Vanessa de Paula Soares-Rachetti

Julia J. Didonet; Judney Cley Cavalcante; Lisiane de S. Souza; Miriam Stela Maris de Oliveira Costa; Eunice André; Vanessa de Paula Soares-Rachetti; Remo Guerrini; Girolamo Calo; Elaine C. Gavioli

Neuropeptide S (NPS) is a 20-aminoacid peptide that selectively activates a G-protein coupled receptor named NPSR. Preclinical studies have shown that NPSR activation promotes anxiolysis, hyperlocomotion, arousal and weakfullness. Previous findings suggest that dopamine neurotransmission plays a role in the actions of NPS. Based on the close relationship between dopamine and Parkinson disease (PD) and on the evidence that NPSR are expressed on brain dopaminergic nuclei, the present study investigated the effects of NPS in motor deficits induced by intracerebroventricular (icv) administration of the dopaminergic neurotoxin 6-OHDA in the mouse rotarod test. 6-OHDA injection evoked motor deficits and significantly reduced tyrosine hidroxylase (TH)-positive cells in the substantia nigra (SN) and ventral tegmental area. However, a positive correlation was found only between the motor performance of 6-OHDA-injected mice and the number of TH-positive cells in SN. The systemic administration of l-DOPA+benserazide (25+6.25 mg/kg) counteracted 6-OHDA-induced motor deficits in mice. Similar to L-DOPA, the icv injection of NPS (0.1 and 1 nmol) reversed motor deficits evoked by 6-OHDA. In conclusion, NPS attenuated 6-OHDA-induced motor impairments in mice assessed in the rota-rod test. We discussed the beneficial actions of NPS based on a putative facilitation of dopaminergic neurotransmission in the brain. Finally, these findings candidate NPSR agonists as a potential innovative treatment for PD.

Lisiane de S. Souza; E.F. Silva; Wilton B. Santos; Laila Asth; Bruno Lobão-Soares; Vanessa de Paula Soares-Rachetti; Iris Ucella de Medeiros; Elaine C. Gavioli

Manic bipolar is diagnosed by psychomotor agitation, increased goal-directed activity, insomnia, grandiosity, excessive speech, and risky behavior. Animal studies aimed to modeling mania are commonly based in psychostimulants-induced hyperlocomotion. The exploration of other behaviors related with mania is mandatory to investigate this phase of bipolar disorder in animals. In this study, the hole board apparatus was suggested for evaluating mania-like behaviors induced by the psychostimulant methylphenidate. The treatment with methylphenidate (10mg/kg, ip) increased locomotion in the open field test. The pretreatment with lithium (50mg/kg, ip) and valproate (400mg/kg, ip) significantly prevented the hyperlocomotion. In the hole-board test, methylphenidate increased interactions with the central and peripheral holes and the exploration of central areas. Lithium was more effective than valproate in preventing all the behavioral manifestations induced by the psychostimulant. These findings were discussed based on the ability of methylphenidate-treated mice mimicking two symptoms of mania in the hole board test: goal-directed action and risk-taking behavior. In conclusion, the results point to a new approach to study mania through the hole board apparatus. The hole board test appears to be a sensitive assay to detect the efficacy of antimanic drugs.

Rebecca A.M. Guimarães; Laila Asth; Rovena C.G.J. Engelberth; Jeferson S. Cavalcante; Vanessa de Paula Soares-Rachetti; Elaine C. Gavioli

Clinical studies have shown that women during perimenopause and menopause have a higher incidence in the diagnoses of psychiatric problems compared with men. However, little literature information about the influence of spontaneous perimenopause on anxiety- and mood-related behaviors in mice is available. To this aim, we compared the behavioral responses of middle-aged and young adult female mice both in the diestrus phase in the elevated plus-maze, open field and forced swimming tests. In middle-aged mice, the duration of the estrous cycle was significantly prolonged compared to young adults, thus indicating that our middle-aged mice are in the perimenopausal period. In the elevated plus-maze test, middle-aged mice explored less the open arms when compared to young adults, suggesting an anxiogenic-like phenotype. No significant differences were observed in the estrogen plasma levels and emotional behavior in the forced swim and open field tests. In conclusion, the spontaneous failure of the estrous cycle increased anxiety in middle-aged females. These data suggest that the perimenopausal period has a significant influence on anxiety-related behaviors in female mice.

A.D. Victor Holanda; Laila Asth; Adair R.S. Santos; Remo Guerrini; Vanessa de Paula Soares-Rachetti; Girolamo Calo; Eunice André; Elaine C. Gavioli

AIMS The present study aimed to investigate the intraplantar (ipl) and central (icv) effects of neuropeptide S (NPS) in the formalin test and to evaluate the role of adenosine receptors, mainly A1 and A2A, in mediating such effects. MAIN METHODS The ipl injection of formalin was used to assess the nociceptive activity. Moreover, by pretreating mice with non-selective and selective antagonists of adenosine receptors, the effects of icv NPS on formalin-induced ongoing nociception were assessed. KEY FINDINGS Morphine-induced antinociceptive effects were observed during phases 1 and 2 of the test, while indomethacin was active only at the later nociceptive phase. The ipl injection of NPS (alone or combined with formalin) did not modify the nociceptive response. However, icv NPS significantly reduced formalin-induced nociception during both phases. Caffeine (3 mg/kg, ip), a non-selective adenosine receptor antagonist, prevented NPS-induced antinociceptive effects. Similar to caffeine, icv ZM241385 (0.01 nmol), an A2A receptor antagonist, prevented the antinociceptive effects of NPS. Moreover, icv DPCPX (0.001 nmol), an A1 receptor antagonist, blocked the effects of NPS only during phase 1. SIGNIFICANCE The above findings suggest that: (i) NPS evokes central antinociceptive effects by activating both A1 and A2A receptors during phase 1, but (ii) only the adenosine A2A receptor during phase 2 of the formalin test.

Raliny O. Santos; Gabriela Lins Medeiros Assunção; Diogo M. B. de Medeiros; Ícaro A. de Sousa Pinto; Keizianny S. de Barros; Bruno Lobao Soares; Eunice André; Elaine C. Gavioli; Vanessa de Paula Soares-Rachetti

Sibutramine is a serotonin and norepinephrine reuptake inhibitor indicated for the treatment of obesity. A pre‐clinical study showed that acute administration of sibutramine promoted anxiolytic‐ and panicolytic‐like effects in male rats. However, in clinical reports, sibutramine favoured the onset of panic attacks in women. In this study, the effect of sibutramine on experimental anxiety in females and the relevance of different oestrous cycle phases for this effect were analysed. In experiment 1, both male and female rats were submitted to acute intraperitoneal injection of sibutramine or vehicle 30 min. before testing in the elevated T‐maze (ETM) and in the open‐field test (OF). Females in the pro‐oestrus (P), oestrus (E), early dioestrus (ED) and late dioestrus (LD) phases were tested in the ETM and OF (experiment 2) or in the elevated plus‐maze (EPM) 30 min. after the injection of sibutramine. Sibutramine impaired the escape response in the ETM in both males and females. This effect was observed for P, E and ED, but not for LD females. Sibutramine altered neither the inhibitory avoidance in the ETM nor the behaviour of females in the EPM. Thus, sibutramine promoted a panicolytic‐like effect in female rats cycling at P, E and ED, but not in the LD phase and did not alter behaviours related to anxiety in both ETM and EPM. Considering that pre‐clinical studies aiming the screening of anxiolytic drugs employ male rodents, data here obtained reinforce the importance of better understanding the effects of drugs in females.

José X. Lima Neto; Vanessa de Paula Soares-Rachetti; E.L. Albuquerque; Vinícius Manzoni; U.L. Fulco

Since the early days of migrainous research, serotonin receptors (5-HTR) have been considered a major target of drugs, and the 5-HT1B and 5-HT1D agonists have been among the most marketed ones for the treatment of migraine attacks. Besides, the 5-HT1BR agonist is also involved in the mechanisms underlying many neurological dysfunctions, making it a critical target for the rational development of drugs. In this context, by taking advantage of its first crystallographic structure co-crystallized with dihydroergotamine (DHE), one of the oldest and largely used antimigraine drugs, a quantum biochemistry study based on the electrostatically embedded molecular fractionation with conjugate caps (EE-MFCC) scheme within the density functional theory (DFT) formalism is performed to unveil this complexs detailed binding energy. In the EE-MFCC model, each fragment is embedded within the electrostatic effect of the full protein, in such a way that all atoms are replaced by their corresponding atomic charges, excluding the reference residues. Our results reveal not only the pivotal role played by the amino-acid residue D129 in the dihydroergotamine–5-HT1BR total binding energy, but also the importance of the residues D352, D123, E198, D204, F330, L126, F351, I130, V201, V200, T355 and R114 in this complex. The total binding energy reaches convergence after a pocket radius r = 7.0 A, with a value around −230.93 kcal mol−1. Furthermore, we predict the relevance (energetically) of the DHE regions, as well as the influence of each protein segment to DHE–serotonin receptor binding. Finally, for completeness, we compared our results obtained by using the EE-MFCC approach with those considering the ordinary MFCC scheme. We believe that our work is a first step using in silico quantum biochemical design as a means to influence the discovery of new drugs to treat migraine and other diseases related to the 5-HT1BR agonist.

Décio D. Junqueira-ayres; Laila Asth; Adriana S.F.S.J. Ayres; Bruno Lobão-Soares; Vanessa de Paula Soares-Rachetti; Elaine C. Gavioli

Anxiety disorders are associated with increased impairments in psychosocial functioning, work productivity and health-related quality of life. In addition, anxiety is a common symptom of ethanol withdrawal and it strongly contributes to relapse. Benzodiazepines are frequently prescribed for relief of anxiety and ethanol withdrawal symptoms but considerable side effects, such sedation, tolerance and dependence, are observed during treatment. Therefore, better drugs are needed for the treatment of anxiety states. The purpose of this study was to investigate whether topiramate would reduce basal levels of anxiety and ethanol-withdrawn induced anxiety in male rats; the elevated plus maze (EPM) was used as an animal model of anxiety. In Experiment 1, topiramate (0, 10, and 40 mg/kg, i.g.) and diazepam (1 mg/kg, i.p.) was acutely and repeatedly administered to naive rats. In Experiments 2 and 3, topiramate (0 or 40 mg/kg, i.g.) was acutely and chronically administered in early (72 hr after ethanol removal) and protracted (21 days after ethanol removal) ethanol-withdrawn rats, respectively. Acute and repeated topiramate treatment induced anxiolytic-like effects in naive rats. Early ethanol withdrawal increased anxiety, and acute topiramate administration counteracted the anxiogenic-like effects of ethanol removal. Protracted withdrawal did not produce lasting changes in anxiety but topiramate was equally effective at reducing anxiety in ethanol-withdrawn and control animals. Importantly, no signs of tolerance to the anxiolytic effects of topiramate were observed. In conclusion, these data support a role for topiramate in the treatment of basal levels of anxiety and ethanol withdrawal-induced anxiety.

Vanessa de Paula Soares-Rachetti; Ícaro A. de Sousa Pinto; Raliny O. Santos; Eunice André; Elaine C. Gavioli; Thelma A. Lovick

Anxiety behavior in female Wistar rats was assessed at different stages of the estrous cycle using the elevated plus maze (EPM). No differences were observed at any cycle stage. Pretreatment with diazepam (1 mg kg−1 intraperitoneal (i.p.)) 30 min before testing produced an anxiolytic effect (significant increase in percentage of time in the open arms compared to control group in the same cycle phase) in animals in proestrus, estrus, and early diestrus but had no effect in rats in late diestrus. Locomotor activity (total arm entries) was unchanged at any cycle phase. When rats in the late diestrus phase were pretreated with the selective serotonin reuptake inhibitor fluoxetine (1.75 mg kg−1 i.p. on the afternoon of early diestrus and again in the morning of late diestrus) diazepam produced an anxiolytic effect (increase percentage time in the open arms). This dose is sufficient to raise brain allopregnanolone concentration without affecting 5-hydroxytryptamine (5-HT) systems. We propose that insensitivity to diazepam in late diestrus is due to increased expression of benzodiazepine insensitive α4 subunit-containing gamma-aminobutyric acid A (GABAA) receptors triggered by a sharp decrease in brain allopregnanolone concentration. Pretreatment with fluoxetine to raise brain allopregnanolone concentration during late diestrus prevents the withdrawal effect.

Jéssica Winne; Leslie Teixeira; Jéssica de Andrade Pessoa; Elaine C. Gavioli; Vanessa de Paula Soares-Rachetti; Eunice André; Bruno Lobão-Soares

In rodents, the novel object preference test has been used as a behavioral parameter for evaluation of neotic exploratory behavior, and also for memory consolidation tasks. Geometric patterns of this preference are poorly understood, and may vary among species. We evaluated in Wistar rats (Rattus norvergicus) a possible exploration preference considering aluminum tripartite rounded and cylindrical objects of different proportions: 1.2; 1.618; 1.8. At the first day, animals were exposed to 1.2; 1.6 and 1.8 rounded objects. At 24h after, these animals were exposed to the same objects, together with three new steel cylindrical objects (same proportions). ANOVA and T tests were used to quantify object exploration for each animal (p<0.05). Data analysis pointed to a longer exploration time of the object 1.2 at the three different protocols indicating a preference pattern on the first day exposition. On the second day the exploration was similar in both familiar and unfamiliar objects, revealing no novel object preference for cylinders. However, we found an object preference related to the 1.2 proportion (balls plus cylinders), in two of three position protocols. In addition, on a single exposition with both cylinders and rounded objects, rats revealed a rounded object preference. The 1.2 preference disclosed by rats also reflected the proportion of their body. From nine main measures of body ratios, seven were close to 1.2 ratio. The correspondence between body ratios and object preference may be explained by habituation learning and by sexual selection, and highlight innate factors regarding aesthetic preferences among species.

Max Kenedy Felix dos Santos; Elaine C. Gavioli; Lorena Santa Rosa; Vanessa de Paula Soares-Rachetti; Bruno Lobão-Soares

Caffeine is the most consumed psychoactive substance in the world; in general, it is not associated to potentially harmful effects. Nevertheless, few studies were performed attempting to investigate the caffeine addiction. The present review was mainly aimed to answer the following question: is caffeine an abuse drug? To adress this point, the effects of caffeine in preclinical and clinical studies were summarized and critically analyzed taking account the abuse disorders described in the Diagnostic and Statistical Manual of Mental Disorders (DSM-V). We concluded that the diagnostic criteria evidenced on DSM-V to intoxication-continued use and abstinence are not well supported by clinical studies. The fact that diagnostic criteria is not widely supported by preclinical or clinical studies may be due specially to a controversy in its exactly mechanism of action: recent literature point to an indirect, rather than direct modulation of dopamine receptors, and auto-limitant consumption due to adverse sensations in high doses. On the other hand, it reports clear withdrawal-related symptoms. Thus, based on a classical action on reward system, caffeine only partially fits its mechanism of action as an abuse drug, especially because previous research does not report a clear effect of dopaminergic activity enhance on nucleus accumbens; despite this, there are reports concerning dopaminergic modulation by caffeine on the striatum. However, based on human and animal research, caffeine withdrawal evokes signals and symptoms, which are relevant enough to include this substance among the drugs of abuse.