Effects of the 5-HT(1A) agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on cocaine choice in cynomolgus monkeys

Drugs that alter brain serotonin (5-HT) function can modulate the behavioral effects of cocaine, but the underlying receptor mechanisms are poorly understood. The present study examined the effects of the selective 5-HT1A receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 0.01-0.1 mg/kg, i.v.) on cocaine self-administration in the context of a choice procedure. Five adult male cynomolgus monkeys self-administered cocaine (saline, 0.003-0.03 mg/kg per injection) under a concurrent fixed-ratio 50 schedule of food (1-g banana-flavored pellets) and cocaine presentation. Allocation of responses to the cocaine-associated lever (cocaine choice) increased in a dose-related manner from < or =20% of total responses when saline or 0.003 mg/kg per injection cocaine was the alternative to food to > or =75% when 0.03 mg/kg per injection cocaine was available. In four of five monkeys, when choice was between a low cocaine dose and food, 0.01 mg/kg 8-OH-DPAT increased injection-lever responding. At cocaine doses which occasioned > or =75% cocaine choice, 8-OH-DPAT did not alter response allocation. In the fifth monkey, 8-OH-DPAT only decreased injection-lever responding. When choice was between saline and food, 8-OH-DPAT did not reliably shift responding to the injection lever, except at doses that disrupted operant performance. These results suggest that a 5-HT1A receptor agonist can increase the reinforcing strength of a low cocaine dose relative to a concurrently available non-drug reinforcer.

Bayesian Estimation for Performance Measures of Two Diagnostic Tests in the Presence of Verification Bias

Sensitivity and specificity are measures that allow us to evaluate the performance of a diagnostic test. In practice, it is common to have situations where a proportion of selected individuals cannot have the real state of the disease verified, since the verification could be an invasive procedure, as occurs with biopsy. This happens, as a special case, in the diagnosis of prostate cancer, or in any other situation related to risks, that is, not practicable, nor ethical, or in situations with high cost. For this case, it is common to use diagnostic tests based only on the information of verified individuals. This procedure can lead to biased results or workup bias. In this paper, we introduce a Bayesian approach to estimate the sensitivity and the specificity for two diagnostic tests considering verified and unverified individuals, a result that generalizes the usual situation based on only one diagnostic test.

Dependence on pseudorapidity and on centrality of charged hadron production in PbPb collisions at root s(NN)=2.76 TeV

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Universal zero-bias conductance through a quantum wire side-coupled to a quantum dot

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Universal zero-bias conductance for the single-electron transistor

The thermal dependence of the zero-bias conductance for the single electron transistor is the target of two independent renormalization-group approaches, both based on the spin-degenerate Anderson impurity model. The first approach, an analytical derivation, maps the Kondo-regime conductance onto the universal conductance function for the particle-hole symmetric model. Linear, the mapping is parametrized by the Kondo temperature and the charge in the Kondo cloud. The second approach, a numerical renormalization-group computation of the conductance as a function the temperature and applied gate voltages offers a comprehensive view of zero-bias charge transport through the device. The first approach is exact in the Kondo regime; the second, essentially exact throughout the parametric space of the model. For illustrative purposes, conductance curves resulting from the two approaches are compared.

Recent developments for smoking cessation and treatment of nicotine dependence

Nicotine is an addictive drug like heroin, amphetamine or cocaine. Addiction to tobacco leads to significant failure rates in programmes for smoking cessation. The alpha(4)beta(2) and alpha(7) nicotinic acetylcholine receptors (nAChRs) and CB1 cannabinoid receptors play an important role in nicotine addiction.

Drug dependence, mental impairment and education

This study aimed to evaluate the mental conditions of cocaine-dependent individuals and school commitment/attachment. We evaluated 50 patients referred to the psychiatry emergency room due to mental disorders from chemical dependence. After clinical diagnosis, clinical interview, Hospital Anxiety and Depression Scale, Hamilton Scale for Depression and Brief Psychiatric Rating Scale were applied. The Spearman and Mann-Whitney nonparametric tests, as well as the t-Student test were utilized for statistical analysis.. The accepted significance value was 0.05. All subjects had used cocaine or crack and other substances. Only 13 (26%) did not drop out of school (group 1). Regarding the other 37 (74%), irregular class attendance , successive failures and definitive school drop out rates (group 2) were verified. These subjects presented an early substance use when compared with those which did not drop out of school (p=0.0001). Patients with an early substance use presented higher school dropout rates than those with a later initiation to substance use. Psychopathological phenomena were frequent in both groups.

Cocaine effects on mouse incentive-learning and human addiction are linked to alpha 2 subunit-containing GABA(A) receptors

Because GABA(A) receptors containing alpha 2 subunits are highly represented in areas of the brain, such as nucleus accumbens (NAcc), frontal cortex, and amygdala, regions intimately involved in signaling motivation and reward, we hypothesized that manipulations of this receptor subtype would influence processing of rewards. Voltage-clamp recordings from NAcc medium spiny neurons of mice with alpha 2 gene deletion showed reduced synaptic GABA(A) receptor-mediated responses. Behaviorally, the deletion abolished cocaine`s ability to potentiate behaviors conditioned to rewards (conditioned reinforcement), and to support behavioral sensitization. In mice with a point mutation in the benzodiazepine binding pocket of alpha 2-GABA(A) receptors (alpha 2H101R), GABAergic neurotransmission in medium spiny neurons was identical to that of WT (i.e., the mutation was silent), but importantly, receptor function was now facilitated by the atypical benzodiazepine Ro 15-4513 (ethyl 8-amido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate). In alpha 2H101R, but not WT mice, Ro 15-4513 administered directly into the NAcc-stimulated locomotor activity, and when given systemically and repeatedly, induced behavioral sensitization. These data indicate that activation of alpha 2-GABA(A) receptors (most likely in NAcc) is both necessary and sufficient for behavioral sensitization. Consistent with a role of these receptors in addiction, we found specific markers and haplotypes of the GABRA2 gene to be associated with human cocaine addiction.

Compulsive features in behavioural addictions: the case of pathological gambling

Aims To describe, in the context of DSM-V, how a focus on addiction and compulsion is emerging in the consideration of pathological gambling (PG). Methods A systematic literature review of evidence for the proposed re-classification of PG as an addiction. Results Findings include: (i) phenomenological models of addiction highlighting a motivational shift from impulsivity to compulsivity associated with a protracted withdrawal syndrome and blurring of the ego-syntonic/ego-dystonic dichotomy; (ii) common neurotransmitter (dopamine, serotonin) contributions to PG and substance use disorders (SUDs); (iii) neuroimaging support for shared neurocircuitries between behavioural and substance addictions and differences between obsessivecompulsive disorder (OCD), impulse control disorders (ICDs) and SUDs; (iv) genetic findings more closely related to endophenotypic constructs such as compulsivity and impulsivity than to psychiatric disorders; (v) psychological measures such as harm avoidance identifying a closer association between SUDs and PG than with OCD; (vi) community and pharmacotherapeutic trials data supporting a closer association between SUDs and PG than with OCD. Adapted behavioural therapies, such as exposure therapy, appear applicable to OCD, PG or SUDs, suggesting some commonalities across disorders. Conclusions PG shares more similarities with SUDs than with OCD. Similar to the investigation of impulsivity, studies of compulsivity hold promising insights concerning the course, differential diagnosis and treatment of PG, SUDs, and OCD.

Endophenotypes and serotonergic polymorphisms associated with treatment response in obsessive-compulsive disorder

OBJECTIVES: Approximately 40-60% of obsessive-compulsive disorder patients are nonresponsive to serotonin reuptake inhibitors. Genetic markers associated with treatment response remain largely unknown. We aimed (1) to investigate a possible association of serotonergic polymorphisms in obsessive-compulsive disorder patients and therapeutic response to selective serotonin reuptake inhibitors and (2) to examine the relationship between these polymorphisms and endocrine response to intravenous citalopram challenge in responders and non-responders to serotonin reuptake inhibitors and in healthy volunteers. METHODS: Patients with obsessive-compulsive disorder were classified as either responders or non-responders after long-term treatment with serotonin reuptake inhibitors, and both groups were compared with a control group of healthy volunteers. The investigated genetic markers were the G861C polymorphism of the serotonin receptor 1D beta gene and the T102C and C516T polymorphisms of the serotonin receptor subtype 2A gene. RESULTS: The T allele of the serotonin receptor subtype 2A T102C polymorphism was more frequent among obsessive-compulsive disorder patients (responders and non-responders) than in the controls (p<0.01). The CC genotype of the serotonin receptor subtype 2A C516T polymorphism was more frequent among the non-responders than in the responders (p<0.01). The CC genotype of the serotonin receptor subtype 1D beta G681C polymorphism was associated with higher cortisol and prolactin responses to citalopram (p<0.01 and p<0.001, respectively) and with a higher platelet-rich plasma serotonin concentration among the controls (p<0.05). However, this pattern was not observed in the non-responders with the same CC genotype after chronic treatment with serotonin reuptake inhibitors. This CC homozygosity was not observed in the responders.

The Dependence of Retention Time on Gate Length in UTBOX FBRAM With Different Source/Drain Junction Engineering

The floating-body-RAM sense margin and retention-time dependence on the gate length is investigated in UTBOX devices using BJT programming combined with a positive back bias (so-called V th feedback). It is shown that the sense margin and the retention time can be kept constant versus the gate length by using a positive back bias. Nevertheless, below a critical L, there is no room for optimization, and the memory performances suddenly drop. The mechanism behind this degradation is attributed to GIDL current amplification by the lateral bipolar transistor with a narrow base. The gate length can be further scaled using underlap junctions.

Concurrent crack and powder cocaine users from Sao Paulo: Do they represent a different group?

Abstract Background Cocaine abuse is a serious and socially damaging illegal drug problem. Different routes of administration are associated with a specific progression of use, different degrees of abuse liability, propensity for dependence and treatment response. There have been relatively few studies comparing different cocaine users groups and no studies into the characterization of the group of individuals reporting concurrent use of powder cocaine and crack cocaine. Methods Six hundred and ninety-nine cocaine users were assessed during the period August 1997 to October 1998 in one outpatient and six inpatient clinics located in the São Paulo, Brazil. Patients were interviewed using a structured questionnaire schedule in Portuguese, designed specifically for the Brazilian population. The statistical analyses were performed using either ANOVA or a chi-squared test and focusing on their preferred form of use/route of administration and other variables. Results For 83% of the variables tested in this study, the Dual Users subgroup (using both powder and crack cocaine) demonstrated statistical differences from the single drug user subgroups. Those differences include the initiation of cocaine, the abuse of other illicit drugs, and rates of criminal history. Conclusion These data suggest cocaine-dependent individuals who report use of both powder and crack cocaine are an at least partially, distinct subgroup. However, further studies will be necessary to confirm this and to determine if they also show a different treatment response.

A note on the use of the generalized odds ratio in meta-analysis of association studies involving bi- and tri-allelic polymorphisms

Abstract Background The generalized odds ratio (GOR) was recently suggested as a genetic model-free measure for association studies. However, its properties were not extensively investigated. We used Monte Carlo simulations to investigate type-I error rates, power and bias in both effect size and between-study variance estimates of meta-analyses using the GOR as a summary effect, and compared these results to those obtained by usual approaches of model specification. We further applied the GOR in a real meta-analysis of three genome-wide association studies in Alzheimer's disease. Findings For bi-allelic polymorphisms, the GOR performs virtually identical to a standard multiplicative model of analysis (e.g. per-allele odds ratio) for variants acting multiplicatively, but augments slightly the power to detect variants with a dominant mode of action, while reducing the probability to detect recessive variants. Although there were differences among the GOR and usual approaches in terms of bias and type-I error rates, both simulation- and real data-based results provided little indication that these differences will be substantial in practice for meta-analyses involving bi-allelic polymorphisms. However, the use of the GOR may be slightly more powerful for the synthesis of data from tri-allelic variants, particularly when susceptibility alleles are less common in the populations (≤10%). This gain in power may depend on knowledge of the direction of the effects. Conclusions For the synthesis of data from bi-allelic variants, the GOR may be regarded as a multiplicative-like model of analysis. The use of the GOR may be slightly more powerful in the tri-allelic case, particularly when susceptibility alleles are less common in the populations.

On the development of novel cocaine-analogues for in vivo imaging of the dopamine transporter status

The present thesis is concerned with the development of novel cocaine-derived dopamine transporter ligands for the non-invasive exploration of the striatal and extra-striatal dopamine transporter (DAT) in living systems. The presynaptic dopamine transporter acquires an important function within the mediation of dopaminergic signal transduction. Its availability can serve as a measure for the overall integrity of the dopaminergic system. The DAT is upregulated in early Parkinson’s disease (PD), resulting in an increased availability of DAT-binding sites in the striatal DAT domains. Thereby, DAT imaging has become an important routine diagnostic tool for the early diagnosis of PD in patients, as well as for the differentiation of PD from symptomatically similar medical conditions. Furthermore, the dopaminergic system is involved in a variety of psychiatric diseases. In this regard, DAT-selective imaging agents may provide detailed insights into the scientific understanding of the biochemical background of both, the progress as well as the origins of the symptoms. DAT-imaging may also contribute to the determination of the dopaminergic therapeutic response for a given medication and thereby contribute to more convenient conditions for the patient. From an imaging point of view, the former demands a high availability of the radioactive probe to facilitate broad application of the modality, whereas the latter profits from short-lived probes, suitable for multi-injection studies. Therefore, labelling with longer-lived 18F-fluoride and in particular the generator nuclide 68Ga is worthwhile for clinical routine imaging. In contrast, the introduction of a 11C-label is a prerequisite for detailed scientific studies of neuronal interactions. The development of suitable DAT-ligands for medical imaging has often been complicated by the mixed binding profile of many compounds that that interact with the DAT. Other drawbacks have included high non-specific binding, extensive metabolism and slow accumulation in the DAT-rich brain areas. However, some recent examples have partially overcome the mentioned complications. Based on the structural speciality of these leads, novel ligand structures were designed and successfully synthesised in the present work. A structure activity relationship (SAR) study was conducted wherein the new structural modifications were examined for their influence on DAT-affinity and selectivity. Two of the compounds showed improvements in in vitro affinity for the DAT as well as selectivity versus the serotonin transporter (SERT) and norepinephrine transporter (NET). The main effort was focussed on the high-affinity candidate PR04.MZ, which was subsequently labelled with 18F and 11C in high yield. An initial pharmacological characterisation of PR04.MZ in rodents revealed highly specific binding to the target brain structures. As a result of low non-specific binding, the DAT-rich striatal area was clearly visualised by autoradiography and µPET. Furthermore, the radioactivity uptake into the DAT-rich brain regions was rapid and indicated fast binding equilibrium. No radioactive metabolite was found in the rat brain. [18F]PR04.MZ and [11C]PR04.MZ were compared in the primate brain and the plasma metabolism was studied. It was found that the ligands specifically visualise the DAT in high and low density in the primate brain. The activity uptake was rapid and quantitative evaluation by Logan graphical analysis and simplified reference tissue model was possible after a scanning time of 30 min. These results further reflect the good characteristics of PR04.MZ as a selective ligand of the neuronal DAT. To pursue 68Ga-labelling of the DAT, initial synthetic studies were performed as part of the present thesis. Thereby, a concept for the convenient preparation of novel bifunctional chelators (BFCs) was developed. Furthermore, the suitability of novel 1,4,7-triazacyclononane based N3S3-type BFCs for biomolecule-chelator conjugates of sufficient lipophilicity for the penetration of the blood-brain-barrier was elucidated.

Vertical bias in neglect: A question of time?

Neglect is defined as the failure to attend and to orient to the contralesional side of space. A horizontal bias towards the right visual field is a classical finding in patients who suffered from a right-hemispheric stroke. The vertical dimension of spatial attention orienting has only sparsely been investigated so far. The aim of this study was to investigate the specificity of this vertical bias by means of a search task, which taps a more pronounced top-down attentional component. Eye movements and behavioural search performance were measured in thirteen patients with left-sided neglect after right hemispheric stroke and in thirteen age-matched controls. Concerning behavioural performance, patients found significantly less targets than healthy controls in both the upper and lower left quadrant. However, when targets were located in the lower left quadrant, patients needed more visual fixations (and therefore longer search time) to find them, suggesting a time-dependent vertical bias.