Neuroprotective effects of (+/-)-huprine Y on in vitro and in vivo models of excitoxicity damage

We have investigated the neuroprotective effects of (+/-)-huprine Y on excitotoxic lesions in rat cerebellar granule cells (CGCs). (+/-)-Huprine Y prevented cell death induced by 100 microM glutamate, as well as, 10 microM MK-801, a NMDA receptor antagonist, in a significant manner. On the other hand, intracellular calcium increase induced by NMDA (200 microM), measured by fura-2 fluorescence, was prevented by (+/-)-huprine Y with an EC(50) of 12.44 microM, which evidences the modulatory action of this compound on NMDA-induced calcium currents. In vivo, we have studied (+/-)-huprine Y neuroprotective effects on striatal lesions induced by the subacute administration of the mitochondrial toxin 3-nitropropionic acid (3-NP, 30 mg/kg, ip, for 10 days). We have assessed that both the behavioral and the morphological consequences of the lesion were prevented by pretreatment with (+/-)-huprine Y (2.5 mg/kg/twice a day, ip). Striatal gliosis induced by 3-NP treatment was prevented by (+/-)-huprine Y pretreatment, as demonstrated by the attenuation of both the increase in [(3)H]PK 11195 specific binding indicative of microgliosis and the expression of hsp27 kDa, a chaperone expressed mainly in astrocytes. In conclusion, (+/-)-huprine Y attenuated excitotoxic-induced lesions, both in vitro and in vivo, and further evidence is provided for the potential use of this compound in the prevention of neurodegenerative disorders.     

Monitoring of idebenone treatment in patients with Friedreich's ataxia by high-pressure liquid chromatography with electrochemical detection

Idebenone is a quinone analog that is applied in the treatment of several neurological disorders including Friedreich ataxia and mitochondrial encephalomyopathies. Our aim was to develop an easy and sensitive analytical HPLC-procedure for the determination of idebenone in the serum of patients treated with this drug. Serum samples from nine paediatric patients diagnosed with Friedreich ataxia and receiving idebenone treatment were analyzed. Idebenone was separated from serum by reverse high-pressure liquid chromatography and analyzed using an electrochemical detection procedure. No interferences were observed during analysis of patient samples obtained prior to idebenone treatment. Calibration of idebenone concentration indicated a linear range between 500 pmol/l and 5 micromol/l and calculation of within-run and between-run coefficients of variation suggested adequate analytical quality for reliable determination. In agreement with previously reported data, during drug therapy, idebenone serum concentrations (basal conditions, range 0.1-0.49 micromol/l) were greatly elevated 90 min after an oral dose (range 0.66-3.63 micromol/l). Thus, we have developed a simple and rapid method that offers adequate analytical quality for accurate idebenone determination.     

Motivational views of reinforcement: implications for understanding the behavioral functions of nucleus accumbens dopamine

Although the Skinnerian 'Empirical Law of Effect' does not directly consider the fundamental properties of stimuli that enable them to act as reinforcers, such considerations are critical for determining if nucleus accumbens dopamine systems mediate reinforcement processes. Researchers who have attempted to identify the critical characteristics of reinforcing stimuli or activities have generally arrived at an emphasis upon motivational factors. A thorough review of the behavioral literature indicates that, across several different investigators offering a multitude of theoretical approaches, motivation is seen by many as being fundamental to the process of reinforcement. The reinforcer has been described as a goal, a commodity, an incentive, or a stimulus that is being approached, self-administered, attained or preserved. Reinforcers also have been described as activities that are preferred, deprived or in some way being regulated. It is evident that this 'motivational' or 'regulatory' view of reinforcement has had enormous influence over the hypothesis that DA directly mediates 'reward' or 'reinforcement' processes. Indeed, proponents of the DA/reward hypothesis regularly cite motivational theorists and employ their language. Nevertheless, considerable evidence indicates that low/moderate doses of DA antagonists, and depletions of DA in nucleus accumbens, can suppress instrumental responding for food while, at the same time, these conditions leave fundamental aspects of reinforcement (i.e. primary or unconditioned reinforcement; primary motivation or primary incentive properties of natural reinforcers) intact. Several complex features of the literature on dopaminergic involvement in reinforcement are examined below, and it is argued that the assertions that DA mediates 'reward' or 'reinforcement' are inaccurate and grossly oversimplified. Thus, it appears as though it is no longer tenable to assert that drugs of abuse are simply turning on the brain's natural 'reward system'. In relation to the hypothesis that DA systems are involved in 'wanting', but not 'liking', it is suggested in the present review that 'wanting' has both directional aspects (e.g. appetite to consume food) and activational aspects (e.g. activation for initiating and sustaining instrumental actions; tendency to work for food). The present paper reviews findings in support of the hypothesis that low doses of DA antagonists and accumbens DA depletions do not impair appetite to consume food, but do impair activational aspects of motivation. This suggestion is consistent with the studies showing that low doses of DA antagonists and accumbens DA depletions alter the relative allocation of instrumental responses, making the animals less likely to engage in instrumental responses that have a high degree of work-related response costs. In addition, this observation is consistent with studies demonstrating that accumbens DA depletions make rats highly sensitive to ratio requirements on operant schedules. Although accumbens DA is not seen as directly mediating appetite to consume food, principles of behavioral economics indicate that accumbens DA could be involved in the elasticity of demand for food in terms of the tendency to pay work-related response costs. Future research must focus upon how specific aspects of task requirements (i.e. ratio requirements, intermittence of reinforcement, temporal features of response requirements, dependence upon conditioned stimuli) interact with the effects of accumbens DA depletions, and which particular factors determine sensitivity to the effects of DA antagonism or depletion.     

Cognitive factors associated with smoking initiation in adolescents

OBJECTIVE: To study the association between cognitive factors of the behavioral change model "Attitude Self Efficacy" (ASE) at different phases of smoking initiation among adolescents. METHODS: We carried out a cross-sectional survey among students in the second grade of Compulsory Secondary Education (13-14 years old) from Cornellà de Llobregat (Barcelona, Spain) in 2000 to obtain information on cognitive factors and smoking. Logistic regression analysis was used to investigate the variables associated with smoking (odds ratio [OR] of experimenters vs. non-smokers and of smokers vs. experimenters). RESULTS: The prevalence of daily smoking was 22.9% (95% CI, 16.5%-29.3%) among boys and 36.2% (95% CI, 29.7%-42.6%) among girls. Factors associated with experimenting (vs. non-smoking) were: attitudes to smoking (disagreement with smoke-free areas [OR = 3.46; 95% CI, 1.65-7.24], agreement with smoking promotion [OR = 3.42; 95% CI, 1.42-8.28]), and subjective norms (perceiving friends as smokers [OR = 2.50; 95% CI, 1.17-5.35]). The variables associated with regular smoking (vs experimenting) belong to: self-efficacy and attitudes to smoking. CONCLUSIONS: Focussing on subjective norms and smoking attitudes with programs targetted younger ages seems appropriate, since these factors are more closely associated with the experimenting phase. Encouraging skills to refuse cigarettes offered by friends is appropriate at a more advanced age, since this determinant is associated with the change from experimenting to regular smoking.     

Ratio and time requirements on operant schedules: effort-related effects of nucleus accumbens dopamine depletions

Accumbens dopamine (DA) depletions produce deficits that are related to the ratio requirement of the operant schedule; however, it is also possible that time without reinforcement is a factor. The present study examined the effects of accumbens DA depletions in rats using variable interval (VI) schedules with additional fixed ratio (FR) requirements. Four VI schedules were used (VI 60/FR 1, VI 120/FR 1, VI 60/FR 10, VI 120/FR 10). Attachment of the additional work requirement increased response rates under control conditions. After surgery, there was no interaction between interval level (i.e. 60 vs. 120 s) and DA depletion, but there was a significant interaction between ratio requirement (i.e. 1 vs. 10) and DA depletion within the first week after surgery. DA depletions substantially impaired performance on the schedules with added FR 10 requirements, an effect that was largely dependent upon a reduction in fast responses (i.e. inter-response times less than 1.0 s). There was little effect of DA depletion on overall responding on VI 60/FR 1 and VI 120/FR 1 schedules. DA depletions also increased the tendency to take long pauses in responding (i.e. > 20.0 s), and this effect was evident across all schedules tested. Thus, accumbens DA depletions interact with work requirements and blunt the rate-enhancing effects of moderate size ratios, and also enhance the tendency to pause. Attachment of ratio requirements to interval schedules is a work-related response cost that provides a challenge to the organism, and DA in nucleus accumbens appears to be necessary for adapting to this challenge.     

Endogenous brain-derived neurotrophic factor protects dopaminergic nigral neurons against transneuronal degeneration induced by striatal excitotoxic injury

Injury to the central nervous system causes atrophy or death of connecting neurons and can modify the expression of neurotrophic factors. We observed transneuronal upregulation of brain-derived neurotrophic factor (BDNF) expression in the rat ipsilateral substantia nigra pars compacta after a striatal lesion induced by kainate. This effect is developmentally regulated because the enhancement of nigral BDNF expression was only observed when striatal lesion was performed on postnatal day (P) 15 and in adulthood, but not at P7. Interestingly, the lack of regulation of BDNF was coincident with the transynaptic degeneration of nigral neurons after striatal excitotoxic injury. Hence, the number of tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta decreased when the lesion was performed at P7, but not at P15 or at P30. The analysis of the functional significance of this BDNF upregulation was done using trkB-IgG fusion proteins. After striatal injury, blockade of endogenous BDNF by trkB fusion proteins induced an atrophy of the dopaminergic neurons of the pars compacta. The injection of trkB-IgG fusion proteins did not modify the effects of kainate in the substantia nigra pars reticulata. Thus, our results show that BDNF exerts an autocrine/paracrine protective effect selectively on dopaminergic neurons against the loss of trophic support from the target striatum.     

An open-label study of amisulpride in the treatment of mania

BACKGROUND: Amisulpride is a selective D(2)-D(3) antagonist that has been reported to be effective in the treatment of schizophrenia and major depressive disorder. However, no prospective study to date has assessed the effectiveness and tolerability of this compound in mania. METHOD: Twenty DSM-IV-defined acutely ill manic bipolar patients with a Young Mania Rating Scale (YMRS) score of 20 or more entered this open, prospective, 6-week study. Assessments included the YMRS, the Hamilton Rating Scale for Depression (HAM-D), the Clinical Global Impressions Scale for Bipolar Disorder, Modified (CGI-BP-M), and the systematic report of adverse events. Amisulpride was added to other medications, but other antipsychotics were not allowed. RESULTS: Fourteen patients (70%) completed the study. Using last-observation-carried-forward (LOCF) analyses, amisulpride produced significant improvements on the YMRS (p = .0001), the HAM-D (p < .0141), and the overall (p = .0003), mania (p = .0001), and depression (p = .0268) subscales of the CGI-BP-M. The most common side effect was sedation (N = 5, 25%), but there were also some extrapyramidal symptoms, galactorrhea, insomnia, and agitation. The mean amisulpride dose was 680 mg/day (LOCF) and 786 mg/day in completers. CONCLUSIONS: This first prospective study on amisulpride in the treatment of mania suggests that, despite the limitations of the open, observational design and small sample size, amisulpride may be effective and reasonably safe in the treatment of bipolar mania. D(2) and D(3) antagonism may be involved in the mechanisms of the therapeutic response to antipsychotics in mania.     

Keeping company in an emotional trip. Emotional intelligence applied to the help relationship

In order to be a good professional and caretaker, it is essential to work on one's capacity to manage one's own feelings and emotions in an adaptable, intelligent manner. This set of abilities form part of the concept known as Emotional Intelligence. One can only give to another what one is and one knows how to give to oneself. The five ability groups which make up affective or emotional intelligence are: self-knowledge, self-control, self-motivation, empathy and relationship abilities. All are necessary in order to carry out good management of our feelings and emotions.