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Early exposure to stressful stimuli is crucial for developing varied behavioural patterns in adulthood such as anxiety, cognitive dysfunction and abuse disorders. The alteration of the hypothalamic–pituitary–adrenal (HPA) axis represents the neurobiological substrate responsible of the behavioural consequences of prenatal stress (PS). Indeed, prenatal manipulation of the HPA axis impacts on cognitive performance of the adult offspring, but also on vulnerability to alcohol consumption. Prenatal acute, moderate restraint stress has proved to facilitate HPA axis development of the offspring, since maternal corticosterone secretion leads to the reduction of anxiogenic behaviour and an improvement in the ability to cope with stress, increasing both the rate of learning and long-term potentiation, but also gestational stress blunts initial alcohol-induced HPA axis activation. In our recent study, moderate alcohol intake proved to reduce emotionality and facilitate the adaptive responses to stress, enhancing behavioural flexibility. Based upon these findings, we aimed at assessing the impact of a single, intense prenatal stress on exposure to alcohol preference and on the effects exerted by ethanol on behavioural reactivity, anxiety-like behaviour and spatial learning in adult male Wistar rats.

Respiratory tract infections are the most common diseases in childhood. The respiratory tract, widely branched system of ducts, is particularly exposed to the action of microorganisms transmitted by air from here the high frequency of infections they face especially in the first years of life. It is usual distinguish: upper respiratory tract infections (URTI) and lower respiratory tract infections (LRTI). In particular, in infections of the upper airways, the inflammatory process, result of the interaction between microbes and the immune response, can be localized to the mucosa of the nose or sinuses (common cold and sinusitis), or the pharynx or larynx (pharyngotonsillitis and laryngitis) and it has predominantly a viral etiology although occasionally it may be followed by bacterial complications such as otitis media. The aim of the following article is the description of these different clinical pictures, highlighting the clinical and epidemiological features and current management guidelines.

Introduction: To examine the putative association between Sleep-Disordered breathing and hearing disorders Material and methods: 120 Sicilian subjects ranging from 14 to 85 years of age who were divided in 46 cases suffering from tinnitus (G1 group) and 74 controls (G2 group) were evaluated through STOP BANG screening questionnaire and Four-Variable Screening Tool; after Data collecting each subject underwent Audiological assessment by multi-frequency audiometry (PTA) and Transient-evoked otoacoustic emissions (TEOAE-diagnostic) for each ear. Results: Cases showed: PTA significantly severe than the control group (58.70% vs. 16.89% hearing loss; P

Infants admitted to the neonatal intensive care unit (NICU), who represent the 4-8% of all births, present problems such as prematurity, low Apgar scores, infections, hyperbilirubinemia and hearing impairment. In particular significant hearing loss is the most common disorder at birth, occurring in 1 to 2 newborns per 1000 in the general population and 24% to 46% of newborns who are admitted to a NICU. This leads more difficulty to develope verbal skills (learning vocabulary, grammar, word order and idiomatic expressions), language, learning and speech. Hearing impairment influences also cognitive and affective development of infants making consequences in their interpersonal relationships. Joint Committee on Infants Hearing (JCIH) identified many risk factors in NICU infants like as prolonged mechanical ventilation, asphyxia, low birth weight and ototoxic medication and therefore the first step for early diagnosis of hearing loss is identify these factors. Second step is to plan a correct screening strategy. Screening procedures to detect hearing impairment may be divided into two categories: behavioral and electrophysiological. Behavioral techniques produce a high number of false-negative results due to the relative subjectivity of the assessment and difficulty in detecting mild or unilateral hearing loss. Electrophysiological procedures have greater sensitivity and specificity and include measuring the following: auditory brainstem responses (ABR), automated auditory brainstem responses (AABR), and evoked otoacoustic emissions (EOAE). In this chapter will analyze the prevalence of the risk factors in NICU infants most often associated with hearing loss and the screening methods to arrive as soon as possible an early diagnosis.

Newborn babies who need intensive medical care are often sheltered into a special area of the hospital called Neonatal Intensive Care Unit (NICU). In this structure, babies are regularly subject to conditions that would be considered harmful by older children and adults. In the last years, many clinical researches have paid particular attention to effectiveness of various pharmacological therapies, regularly used in neonatal intensive care that have sharply reduced mortality of newborn and preterm infants. Although there are many classes of drugs used for the treatment of different diseases (sepsis, pain, seizures, pulmonary hypertension and infection), the fledgling population is more difficult to handle because there are many physiological changes that happen in infants which do not occur at any other time of life. Furthermore, there are many drugs used during the first stage of life, able to induce various toxic effects on the principal organs and apparatus. For example, there are many relationships between amikacina serum levels and central conduction time in brainstem auditory evoked potentials within therapeutic range levels in newborns as index of drug toxicity in brainstem auditory centers in neonatally exposed infants. In this chapter, we will focus mainly on the principal pharmacological strategies used for dealing with neonatal diseases in the Neonatal Intensive Care Unit.

Tinnitus is a frequent symptom in audiological clinical practice characterized by an abnormal noise perceived in one or both ears or in the head, in which a patient has a conscious hearing percept in absence of external sound. Tinnitus might be caused by a homeostatic response of central dorsal cochlear nucleus auditory neurons that makes them hyperactive in compensation to auditory input loss. One hypothesis suggests that tinnitus is a sensory form of epilepsy that involves the cochlear nucleus and the inferior colliculus, which display impairment in the electrical activity in the auditory system. This alteration determines a synaptic plasticity in the dorsal cochlear nucleus that becomes a target for pharmacological compounds able to treat tinnitus. There is no effective drug treatment for tinnitus, but different studies propose the use of cannabinoid receptors agonist for their anti-epileptic activity, although their practical effects are still unclear. In this review, we want to analyze the emerging pharmacological approaches of cannabinoid receptor agonists to the therapy of tinnitus.

In the rat, prenatal exposure to diazepam (DZ) induces a permanent reduction in GABA/BZ receptor (R) function and behavioural abnormalities. Environmental modifications during early stages of life can influence brain development and induce neurobiological and behavioural changes throughout adulthood. Indeed, a subtle, periodic, postnatal manipulation increases GABA/BZ R activity and produces facilitatory effects on neuroendocrine and behavioural responses. We here investigated the impact of prenatal treatment with DZ on learning performance in adult 3- and 8-month-old male rats and the influence of a brief, periodic maternal separation on the effects exerted by prenatal DZ exposure. Learning performance was examined employing a non-aversive spatial, visual and/or tactile task, the "Can test". Behavioural reactivity, emotional state and fear/anxiety-driven behaviour were also examined using open field (OF), acoustic startle reflex (ASR) and elevated plus-maze (EPM) tests. A single daily injection of DZ (1.5 mg/kg, s.c.), over gestational days (GD) 14-20, induced, in an age-independent manner, a severe deficit in learning performance, a decrease in locomotor and explorative activity and an increase in peak amplitude in the ASR. Furthermore, anxiety-driven behaviour in EPM was disrupted. Daily maternal separation for 15 min over postnatal days 2-21 exerted opposite effects in all the paradigms examined. Prenatally DZ-exposed maternal separated rats, in contrast to respective non-separated rats, showed an improvement in learning performance, a decrease in emotionality and a normalization of the exploratory behaviour in EPM. These results suggest that a greater maternal care, induced by separation, can serve as a source for the developing brain to enhance neuronal plasticity and to prevent the behavioural abnormalities induced by prenatal DZ exposure. © 2005 Elsevier B.V. All rights reserved.

While a lot is known about the mechanisms promoting aversive learning, the impact of rewarding factors on memory has received comparatively less attention. This research investigates reward-related explicit memory in male rats, by taking advantage of the emotional-object recognition test. This is based on the prior association, during conditioned learning, between a rewarding experience (the encounter with a receptive female rat) and an object; afterwards rat discrimination and recognition of the â emotional objectâ is recorded in the presence of a novel object, as a measure of positive limbic memory formation. Since endocannabinoids are critical for processing reward and motivation, the consequences of the stimulation of cannabinoid signalling are also assessed by the administration of WIN 55,212-2 at pre- and post-conditioning time. Our results show that rats encode the association between object and rewarding experience, form positive limbic memory of the emotional object, and retrieve this information in the face of novelty. Stimulation of the cannabinoid system at pre-conditioning time is able to strengthen reward-related explicit memory in the presence of novelty, whereas post-conditioning activation increases approach behaviour to novel stimuli. The assessment of limbic memory by the emotional-object recognition test can help unveiling the addictive and confounding properties of psychotropic drugs.

The ability of several N-phenyl-1H-pyrazole-4-carboxamide derivatives and other pyrazoles opportunely modified at the positions 3, 4 and 5, to reduce the formation of the biofilm in some Staphylococcus aureus strains (ATCC 29213, ATCC 25923 and ATCC 6538) were investigated. All the tested compounds were able, although to a different extent, to reduce the biofilm formation of the three bacterial strains considered. Among these, the 1-(2,5-dichlorophenyl)-5-methyl-N-phenyl-1H-pyrazole-4-carboxamide 14 resulted as the best inhibitor of biofilm formation showing an IC50 ranging from 2.3 to 32 μM, against all the three strains of S. aureus. Compound 14 also shows a good protective effect in vivo by improving the survival of wax moth larva (Galleria mellonella) infected with S. aureus ATCC 29213. These findings indicate that 14d is a potential lead compound for the development of new anti-virulence agents against S. aureus infections.

A natural like O -glycoconjugate polycyclic compound 4 was obtained by a multistep procedure starting from N -(3-methyl-1-(4-nitrophenyl)-1 H -pyrazol-5-yl)acetamide. The glycosyl derivative 4 showed antiproliferative activity against all the tumoral cell lines of the NCI panel in the range 0.47–5.43 μ M. Cytofluorimetric analysis performed on MDA-MB231, a very aggressive breast cancer cell line, which does not express estrogen, progesterone and HER-2/neu receptors, showed that 4 is able to induce prolonged cell cycle arrest at G2/M phase and morphological signs of differentiation. These events are correlated with down-regulation of both cyclin B1 and cdc2, the cyclins involved in G2/M transition, as well as up-regulation of cyclin-dependent kinase (CDK) inhibitor p21 Cip1/Waf1.

The mesolimbic dopamine (DA) system plays a key role in drug reinforcement and is involved in the development of alcohol addiction. Manipulation of the DAergic system represents a promising strategy to control drug-seeking behavior. Previous studies on 2-amino-N-[2-(3,4-dihydroxy-phenyl)-ethyl]-3-phenyl-propionamide (DA-Phen) showed in vivo effects as a DA-ergic modulator. This study was aimed at investigate DA-Phen effects on operant behavior for alcohol seeking behavior, during reinstatement following subsequent periods of alcohol deprivation. For this purpose, male Wistar rats were tested in an operant paradigm of self-administration; behavioral reactivity and anxiety like-behavior during acute abstinence were evaluated. A characterization of DA-Phen CNS targeting by its quantification in the brain was also carried out. Our findings showed that DA-Phen administration was able to reduce relapse in alcohol drinking by 50% and reversed the alterations in behavioral reactivity and emotionality observed during acute abstinence. In conclusion, DA-Phen can reduce reinstatement of alcohol drinking in an operant-drinking paradigm following deprivation periods and reverse abstinence-induced behavioral phenotype. DA-Phen activity seems to be mediated by the modulation of the DAergic transmission. However further studies are needed to characterize DA-Phen pharmacodynamic and pharmacokinetic properties, and its potential therapeutic profile in alcohol addiction.

Although binge drinking is on the rise in women of reproductive age and during pregnancy, the consequences in the offspring, in particular the inheritance of alcohol-related mood disturbances and alcohol abuse vulnerability, are still poorly investigated. In this study, we modeled both Habitual- and Binge Alcohol Drinking (HAD and BAD) in female rats by employing a two-bottle choice paradigm, with 20% alcohol and water. The exposure started 12 weeks before pregnancy and continued during gestation and lactation. The consequences induced by the two alcohol drinking patterns in female rats were assessed before conception in terms of behavioral reactivity, anxiety- and depressive-like behavior. Afterwards, from adolescence to young-adulthood, male offspring was assessed for behavioral phenotype and alcohol abuse vulnerability. At pre-conceptional time BAD female rats showed higher mean alcohol intake and preference than HAD group; differences in drinking trajectories were attenuated during pregnancy and lactation. Pre-conceptional BAD induced a prevalent depressive/anhedonic-like behavior in female rats, rather than an increase in anxiety-like behavior, as observed in HAD rats. In the adolescent offspring, peri-gestational BAD did not affect behavioral reactivity in the open field and anxiety-like behavior in the elevated plus maze. Rather, BAD dams offspring displayed higher despair-behavior and lower social interaction with respect to control- and HAD dams progeny. Notably, only binge drinking exposure increased offspring vulnerability to alcohol abuse and relapse following forced abstinence. This is the first report showing that binge-like alcohol consumption from pre-conceptional until weaning induces relevant consequences in the affective phenotype of both the mothers and the offspring, and that such effects include heightened alcohol abuse vulnerability in the offspring. These findings highlight the need for more incisive public education campaigns about detrimental consequences of peri-gestational alcohol exposure.

Based on the encouraging results found for 3,5-dimethyl-6-phenyl-8-(trifluoromethyl)-5,6-dihydropyrazolo[3,4-f][1,2,3,5]tetrazepin-4-(3H)-one 7 previously tested by us, as well as the consideration that heterocycle fused tetrazepinones bearing the 2-chloroethyl substituent show a better cytotoxic profile than temozolomide and mitozolomide against human cancer cell lines which express the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT), in this paper we report the multistep synthesis and the biological study of 3-(2-cloroethyl)-5-methyl-6-phenyl-8-(trifluoromethyl)-5,6-dihydropyrazolo[3,4-f][1,2,3,5]tetrazepin-4-(3H)-one 10. Like compound 7, it was active on P-glycoprotein expressing cells (MDR) HL60 and on K562 cell line that are resistant to apoptosis induced by different stimuli, showing GI50 values of 14 and 18 µM respectively. As an antiproliferative agent against the above cells compound 10 was about 2.2 times more active than compound 7. Compound 10 was also tested against WiDR cells which are overexpressing the DNA repair protein MGMT, showing a GI50 value of 2.3 µM. Finally, concerning the effect on cell cycle we observed an evident difference between compounds 7 and 10. In fact, compound 7 induces a block of cell cycle in G0-G1, therefore acting as phase-specific drug, in contrast, compound 10 is a not phase-specific agent. Both the compounds are able to increase the apoptotic sub G0-G1 peak of cell cycle.

In this review we report the recent advances in anticancer activity of the family of natural occurring flavonoids, covering the time span of the last five years. The bibliographic data will be grouped, on the basis of biological information, in two great categories: reports in which the extract plants bioactivity is reported and the identification of each flavonoid is present or not, and reports in which the anticancer activity is attributable to purified and identified flavonoids from plants. Wherever possible, the targets and mechanisms of action as well as the structure-activity relationships of the molecules will be reported. Also, in the review it was thoroughly investigated the recent discovery on flavonoids containing the 2-phenyl-4H-chromen-4-one system even if some examples of unusual flavonoids, bearing a non-aromatic B-ring or other ring condensed to the base structure are reported.

Several experimental and clinical studies have shown that a variety of ototoxic agents (such as drugs, industrial chemicals and noise) can cause sensorineural hearing loss. The most common ototoxic drugs used in clinical practice include: aminoglycoside and macrolide antibiotics, quinoline anti-malarials, platinum analog antineoplastics, loop diuretics, and acetylsalicylic acid. Among chemical agents with potential ototoxic properties are: organic solvents, heavy metals, organotins, nitriles, asphyxiants, and pesticides/herbicides. Acoustic exposure to high intensity and/or prolonged noise can also cause permanent threshold shifts in auditory perception. Ototoxic agents can influence auditory function by different mechanisms: RO S overload, inhibition of mitochondrial protein synthesis, DNA/RNA damage, activation of the apoptotic pathways, excessive calcium influx, increase of proinflammatory cytokines, interference with fluid and electrolyte balance of the endolymph, atrophy of the stria vascularis, changes in blood-labyrinth barrier and overstimulation of the stereocilia of the ear cells. Since noise exposure and many drugs or chemical compounds frequently share the same ototoxic mechanisms, this may explain why hearing loss can be potentiated by combined exposure to these agents. However, a great variability in the individual’s response to a given xenobiotic exists and depends on a complex interplay between endogenous and exogenous factors.

This study aims at providing an insight into early handling procedures on learning and memory performance in adult female rats. Early handling procedures were started on post-natal day 2 until 21, and consisted in 15 min, daily separations of the dams from their litters. Assessment of declarative memory was carried out in the novel-object recognition task; spatial learning, reference- and working memory were evaluated in the Morris water maze (MWM). Our results indicate that early handling induced an enhancement in: (1) declarative memory, in the object recognition task, both at 1h and 24h intervals; (2) reference memory in the probe test and working memory and behavioral flexibility in the "single-trial and four-trial place learning paradigm" of the MWM. Short-term separation by increasing maternal care causes a dampening in HPA axis response in the pups. A modulated activation of the stress response may help to protect brain structures, involved in cognitive function. In conclusion, this study shows the long-term effects of a brief maternal separation in enhancing object recognition-, spatial reference- and working memory in female rats, remarking the impact of early environmental experiences and the consequent maternal care on the behavioral adaptive mechanisms in adulthood.

Rationale: In depressive disorders, one of the mechanisms proposed for antidepressant drugs is the enhancement of synaptic plasticity in the hippocampus and cerebral cortex. Previously, we showed that the muscarinic acetylcholine receptor (mAChR) agonist oxotremorine (Oxo) increases neuronal plasticity in hippocampal neurons via FGFR1 transactivation. Objectives: Here, we aimed to explore (a) whether Oxo exerts anxiolytic effect in the rat model of anxiety-depression-like behavior induced by chronic restraint stress (CRS), and (b) if the anxiolytic effect of Oxo is associated with the modulation of neurotrophic factors, brain-derived neurotrophic factor (BDNF) and fibroblast growth factor-2 (FGF2), and phosphorylated Erk1/2 (p-Erk1/2) levels in the dorsal or ventral hippocampus and in the medial prefrontal cortex. Methods: The rats were randomly divided into four groups: control unstressed, CRS group, CRS group treated with 0.2mg/kg Oxo, and unstressed group treated with Oxo. After 21days of CRS, the groups were treated for 10days with Oxo or saline. The anxiolytic role of Oxo was tested by using the following: forced swimming test, novelty suppressed feeding test, elevated plus maze test, and light/dark box test. The hippocampi and prefrontal cortex were used to evaluate BDNF and FGF2 protein levels and p-Erk1/2 levels. Results: Oxo treatment significantly attenuated anxiety induced by CRS. Moreover, Oxo treatment counteracted the CRS-induced reduction of BDNF and FGF2 levels in the ventral hippocampus and medial prefrontal cerebral cortex Conclusions: The present study showed that Oxo treatment ameliorates the stress-induced anxiety-like behavior and rescues FGF2 and BDNF levels in two brain regions involved in CRS-induced anxiety, ventral hippocampal formation, and medial prefrontal cortex.

Background: Alcohol consumption during pregnancy and lactation induces detrimental consequences, that are not limited to the direct in utero effects of the drug on fetuses, but extend to maternal care. However, the occurrence and severity of alcohol toxicity are related to the drinking pattern and the time of exposure. The present study investigated in female rats long-term alcohol drinking trajectories, by a continuous and intermittent free-choice paradigm, during pre-gestational time, pregnancy, and lactation; moreover, the consequences of long-term alcohol consumption on the response to natural reward and maternal behavior were evaluated. Methods: Virgin female rats were exposed to home-cage two-bottle continuous- or intermittent “alcohol (20% v/v) vs. water” choice regimen along 12 weeks and throughout pregnancy and lactation. Animals were tested for saccharin preference, and maternal behavior was assessed by recording dams' undisturbed spontaneous home-cage behavior in the presence of their offspring. Results: Our results show that the intermittent alcohol drinking-pattern induced an escalation in alcohol intake during pre-gestational time and lactation more than the continuous access, while a reduction in alcohol consumption was observed during pregnancy, contrarily to the drinking trajectories of the continuous access-exposed rats. Long-term voluntary alcohol intake induced a decreased saccharin preference in virgin female rats and a significant reduction in maternal care, with respect to control dams, although the intermittent drinking produced a greater impairment than the continuous-access paradigm. Conclusion: The present data indicate that both alcohol-drinking patterns are associated to modifications in the drinking trajectories of female rats, in pre-gestational time, during pregnancy and lactation. Moreover, long-lasting alcohol intake can affect sensitivity to natural rewarding stimuli and maternal behavior and sensitivity to natural rewarding stimuli in a pattern–related manner. This study underlies the importance of modeling human alcohol habit and its consequences on the mother-infant dyad, in order to prevent detrimental effects on offspring development and maturation.

New N-methyl and N-ethyl substitutions in the indazole nucleus are reported by reacting 3-(2-aminobenzamido)indazole and the appropriate trimethyl/triethyl orthobenzoate. Single crystal X-ray analysis confirms the N-ethylation position for the 3-(1-ethyl-1H-indazol-3-yl)-2-phenylquinazolin-4(3H)-one derivative 3f. Compounds 11a-d and 3a-d were tested to evaluate their antimicrobial, their antiproliferative activity and their COX inhibitory activities showing scarce or moderately antiproliferative activity and some inhibitory activity against COX-1 and COX-2.

The multistep synthesis of 3,5-dimethyl-6-phenyl-8-(trifluoromethyl)-5,6-dihydropyrazolo[3,4-f][1,2,3,5]tetrazepin-4(3H)-one 15 has been carried out. The compound showed antiproliferative and apoptotic effects against K562, K562-R (imatinib mesilate resistant), HL60 and multidrug resistant (MDR) HL60 cell lines. Compound 15 showed a pro-apoptotic activity against HL60 and K562 resistant cell lines markedly higher than etoposide and busulfan, respectively. Flow cytometry studies carried out on K562 cells allowed to establish that 15 induces G0-G1 phase arrest followed by apoptosis.

Several new 2-(2-phenoxyacetamido)benzamides 17a-v, 21 and 22 were synthesized by stirring in pyridine the acid chlorides 16a-e and the appropriate5-R-4-R1-2-aminobenzamide 15a-e and initially evaluated in vitro for antiproliferative activity against the K562 (human chronic myelogenous leukemia) cell line. Some of synthesized compounds were evaluated for their in vitro antiproliferative activity against the full NCI tumor cell line panel derived from nine clinically isolated cancer types (leukemia, non-small cell lung, colon, CNS, melanoma, ovarian, renal, prostate and breast). The most active compounds caused an arrest of K562 cells in the G0-G1 phase of cell cycle and induction of apoptosis, which was mediated by caspase activation.

N-(1-Phenyl-4-carbetoxypyrazol-5-yl)-, N-(indazol-3-yl)- and N-(indazol-5-yl)-2-iodobenzamides 6, with a Benodanil-like structure, were synthesized by refluxing in acetic acid the corresponding benzotriazinones 5 with potassium iodide for 1 h in order to study the role on the antifungal activity of the N-substitution with an aromatic heterocyclic system on benzamide moiety. Among the tested iododerivatives, compounds 6d,f,g,h possess interesting activities toward some phytopathogenic fungal strains.

The aims of this study were to determine the distribution of risk factors associated with tinnitus analysing their role in the development of tinnitus and the effects of their interaction; to evidence the importance of a suitable and adequate clinical and audiologic assessment to avoid those modifiable risk factors responsible for cochlear dysfunction and tinnitus onset. 46 subjects with tinnitus and 74 controls were studied according to: age, sex, Body Mass Index (BMI), neck circumference, tobacco smoking, feeling fatigue or headache, self reporting snoring, hypertension, diabetes, coronary heart disease, and/or hyperlipidemia, and laboratory finding as lipid profile and levels of reactive oxygen metabolites (d-ROM). Audiological assessment was performed by multi-frequency audiometry (PTA0.5–16 kHz) and transient-evoked otoacoustic emissions (TEOAE diagnostic). Univariate analysis was performed to examine the association between determinants and occurrence of tinnitus; Mantel–Haenszel test (G.or) was used to investigate the joint effect of determinants on tinnitus. Tinnitus was more frequent among males with age >50 years; BMI >30 kg/m2, neck circumference >40 cm, headache, hypertension, hypercholesterolemia resulted significant risk factors for tinnitus (P < 0.0001). Tinnitus group had more comorbidity (P < 0.0001) and worse audiometric thresholds (60.87 Vs 21.62 % hearing loss; P < 0.0001) with respect to control group. The interaction between hypertension–BMI ≥ 30 kg/m2 (G.or = 8.45) and smoking–hypercholesterolemia (G.or = 5.08) increases the risk of tinnitus (P < 0.0001). Our results underline that several factors either individually or jointly contribute to tinnitus onset; a comprehensive knowledge about tinnitus risk factors and associated clinical conditions could contribute to minimizing this disorder.

Several new 4-diazopyrazole derivatives 6a – g and 9a – c were obtained by the reaction of 1-(R-substituted-phenyl)-3-(1,3-dimethyl-1 H -pyrazol-5-yl)ureas 5a – g and N -(1,3-dimethyl-1 H -pyrazol-5-yl)-2-(R-substituted-phenyl)acetamides 8a – c respectively with a sevenfold excess of nitrous acid in acetic acid solution. The compounds were assayed for their activity against the Staphylococcus aureus reference strains ATCC 25923, ATCC 29213 and ATCC 6538, as well as six veterinary strains. The best anti-staphylococcal profile was showed by [(R-substituted-phenyl)acetyl](4-diazonio-1,3-dimethyl-1 H -pyrazol-5-yl)azanides 9a , c . Compound 9c was also able at 3.1 μg mL −1 to inhibit of 45.7% the biofilm formation of the strains S. aureus ATCC 29213.

Alcohol abuse is a substantial and growing health problem in Western societies. In the last years in vivo and in vitro studies have suggested that males and females display a different alcohol drinking behaviour, with swingeing differences not only in the propensity for alcohol use but also in the metabolic and behavioural consequences. In this study we investigated, in adult female rats, ethanol self-administration and preference pattern using a 3-bottle paradigm with water, 10% ethanol solution, and white wine (10%, v/v), along a four-week period. The influence of alcohol free-access on explorative behaviour in the open field (OF), and on spatial learning and reference memory in the Morris water maze (MWM) were also evaluated. Our results indicate that: (i) female rats show a higher preference for alcohol, in the first two weeks of the paradigm, displaying a higher consumption of 10% ethanol solution than white wine; in the last two weeks, they reduce their alcoholic preference, drinking the same moderate amounts of the two alcoholic beverages; (ii) at the fourth week of the free-access paradigm rats show a lower explorative behaviour in the open field and a worsening in spatial memory retention in the Morris water maze. In conclusion our data suggest that, despite the ability to self-regulate alcohol intake, female rats suffer from relevant impairments in spatial memory retention and cognitive flexibility, displaying a sexually dimorphic modification in the adaptive strategies.

Chronic ethanol consumption is able to modify emotional behaviour and cognition in humans. In particular, the effects exerted by alcohol may depend on doses, time and modalities of administration. In this study we investigated, in adult male rats, ethanol self-administration and preference patterns using a 3-bottle choice paradigm with water, 10% ethanol solution, and white wine (10%, v/v), along a four-week period. The influence of alcohol free-access on novelty-induced explorative behaviour in the open field, and on spatial learning and reference memory in the Morris water maze was also evaluated. Our results indicate that: (i) rats show a higher preference for alcohol, in the first two weeks of the paradigm, displaying a higher consumption of 10% ethanol solution than white wine; in the last two weeks, they reduce their alcoholic preference, drinking the same moderate amounts of the two alcoholic beverages; (ii) at the fourth week of the free-access paradigm rats show a high explorative behaviour in the central squares of the open field and an improvement in spatial information processing in the new-place learning task of the Morris water maze. In conclusion our data suggest that, interestingly, rats exposed to the free-access paradigm were able to self-regulate their alcoholic intake, and indicated that a moderate alcohol consumption was able to induce an increase in behavioural reactivity and an enhancement in spatial learning flexibility.

The pyrazolo[3,4-d]pyrimidine system shows a multitude of interesting pharmacological properties. Owing to the potential anti-inflammatory activity of 5-benzamido-pyrazolo[3,4-d]pyrimidin- 4-one derivatives and considering the easy synthesis of this class of compounds, a set of new 5- benzamido-1H-pyrazolo[3,4-d]pyrimidin-4-ones has been prepared in 42-80% yields by reacting 5- aminopyrazole-4(N-benzoyl)carbohydrazide derivatives and the opportune triethylorthoesters. Compounds 8a, b, 10a–d, and 11a, b revealed a superior inhibitory profile against COX-2, when compared to that of reference standards NS398 and indomethacin. Molecular modelling studies confirmed the obtained biological results.

Serotonin is involved in a wide range of physiological and patho-physiological mechanisms. In particular, 5-HT1A receptors are proposed to mediate stress-adaptation. The aim of this research was to investigate in adolescent rats: first, the consequences of perinatal exposure to 5-metoxytryptamine (5MT), a 5-HT1/5-HT2 serotonergic agonist, on behavioural-stress reactivity in elevated plus maze, open field and forced swim tests; secondly, whether the behavioural effects induced by perinatal exposure to 5MT on open field and forced swim tests were affected by the selective 5-HT1A receptor agonist LY 228729, a compound able to elicit a characteristic set of motor behaviours on these experimental models, and by the co-administration of the selective and silent 5-HT1A antagonist WAY 100635. Results indicate that a single daily injection of 5MT to, pregnant dams from gestational days 12 to 21 (1 mg/kg s.c.), and to the pups from postnatal days 2 to 18 (0.5 mg kg s.c.), induce in the adolescent rat offspring: an increase in the percentage of entries and time spent on the open arms in the elevated plus maze; a reduction in locomotor activity and rearing frequency, and an increase in the time spent on the central areas in the open field test; a decrease in immobility and an increase in swimming in the forced swim test. Acute administration of LY 228729 (1.5 mg/kg s.c.) strongly decreases rearing frequency and increases peripheral activity in the open field test, and decreases immobility and increases swimming in the forced swim test both in perinatally vehicle and 5MT-exposed offspring. Co-administration of WAY 100635 (0.25 mg/kg s.c.) abolishes the effects exerted by LY 228729. These results suggest that, in the adolescent rat, perinatal exposure to 5MT enhances the stress-related adaptive behavioural responses, presumably through a predominant action on presynaptic 5-HT1A receptors and does not deteriorate the functional response of 5-HT1A receptors to selective agonist and antagonist compounds.

A reduction in 5-HT1A receptor response enhances learning and memory performance in rats. Pre- and postnatal treatment with 5-methoxytryptamine (5MT), a non-selective serotonergic agonist, and early handling, reduce the number of 5-HT1A receptors in neonatal and pre-pubertal rat progeny. The aim of this study was to investigate in adolescent male rats the consequences of pre- and postnatal treatment with 5MT and its interaction with early handling on an object-place association learning task, the "Can test", a motivated, non-aversive, spatial/object discrimination task. Results show that a single daily injection of 5MT from gestational days 12 to 21 (1 mg/kg s.c.) and from postnatal days 2 to 18 to pups (0.5 mg/kg s.c.), increases the level of activity and the number of correct responses, and decreases the number of reference memory errors in the progeny as adolescent, compared to vehicle-treated rats. Similar effects are observed following a daily, brief, maternal separation of the pups from postnatal days 2 until 21. Furthermore, when 5MT-treated rats underwent to early handling procedure, the effects induced by 5MT increased handling-induced facilitation of the object-place association. These results suggest that pre- and postnatal treatment with 5MT enhances learning in the "Can test", probably due to a reduction in 5-HT1A receptors in the hippocampus. Whether the potentiation exerted by pre- and postnatal 5MT on early handling effects may be related to a further damping of 5-HT1A receptor response is not yet assessed; however, our data demonstrate that this association is able to induce long-term facilitative effects on spatial learning performance in a non-aversive spatial/object discrimination task in the adolescent rat offspring.

As ethanol, its first metabolite, acetaldehyde (ACD), enhances dopamine neurotransmission and exerts rewarding and motivational effects in animal models tailored for studying addictive-like behaviours. The endocannabinoid system fine-tuning dopamine cell activity, affects distinct drug-related behaviours and specific drug-induced effects. In light of this, it becomes urgent to investigate the implications of …

3-(3-Methylisoxazol-5-yl) and 3-(pyrimidin-2-yl)-2-styrylquinazolin-4(3H)-ones 8a–l and 9a,c–e,h–l were synthesized by refluxing in acetic acid the corresponding 2-methylquinazolinones 6 and 8 with the opportune benzoic aldehyde for 12 h. The synthesized styrylquinazolinones 8a–l and 9a,c–e,h–l were tested in vitro for their antileukemic activity against L-1210 (murine leukemia), K-562 (human chronic myelogenous leukemia) and HL-60 (human leukemia) cell lines showing in some cases good activity.