QTL was such that the LP/J allele was associated with low withdrawal and high consumption. The QTL appears to be located in a gene-poor region between 170 and 173 Mbp. Based on available sequence data, two plausible candidate genes emerge—Nos1ap and Atf6α. Conclusions  The data presented here confirm some aspects of the negative genetic relationship between acute ethanol withdrawal and ethanol consumption. The QTL data point to the potential involvement of NO signaling and/or the unfolded protein response. This study was supported in part by AA 10760, 11034, and 13484.     

Discriminative stimulus properties of S32504, a novel D3/D2 receptor agonist and antiparkinson agent, in rats: attenuation by the antipsychotics, aripiprazole, bifeprunox, N-desmethylclozapine, and by selective antagonists at dopamine D2 but not D3 receptors

Rationale Drug-discrimination studies have proven instructive in the characterization of psychotropic agents, a procedure applied herein to the novel antiparkinson agent, S32504. This highly selective agonist at dopamine D₃ and (less potently) D₂ receptors displays potent antiparkinson, neuroprotective and antidepressant properties (Millan et al., J Pharmacol Exp Ther 309:936–950, 2004a; Millan et al., J Pharmacol Exp Ther 309:903–920, 2004b; Millan et al., J Pharmacol Exp Ther 309:921–935, 2004c). Objectives To generate a discriminative stimulus (DS) with S32504 and undertake substitution/antagonism studies with diverse antiparkinson and antipsychotic agents. Materials and methods Using a two-lever, fixed-ratio 10 schedule, rats were trained to recognize S32504 (0.04 mg/kg, s.c.) from saline. Results S32504 displayed dose-dependent and stereospecific substitution in comparison to its less active racemic form, (±) S31411, and to its inactive (−) distomer, S32601. Apomorphine, and the selective D₃/D₂ receptor agonists, ropinirole, PD128,907, 7-OH-DPAT and CGS15855A, fully (=80%) substituted for S32504, whereas D₄ and D₁/D₅ receptor agonists were ineffective. The selective D₃ vs D₂ receptor partial agonist, BP897, did not substitute for S32504 and the selective D₃ receptor antagonists, S33084, SB277,011, GR218,231, PNU99194A and S14297, did not block its DS properties. By contrast, S32504 lever selection was blocked by the preferential D₂ vs D₃ receptor antagonists, L741,626 and S23199, and by the D₂/D₃ antagonists, raclopride and haloperidol. The D₂/D₃ receptor partial agonists and antipsychotics, aripiprazole, bifeprunox, N-desmethylclozapine and preclamol did not substitute for S32504: indeed, they dose-dependently attenuated its DS properties. Conclusion The antiparkinson agent, S32504, displays DS properties principally mediated by high-efficacy activation of D₂ receptors Antipsychotics known to act as partial agonists at D₂/D₃ receptors attenuate DS properties of S32504, actions reflecting their low efficacy at these sites.     

Synthesis and in vitro and in vivo antimalarial activity of novel 4-anilinoquinoline Mannich base derivatives

Development of resistance has severely limited the choice of available antimalarial drugs, which clearly highlights the urgent need of novel chemotherapeutic agents for the treatment of malaria. The purpose of this study was to develop new potential antimalarial agents with 4-anilinoquinoline ring. A series of novel 4-anilinoquinoline Mannich base drug molecules have been synthesized. The synthesis involves the preparation of Mannich base and these bases subsequently coupled with 4,7-dichloroquinoline to get targeted drug molecules (Burckhalter et al. in J Am Chem Soc 70:1363–1373, 1948). Their structures were confirmed by IR, NMR, and mass spectral data. The synthesized molecules were evaluated for in vitro and in vivo antimalarial activity against the chloroquine sensitive 3D7 (West Africa) and RKL-2 strain of Plasmodium falciparum and rodent malaria parasite Plasmodium yoelii (strain N-67) in Swiss mice model, respectively (Charmot et al. in Prev Med 15:889, 1986). Except one molecule (containing diphenylamine), all the tested molecules showed activity while one of them (containing morpholine) showed promising in vitro and significant in vivo antimalarial activity under given test conditions.     

Lactoferrin Conjugated with 40-kDa Branched Poly(ethylene Glycol) Has an Improved Circulating Half-Life

Purpose  We developed a lactoferrin conjugate by modifying bovine lactoferrin (bLF) with a 40-kDa branched poly(ethylene glycol) (PEG) molecule (designated 40 k-PEG-bLf), and we evaluated its in vitro activities and pharmacokinetic properties. Materials and Methods  We prepared 40k-PEG-bLf by amino conjugation with N-hydroxysuccinimide-activated PEG. This conjugate was purified by cation exchange chromatography and its in vitro biological activities, such as iron binding, anti-inflammatory effects, and resistance to proteolytic enzymes were investigated. In vivo pharmacokinetics analyses, were also performed to examine the rate of clearance from the plasma in rats. Results  The 40k-PEG-bLf conjugate was fully active in iron binding and exhibited 97.1 ± 5.5% (mean ± S.E., n = 6) of the original anti-inflammatory activity. The in vitro peptic susceptibility of 40 k-PEG-bLf revealed that the proteolytic half-life increased at least 6-fold that of unmodified LF. This PEGylated conjugate demonstrated a plasma half-life that was 8.7-fold longer than that of the unmodified bLF in rats. Conclusions  The 40k-PEG-bLf exhibited improved in vitro bioactivity and stability and enhanced pharmacokinetic properties as compared to those of the unmodified bLF and the 20 k-PEG-bLf conjugate, which was recently developed by PEGylation of bLF with a 20-kDa branched PEG [Nojima Y. et al. Bioconjugate Chem. 19:2253–2259 (2008)].     

Potential of the octanol–water partition coefficient (log P) to predict the dermal penetration behaviour of amphiphilic compounds in aqueous solutions

Aqueous amphiphilic compounds may exhibit enhanced skin penetration compared with neat compounds. Conventional models do not predict this percutaneous penetration behaviour. We investigated the potential of the octanol–water partition coefficient (log P) to predict dermal fluxes for eight compounds applied neat and as 50% aqueous solutions in diffusion cell experiments using human skin. Data for seven other compounds were accessed from literature. In total, seven glycol ethers, three alcohols, two glycols, and three other chemicals were considered. Of these 15 compounds, 10 penetrated faster through the skin as aqueous solutions than as neat compounds. The other five compounds exhibited larger fluxes as neat applications. For 13 of the 15 compounds, a consistent relationship was identified between the percutaneous penetration behaviour and the log P. Compared with the neat applications, positive log P were associated with larger fluxes for eight of the diluted compounds, and negative log P were associated with smaller fluxes for five of the diluted compounds. Our study demonstrates that decreases or enhancements in dermal penetration upon aqueous dilution can be predicted for many compounds from the sign of log P (i.e., positive or negative). This approach may be suitable as a first approximation in risk assessments of dermal exposure.     

Theoretical Considerations of Target-Mediated Drug Disposition Models: Simplifications and Approximations

Purpose  

To clarify relationships among various types of target-mediated disposition (TMD) models including the Michaelis-Menten, quasi-steady-state (Qss), and rapid binding models and propose measures for the closeness of some models as approximations to the general TMD model (Mager and Jusko, J Pharmacokinet Pharmacodyn 28(6):507–532, 2001).