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Made available in DSpace on 2022-04-28T19:47:04Z (GMT). No. of bitstreams: 0 Previous issue date: 2022-02-10 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) The antidepressant effect of ketamine has been widely acknowledged and the use of one of its enantiomers, S-ketamine (esketamine), has recently been approved for the clinical management of treatment-resistant depression. As with ketamine, the non-selective opioid receptor-interacting drug buprenorphine is reported to have antidepressant and anxiolytic properties in humans and rodents. Given the fact that antidepressant drugs are also first line treatment for panic disorder, it is surprising that the potential panicolytic effect of these compounds has been scarcely (ketamine), or not yet (buprenorphine) investigated. We here evaluated the effects of ketamine (the racemic mixture), esketamine, and buprenorphine in male Wistar rats submitted to a panicogenic challenge: acute exposure to hypoxia (7% O2). We observed that esketamine (20 mg/kg), but not ketamine, decreased the number of escape attempts made during hypoxia, and this effect could be observed even 7 days after the drug administration. A panicolytic-like effect was also observed with MK801, which like esketamine, antagonizes NMDA glutamate receptors. Buprenorphine (0.3 mg/kg) also impaired hypoxia-induced escape, an effect blocked by the non-selective opioid receptor antagonist naloxone, indicating an interaction with classical ligand sites, such as µ and kappa receptors, but not with nociception/orphanin FQ receptors. Altogether, the results suggest that esketamine and buprenorphine cause rapid-onset panicolytic-like effects, and may be alternatives for treating panic disorder, particularly in patients who are refractory to standard pharmacological treatment. Department of Pharmacology School of Medicine of Ribeirão Preto University of São Paulo Department of Biomolecular Sciences School of Pharmaceutical Sciences University of São Paulo Aarhus Institute of Advanced Studies (AIAS) Aarhus University Behavioural Neurosciences Institute (INeC) Department of Pharmacology and Therapeutics State University of Maringá (UEM) Department of Biological Sciences School of Sciences São Paulo State University (UNESP) Department of Biological Sciences School of Sciences São Paulo State University (UNESP) CNPq: 142509/2018-3 FAPESP: 2018/00153-5

Made available in DSpace on 2022-04-29T08:45:34Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-08-01 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) The ability to distinguish between threatening (repulsors), neutral and appetitive stimuli (attractors) stimuli is essential for survival. The orexinergic neurons of hypothalamus send projections to the limbic structures, such as different subregions of the medial prefrontal cortex (mPFC), suggesting that the orexinergic mechanism in the prelimbic cortex (PL) is involved in the processing of fear and anxiety. We investigated the role of orexin receptors type 1 (OX1R) and type 2 (OX2R) in the PL in such processes upon confrontation with an erratically moving robo-beetle in mice. The selective blockade of OX1R and OX2R in the PL with SB 334867 (3, 30, 300 nM) and TCS OX2 29 (3, 30, 300 nM), respectively, did not affect general exploratory behavior or reactive fear such as avoidance, jumping or freezing, but significantly enhances tolerance and approach behavior at the highest dose of each antagonist tested (300 nM). We interpret these findings as evidence for an altered cognitive appraisal of the potential threatening stimulus. Consequently, the orexin system seems to bias the perception of stimuli towards danger or threat via OX1R and OX2R in the PL. Department of Biological Sciences School of Sciences Humanities and Languages of the São Paulo State University (UNESP) Neuronal Plasticity Research Group Max Planck Institute of Psychiatry Department of Pharmacology Ribeirão Preto Medical School of the University of São Paulo (FMRP-USP) Department of Anatomy Biomedical Sciences Institute of the University of São Paulo (ICB-USP) Behavioural Neuroscience Institute (INeC) NAP-USP-Neurobiology of Emotions Research Centre (NuPNE) Ribeirão Preto Medical School of the University of São Paulo Central Nervous System Diseases Research Boehringer Ingelheim Pharmaceuticals Die Gesellschaft mit Beschränkter Haftung & Compagnie Kommanditgesellschaft Department of Biological Sciences School of Sciences Humanities and Languages of the São Paulo State University (UNESP)

Changes in 5-HT

Made available in DSpace on 2018-12-11T17:32:45Z (GMT). No. of bitstreams: 0 Previous issue date: 2017-12-01 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) The median raphe nucleus (MRN) is related to stress resistance and defensive responses, a crucial source of serotonergic neurons that project to prosencephalic structures related to stress and anxiety. Estrogen receptors were identified in this mesencephalic structure. It is possible that the estrogen action is related to serotonin effect on somatodendritic 5-HT1A receptors, inhibiting the function of serotonergic neurons and thus preventing of the stress effect and inducing anxiolysis. So, in order to evaluate these aspects, female Wistar rats were ovariectomized and 21 days later were given a direct microinjection of estradiol benzoate (EB) (1200 ng) into the MRN, preceded by microinjections of saline or WAY100.635 (100 ng), a 5-HT1A receptor antagonist. Immediately after the two microinjections, the ovariectomized rats were conditioned with an aversive event (foot shock) session in a Skinner box. Twenty-four hours later, they were exposed to the same context in a test session for 5 min for behavioral assessment: freezing, rearing, locomotion, grooming, and autonomic responses (fecal boluses and micturition). EB microinjection in the MRN prior to the exposure of animals to the foot shocks in the conditioning session did not alter their behavior in this session, but neutralized the association of the aversive experience to the context: there was a decrease in the expression of freezing and an increased rearing activity in the test session. This effect was reversed by prior microinjection of WAY100.635. In conclusion, EB acted on serotonergic neurons in the MRN of the ovariectomized rats, impairing the association of the aversive experience to the context, by co-modulating the functionality of somatodendritic 5-HT1A. UNESP – Univ Estadual Paulista FCL Department of Biological Science, Avenida Dom Antonio, 2100 Laboratory of Physiology UNESP UNESP – Univ Estadual Paulista FCL Department of Biological Science, Avenida Dom Antonio, 2100 Laboratory of Physiology UNESP FAPESP: 2010/06414-3

Made available in DSpace on 2019-10-06T15:32:22Z (GMT). No. of bitstreams: 0 Previous issue date: 2019-04-01 Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) The role of 5-HT2C receptors (5-HT2CRs) in the regulation of anxiety has been widely acknowledged. However, conflicting results have been reported on whether stimulation of these receptors increases or decreases anxiety. We here investigated the role of 5-HT2CRs of the dorsal hippocampus (DH) in the mediation of anxiety- or panic-associated defensive behaviors and in the anxiolytic effect of the tricyclic antidepressant imipramine. In the Vogel conflict test, administration of the mixed 5-HT2CR agonist mCPP into the DH of male Wistar rats was anxiogenic, whereas infusions of the more selective agonists MK-212 and RO-600175 were anxiolytic. The 5-HT2CR antagonist SB-242084, on the other hand, was anxiogenic. A sub-effective dose of this antagonist blocked the anxiolytic effect of RO-600175, but not the increase in anxiety observed with mCPP, indicating that the latter effect was not due to 5-HT2CR activation. In full agreement with these findings, MK-212 and RO-600175 in the DH also inhibited inhibitory avoidance acquisition in the elevated T-maze, whereas SB-242084 caused the opposite effect. None of these drugs interfered with escape expression in this test, which has been associated with panic. Chronic administration of imipramine (15 mg/kg, ip, 21 days) caused an anxiolytic effect in the elevated T-maze and light-dark transition tests, which was not blocked by previous infusion of SB-242084 into the DH. Therefore, facilitation of 5-HT2CR-mediated neurotransmission in the DH decreases the expression of anxiety-, but not panic-related defensive behaviors. This mechanism, however, is not involved in the anxiolytic effect caused by imipramine. Department of Pharmacology School of Medicine of Ribeirão Preto University of São Paulo (USP) Department of Biological Science São Paulo State University (UNESP) Department of Biological Science São Paulo State University (UNESP) FAPESP: 2012/20016-6 FAPESP: 2017/18437-7

Made available in DSpace on 2018-12-11T16:53:03Z (GMT). No. of bitstreams: 0 Previous issue date: 2018-07-13 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Often the manifestation of anxiety cannot be explained by known environmental or hereditary factors. With this perspective, it has been reported that prenatal stress may lead to emotional disturbances in the offspring. However, studies relating prenatal stress to anxiety are controversial and generally the stressors used do not mimicks the reality experienced by mothers. Thus, this investigation evaluated the effects of an unpredictable chronic stress scheme applied in one of the three gestational weeks of rats on the manifestation of generalized anxiety and panic disorder in the progeny (males), analyzing, respectively, the avoidances and escapes in the elevated T-maze, at the 1st, 3rd or 6th month of progeny life. Control offspring showed increased generalized anxiety disorder and reduced panic at 6 months. The effects of prenatal stress depended on the gestational week where it occurred and on the progeny age: during the 1st gestational week the generalized anxiety decreased in 6 month old rats. Animals in the 3rd month, prenatally stressed during the last gestational week, showed anxiogenesis and panicogenesis, but effects reverted at the 6th month, when they presented anxiolysis and no changes related to panic. Together the results show that not only the gestational period in which the aversive experience occurred was important, but the age of the evaluated progeny, since the type and the intensity of behaviors related to anxiety may vary with the developmental stage. For the model of stress used in the present study, the effects of prenatal stress were more prominent when the exposure occurred during the 3rd gestational week in rats. Laboratory of Physiology Department of Biological Sciences São Paulo State University (Unesp) School of Sciences Laboratory of Physiology Department of Biological Sciences São Paulo State University (Unesp) School of Sciences FAPESP: 2012/19973-6 FAPESP: 2013/10808-5

Although the role of the median raphe nucleus (MRN) in the regulation of anxiety has received less attention than that of the dorsal raphe nucleus (DRN) there is substantial evidence supporting this function. Reported results with different animal models of anxiety in rats show that whereas inactivation of serotonergic neurons in the MRN causes anxiolysis, the stimulation of the same neurons is anxiogenic. In particular, studies using the elevated T-maze comparing serotonergic interventions in the MRN and in the DRN indicate that the former affect only the inhibitory avoidance task, which has been related to generalized anxiety. In contrast, similar operations in the DRN change both the inhibitory avoidance and the one-way escape task, the latter being representative of panic disorder. Simultaneous injections of 5-HT-acting drugs in the MRN and in the dorsal hippocampus (DH) suggest that the MRN-DH pathway mediates the regulatory function of the MRN in anxiety. Overall, the results discussed in this review point to a relevant role of the MRN in the regulation of anxiety, but not panic, through the 5-HT pathway that innervates the DH.

The present work aimed to evaluate the effects of social separation for 14 days (chronic stress) and of withdrawal from a 14-day treatment with diazepam (acute stress) on the exploratory behaviour of male rats in the elevated plus-maze and on serotonin (5-hydroxytryptamine) turnover in different brain structures. Social separation had an anxiogenic effect, evidenced by fewer entries into, and less time spent on the open arms of the elevated plus-maze. Separation also selectively increased 5-hydroxytryptamine turnover in the hippocampus and median raphe nucleus. Diazepam withdrawal had a similar anxiogenic effect in grouped animals and increased 5-hydroxytryptamine turnover in the same brain structures. Chronic treatment with imipramine during the 14 days of separation prevented the behavioural and neurochemical changes caused by social separation. It is suggested that the increase in anxiety determined by both acute and chronic stress is mediated by the activation of the median raphe nucleus-hippocampal 5-hydroxytryptamine pathway.

The possibility to treat Duchenne muscular dystrophy (DMD), a lethal X-linked disorder, through cell therapy with mesenchymal stromal cells (MSCs) has been widely investigated in different animal models. However, some crucial questions need to be addressed before starting human therapeutic trials, particularly regarding its use for genetic disorders. How safe is the procedure? Are there any side effects following mesenchymal stem cell transplantation? To address these questions for DMD the best model is the golden retriever muscular dystrophy dog (GRMD), which is the closest model to the human condition displaying a much longer lifespan than other models. Here we report the follow-up of 5 GRMD dogs, which were repeatedly transplanted with human adipose-derived mesenchymal stromal cells (hASC), derived from different donors. Xenogeneic cell transplantation, which was done without immunosuppression, was well tolerated in all animals with no apparent long-term adverse effect. In the present study, we show that repeated heterologous stem-cell injection is a safe procedure, which is fundamental before starting human clinical trials.

The cell bodies of 5-HT containing neurons that innervate the limbic forebrain are mainly found in the dorsal raphe nucleus and in the median raphe nucleus (MRN). To assess the role of the median raphe nucleus in anxiety, rats bearing either electrolytic or 5-HT-selective neurotoxic lesion of the MRN were tested in the elevated T-maze. This apparatus consists of two opposed open arms perpendicular to one enclosed arm. Two tasks are performed in succession by the same rat in one experimental session, namely inhibitory avoidance of the open arm, taken as a measure of conditioned anxiety and one-way escape from the open arm, considered as a measure of unconditioned fear. The test was performed 7 days after the electrolytic lesion (3 mA, 10s) or 14 days after the neurotoxic lesion (5,7-DHT, 8 microg/1 microl). The results showed that while the electrolytic lesion impaired both inhibitory avoidance and one-way escape, the neurotoxic lesion impaired only inhibitory avoidance. Therefore, serotonergic pathways originating in the MRN seem to participate in the modulation of conditioned anxiety but not unconditioned fear. Other neurotransmitter systems that either originate in or pass through the MRN may regulate unconditioned fear.

It has been proposed that the ascending dorsal raphe (DR)-serotonergic (5-HT) pathway facilitates conditioned avoidance responses to potential or distal threat, while the DR-periventricular 5-HT pathway inhibits unconditioned flight reactions to proximal danger. Dysfunction on these pathways would be, respectively, related to generalized anxiety (GAD) and panic disorder (PD). To investigate this hypothesis, we microinjected into the rat DR the benzodiazepine inverse receptor agonist FG 7142, the 5-HT(1A) receptor agonist 8-OH-DPAT or the GABA(A) receptor agonist muscimol. Animals were evaluated in the elevated T-maze (ETM) and light/dark transition test. These models generate defensive responses that have been related to GAD and PD. Experiments were also conducted in the ETM 14 days after the selective lesion of DR serotonergic neurons by 5,7-dihydroxytriptamine (DHT). In all cases, rats were pre-exposed to one of the open arms of the ETM 1 day before testing. The results showed that FG 7142 facilitated inhibitory avoidance, an anxiogenic effect, while impairing one-way escape, an anxiolytic effect. 8-OH-DPAT, muscimol, and 5,7-DHT-induced lesions acted in the opposite direction, impairing inhibitory avoidance while facilitating one-way escape from the open arm. In the light/dark transition, 8-OH-DPAT and muscimol increased the time spent in the lighted compartment, an anxiolytic effect. The data supports the view that distinct DR-5-HT pathways regulate neural mechanisms underlying GAD and PD.

Here we summarize the clinical history of Ringo, a golden retriever muscular dystrophy (GRMD) dog, who had a mild phenotype despite the absence of muscle dystrophin. Ringo died of cardiac arrest at age 11 and therefore displayed a normal lifespan. One of his descendants, Suflair, born April 2006, also displays a mild course. Dystrophin analysis confirmed total absence of muscle dystrophin in both dogs. Muscle utrophin expression did not differ from severely affected GRMD dogs. Finding what protects these special dogs from the dystrophic degeneration process is now a great challenge that may open new avenues for treatment. But most importantly, the demonstration that it is possible to have a functional muscle, in a medium-large animal even in the absence of dystrophin, brings new hope for Duchenne patients.

Duchenne muscular dystrophy (DMD), a lethal X-linked disorder, is the most common and severe form of muscular dystrophies, affecting 1 in 3,500 male births. Mutations in the DMD gene lead to the absence of muscle dystrophin and a progressive degeneration of skeletal muscle. The possibility to treat DMD through cell therapy has been widely investigated. We have previously shown that human adipose-derived stromal cells (hASCs) injected systemically in SJL mice are able to reach and engraft in the host muscle, express human muscle proteins, and ameliorate the functional performance of injected animals without any immunosuppression. However, before starting clinical trials in humans many questions still need to be addressed in preclinical studies, in particular in larger animal models, when available. The best animal model to address these questions is the golden retriever muscular dystrophy (GRMD) dog that reproduces the full spectrum of human DMD. Affected animals carry a mutation that predicts a premature termination codon in exon 8 and a peptide that is 5% the size of normal dystrophin. These dogs present clinical signs within the first weeks and most of them do not survive beyond age two. Here we show the results of local and intravenous injections of hASCs into GRMD dogs, without immunosuppression. We observed that hASCs injected systemically into the dog cephalic vein are able to reach, engraft, and express human dystrophin in the host GRMD dystrophic muscle up to 6 months after transplantation. Most importantly, we demonstrated that injecting a huge quantity of human mesenchymal cells in a large-animal model, without immunosuppression, is a safe procedure, which may have important applications for future therapy in patients with different forms of muscular dystrophies.

Several reports have shown that the hippocampus plays an important role in different aspects of the emotional control. There is evidence that lesions in this structure cause behavioral disinhibition, with reduction of reactions expressing fear and anxiety. Thus, to portray the aptitude of cell therapy to abrogate injuries of hippocampal tissue, we examined the behavioral effects of bone marrow mononuclear cells (BMMCs) transplantation on C57BL/6 mice that had the hippocampus damaged by electrolytic lesion. For this purpose, mice received, seven days after bilateral electrolytic lesion in the dorsal hippocampus, culture medium or BMMCs expressing the enhanced green fluorescent protein (EGFP) transgene. One week after transplantation, animals were tested in the elevated plus-maze (EPM). On the whole, three assessment sessions in the EPM were carried out, with seven days separating each trial. Thirty-five days after the induction of injury, mice were sacrificed and their brains removed for immunohistochemistry. The behavioral evaluation showed that the hippocampal lesion caused disinhibition, an effect which was slightly lessened, from the second EPM test, in transplanted subjects. On the other hand, immunohistochemical data revealed an insignificant presence of EGFP(+) cells inside the brains of injured mice. In view of such scenario, we hypothesized that the subtle rehabilitation of the altered behavior might be a result from a paracrine effect from the transplanted cells. This might have been caused by the release of bioactive factors capable of boosting endogenous recuperative mechanisms for a partial regaining of the hippocampal functions.

Estrogen deficiency has been associated with stress, anxiety and depression. Estrogen receptors have been identified in the median raphe nucleus (MRN). This structure is the main source of serotonergic projections to the hippocampus , a forebrain area implicated in the regulation of defensive responses and in the resistance to chronic stress. There is reported evidence indicating that estrogen modulates 5-HT 1A receptor function. In the MRN, somatodendritic 5-HT1A receptors control the activity of serotonergic neurones by negative feedback. The present study has evaluated the effect of intra-MRN injection of estradiol benzoate (EB, 600 or 1200 ng/0.2 μl) on the performance of ovariectomized rats submitted to contextual conditioning. Additionally, the same treatment was given after intra-MRN injection of Way 100635 (100 ng/0.2 μl), a 5-HT1A receptor antagonist . Both doses of EB decreased freezing and increased rearing, indicating an anxiolytic effect. Pretreatment with Way 100635 antagonized the anxiolytic effect of estradiol. On the basis of these results, it may be suggested that estrogens modulate anxiety by acting on 5-HT 1A receptors localized in the MRN.

Changes in 5-HT1A receptor-mediated neurotransmission at the level of the median raphe nucleus (MRN) are reported to affect the expression of defensive responses that are associated with generalized anxiety disorder (e.g. inhibitory avoidance) but not with panic (e.g. escape). The objective of this study was to further explore the involvement of MRN 5-HT1A receptors in the regulation of generalized anxiety-related behaviours. Results of experiment 1 showed that intra-MRN injection of the 5-HT1A/7 receptor agonist 8-OH-DPAT (0.6 nmol) in male Wistar rats impaired the acquisition of inhibitory avoidance, without interfering with the performance of escape in the elevated T-maze test of anxiety. Pre-treatment with the 5-HT1A receptor antagonist WAY-100635 (0.18 nmol) fully blocked this anxiolytic-like effect. As revealed by experiment 2, intra-MRN injection of 8-OH-DPAT (0.6, 3 or 15 nmol) also caused anxiolytic effect in rats submitted to the light-dark transition test, another animal model that has been associated with generalized anxiety. In the same test, intra-MRN injection of WAY-100635 (0.18, 0.37 or 0.74 nmol) caused the opposite effect. Overall, the current findings support the view that MRN 5-HT neurons, through the regulation of 5-HT1A somatodendritic autoreceptors, are implicated in the regulation of generalized anxiety-associated behaviours.

We evaluated the involvement of dorsal hippocampus (DH) 5-HT1A receptors in the mediation of the behavioral effects caused by the pharmacological manipulation of 5-HT neurons in the median raphe nucleus (MRN). To this end, we used the rat elevated T-maze test of anxiety. The results showed that intra-DH injection of the 5-HT1A/7 agonist 8-OH-DPAT facilitated inhibitory avoidance, an anxiogenic effect, without affecting escape. Microinjection of the 5-HT1A antagonist WAY-100635 was ineffective. In the elevated T-maze, inhibitory avoidance and escape have been related to generalized anxiety and panic disorders, respectively. Intra-MRN administration of the excitatory amino acid kainic acid, which non-selectively stimulates 5-HT neurons in this brain area facilitated inhibitory avoidance and impaired escape performance, but also affected locomotion. Intra-MRN injection of WAY-100635, which has a disinhibitory effect on the activity of 5-HT neurons in this midbrain area, only facilitated inhibitory avoidance. Pre-administration of WAY-100635 into the DH blocked the behavioral effect of intra-MRN injection of WAY-100635, but not of kainic acid. These results indicate that DH 5-HT1A receptors mediate the anxiogenic effect induced by the selective stimulation of 5-HT neurons in the MRN.

Estrogen deficiency has been associated with stress, anxiety and depression. Estrogen receptors have been identified in the median raphe nucleus (MRN). This structure is the main source of serotonergic projections to the hippocampus, a forebrain area implicated in the regulation of defensive responses and in the resistance to chronic stress. There is evidence showing that estrogen modulates 5-HT1A receptor functions. In the MRN, somatodendritic 5-HT1A receptors control the activity of serotonergic neurones by negative feedback. The present study evaluated the effect of intra-MRN injection of estradiol benzoate (EB) (600 or 1200ng/0.2microl) on the performance of ovariectomised rats submitted to the elevated plus-maze test of anxiety and to the open-field test. Additionally, the same effect was evaluated with a previous intra-MRN injection of WAY 100635(100ng/0.2microl), an antagonist of 5-HT1A receptors. The results showed that both doses of EB increased the percentage of entries and the percentage of time spent into the open arms, suggestive of an anxiolytic effect. The highest dose of the drug also increased the number of entries into the enclosed arm and locomotion in the open field, indicating a stimulatory motor effect. WAY 100635 antagonised the effect of estradiol in the elevated plus-maze and in the open-field. The results show that estrogen receptors of the MRN are implicated in the regulation of anxiety-related behaviour. The results also support claims that the effect of estrogen involves a change in 5-HT1A receptor function.

A wealth of evidence supports the involvement of the serotonergic neurons of the median raphe nucleus (MRN) in anxiety. However, it is presently unclear whether serotonergic pathways arising from this nucleus play distinguishing regulatory roles in defensive behaviors that have been associated with specific subtypes of anxiety disorders. To evaluate the role of the MRN serotonergic neurons in the regulation of two defensive behaviors, inhibitory avoidance and escape, which have been related, respectively, to generalized anxiety and panic disorders. Male Wistar rats were submitted to the elevated T-maze test of anxiety after intra-MRN administration of drugs that either non-selectively or selectively change the activity of the serotonergic neurons. Intra-MRN injection of FG 7142 (0.04 and 0.08 nmol) and kainic acid (0.03 and 0.06 nmol), drugs that non-selectively stimulate the MRN serotonergic neurons, facilitated inhibitory avoidance acquisition, but impaired escape performance. Microinjection of muscimol (0.11 and 0.22 nmol), a compound that non-selectively inhibits the activity of the MRN serotonergic neurons, impaired inhibitory avoidance and facilitated escape performance. Both kainic acid and muscimol also changed rat locomotion in the open-field test. Intra-MRN injection of 8-OH-DPAT (0.6–15 nmol) and WAY-100635 (0.18–0.74 nmol), respectively an agonist and an antagonist of somatodendritic 5-HT1A receptors located on serotonergic neurons of the MRN, only affected inhibitory avoidance—while the former inhibited the acquisition of this behavior, the latter facilitated it. MRN serotonergic neurons seem to be selectively involved in the regulation of inhibitory avoidance in the elevated T-maze. This result supports the proposal that 5-HT pathways departing from this nucleus play an important role in anxiety processing, with implications for pathologies such as generalized anxiety disorder.

We conducted a longitudinal study about daily variation of Wistar male rats' behavior in the elevated plus-maze (EPM) evaluated in the 1st, 2nd, 3rd, 6th, 12th, and 18th months of life. Animals were submitted to the plus-maze in 12 sessions at 2-h intervals (n=72, 6 per time point). Spontaneous rest–activity rhythm of four animals was assessed by observation of 24-h videotape records. Time series were analyzed by Cosinor method. Behavioral rates on the six occasions and in light and dark phases were compared by means of two-way ANOVA with repeated measures. Exploratory behavior in EPM was smaller in the light phase and in older animals. Higher values of open and closed arms exploration were observed in the first and third months of the dark phase, and in the first month of the light phase. Adjustment to the 24-h period was significant at all stages for rest–activity data, number of entries in closed arms, and time on center, and for three to five stages for open-arm exploration. In general, 24 h variability was more pronounced in younger animals compared with older ones. The present study showed that: (1) a significant amount of total variability of the behavioral indexes analyzed could be attributed to 24 h variation, (2) light/dark phases differences in EPM exploration were present at all developmental stages, (3) older Wistar rats explored less the EPM and were less active in their home cage compared with younger ones, and (4) behavioral indexes (EPM) decrease was phase related and partially related to a reorganization of rest–activity rhythm.

Erratum to “The dorsal raphe nucleus exerts opposed control on generalized anxiety and panic-related defensive responses in rats” [Behav Brain Res 2003; 142] Ligia Moreiras Sena a, Cintia Bueno a, Roger L.H. Pobbe c, Telma G.C.S. Andrade b, Helio Zangrossi Jr. c, Milena B. Viana a,∗ a Laboratory of Psychopharmacology, FFCLRP, University of Sao Paulo, 14040-901 Ribeirao Preto, Brazil b Departament of Biological Science, FCLA, Unesp, 19800-000 Assis, Brazil c Department of Pharmacology, FMRP, University of Sao Paulo, 14049-900 Ribeirao Preto, Brazil

Made available in DSpace on 2021-07-14T10:46:59Z (GMT). No. of bitstreams: 0 Previous issue date: 2002-09 O presente estudo teve como objetivo verificar a associação entre o afastamento por acidente de trabalho e a ocorrência de ansiedade e de depressão, averiguando se houve desencadeamento de transtornos somáticos e/ou transtornos nas relações sociais dos indivíduos. Em todos os casos estudados, constatamos que houve aumento significativo de sintomas após o afastamento e que o retorno ao trabalho foi impossibilitado devido à persistência da patologia e ao desenvolvimento de outras manifestações. Assim, o afastamento pôde ser considerado um estímulo estressor, pois além de causar transtornos psíquicos provocou alterações orgânicas. The present study has the goal of verifing the association between the removal by work accident and the occurrence of anxiety and depression, checking if this first factor had influence in the appearance of somatic disturbances and/or disturbances in the social relationships of the individuals. In all the cases studied, it was noted that there was a significative increase in the symptoms after the removal and that the return to work was not possible because of the persistence of the pathology and the development of other manifestations. Thus, the removal was considered a stressor stimulus, since it has caused psychological disturbances and also occasioned organic modifications. Universidade Estadual Paulista, Faculdade de Ciências e Letras Universidade Estadual Paulista, Faculdade de Ciências e Letras

Este estudo investigou os efeitos agudos da imagética motora (IM) sobre o desempenho de atletas de basquetebol. Para tanto 3 estudos foram elaborados. Inicialmente uma revisão sistemática específica sobre a utilização da imagética motora em atletas levantou os principais achados e lacunas da literatura. Em seguida um estudo piloto envolvendo 11 atletas juniores de basquetebol do sexo masculino, que realizaram a sessão de imagética motora + vídeo, com posterior teste de desempenho envolvendo 10 lances livres seguidos. Também foi avaliado a percepção de autoeficácia, através do questionário EAEGP, antes e após a sessão de imagética. A intervenção foi capaz de causar com 84% de chance, um efeito benéfico sobre os dois primeiros arremessos convertidos, entretanto, a percepção de autoeficácia não sofreu alteração. Por fim, um terceiro estudo envolvendo também atletas juniores de basquete (n=9), utilizou-se de uma intervenção mais ecológica. Os atletas forma submetidos a sessões de imagética tanto estática (IE) quanto dinâmica (ID), em situações de fadiga (F) ou somente aquecidos (C). Para elevar o estado de cansaço dos atletas foi utilizado o teste de Shuttle-run 20 metros. Foram avaliadas a frequência cardíaca, nível de cansaço (escala de OMNI), nível de imagética (Escala likert de 1-6) e desempenho no teste de lance livre (até 5 arremessos), averiguando tanto arremessos convertidos quanto precisão dos arremessos. Todas as condições foram superior a condição C. Quando descansados a ID se mostrou superior a IE, entretanto quando levados a um estado de fadiga a IE causou os maiores efeitos encontrados, enquanto a ID não mais foi efetiva além da própria fadiga, a qual também se mostrou benéfica em relação a condição C. O fator emocional envolvido na imagética ainda se mantém incerto. Assim sendo, a ID e a IE possuem momentos específicos dentro de um jogo para serem utilizadas com maior especificidade. This study investigated the acute effects of motor imagery (MI) on basketball athletes performance. For such 3 studies were conducted. Firstly a systematic review regarding the MI use on athletes rised the main findings and gaps in the literature, the main results were the absence of studies using motor imagery acutely, the new perspective with the dynamic imagery and the MI accuracy lost caused by fatigue. Next, a pilot study with 11 male junior basketball athletes, which performed a motor imagery session + video, with posterior free-throw performance test (10 consecutives free-throws). Still the self-efficacy perception was evaluated before and after the MI session. The intervention were capable of causing, with 84% of chance, a beneficial effect until 2 free-throws, however the self-efficacy perception didn’t sufer modifications. For last, a third study also with junior basketball players (n=9) employed a more ecological approach. The athletes underwent motor imagery sessions, both motionless (IE) and dynamic (ID), in fatigue situation (F) ou only warmed (C). To elevate the fatigue level of the athletes the 20 meters Shuttle-run teste was used until exhaustion. Were measured the heart rate, fatigue level (OMNI scale), imagery level (Likert scale of 1 to 6) and free-throw performance (until 5 shots), ascertaining both converted shots and and shots precision. All conditions were superior to C. When rested the ID was superior to IE, however once the athletes were fatigued the IE caused the biggest effects founded, and the ID was no more effective beyond the fatigue itself, which was also benficial when compared to C. The emoctional effect is still uncertain. Thus, ID and IE are to be used in specific moments inside a game with better specificity.

A substância cinzenta periaquedutal dorsal (SCPd) é considerada uma das principais estruturas do teto mesencefálico envolvida no substrato neural da aversão a estímulos proximais. GABA e 5-HT são apontados como neurotransmissores envolvidos na modulação das respostas defensivas elaboradas na SCPd. Recentemente, mecanismos neurocininérgicos também têm sido propostos como mediadores das reações de defesa organizadas nessa estrutura. O objetivo do presente estudo foi avaliar o envolvimento dos receptores NK-1 e NK-3 da SCPd no comportamento defensivo induzido pela estimulação elétrica dessa região em ratos com e sem experiência prévia ao condicionamento contextual aversivo. Para isso, os limiares aversivos de congelamento e fuga foram medidos durante a estimulação elétrica da SCPd em ratos ingênuos e em animais submetidos previamente ao procedimento de condicionamento contextual aversivo. A mediação destas repostas defensivas pelos receptores NK-1 e NK-3 foi avaliada pela injeção local de spantide (100 pmol/0,2 L) e SB 222200 (50 e 100 pmol/0,2 L), antagonistas seletivos de receptores NK-1 e NK-3, respectivamente. Os resultados mostraram que a injeção intra-SCPd de spantide aumentou os limiares aversivos determinados pela estimulação elétrica da SCPd em animais ingênuos e com experiência aversiva prévia. Injeções similares de 100 pmol de SB 222200 na SCPd também causaram um aumento nos limiares de congelamento e fuga. Entretanto, esses efeitos devem ser atribuídos a um déficit motor causado por essa dose da droga, uma vez que SB 222200 na dose de 100 pmol, reduziu significativamente a atividade motora dos animais submetidos ao teste do campo aberto. Estes resultados sugerem que receptores NK-1, mas não NK-3, estão envolvidos na mediação do comportamento defensivo induzido pela estimulação elétrica da SCPd. The dorsal periaqueductal gray (dPAG) constitutes the main structure of the neural substrate for the defensive response to proximal aversive stimuli. It is well established that GABA and 5-HT are important neuromediators of the defense reaction at the dPAG level but neurokinin-mediated mechanisms have also been recently implicated in these processes. The aim of the present investigation was to examine the involvement of NK-1 and NK-3 receptors of the dPAG in the unconditioned defensive behaviors induced by electrical stimulation of the dPAG of rats with and without previous experience with contextual fear conditioning. For this, aversive thresholds were measured as the lowest intensity of electric current to produce freezing and escape behaviors using a procedure of gradual increases of the electrical stimulation of the dPAG. These thresholds were also measured in rats previously submitted to a contextual fear conditioning procedure. The mediation of these defensive responses by NK-1 and NK-3 receptors of the dPAG was evaluated by local injections of spantide (100 pmol/0.2 L) and SB 222200 (50 and 100 pmol/0.2 L), selective antagonists of NK-1 and NK-3 receptors, respectively. The present results showed that spantide injections into the dPAG increased the aversive thresholds (anti-aversive effects) determined by stimulation of the dPAG in naive and in animals subjected previously to the contextual fear conditioning. Similar injections of SB 222200 100 pmol into the dPAG increased the freezing and escape thresholds. However, this effect can be attributable to a motor deficit since this dose of SB 222200 decreased the exploratory activity of the animals subjected to the open field test. These results suggest that NK-1 receptors, but not NK-3 receptors, are involved in the mediation of the defensive behaviors induced by electrical stimulation of the dPAG.

Diversos estudos sugerem que as células-tronco da medula óssea podem ser úteis no tratamento de lesões do tecido nervoso. O presente estudo investigou se a terapia com células medulares seria capaz de modificar os efeitos comportamentais de lesões no hipocampo. Células mononucleares da medula óssea marcadas com a proteína fluorescente verde (EGFP) foram transplantadas em camundongos C57BL/6 que tiveram o hipocampo dorsal danificado por lesão eletrolítica bilateral. Os resultados da avaliação comportamental no labirinto em cruz elevado mostraram que a lesão hipocampal produziu ansiólise, quadro que foi atenuado nos animais transplantados. Na análise imuno-histoquímica do tecido cerebral, foi observada presença limitada de células EGFP+ no cérebro dos animais lesionados. Dada a não recuperação da citoarquitetura tissular, acredita-se que os benefícios observados sobre o comportamento tenham resultado de um efeito parácrino das células mononucleares, que auxiliaram na ação de mecanismos endógenos para restituição parcial das funções do hipocampo. Several studies suggest that stem cells from bone marrow may be useful in treating lesions of the nervous tissue. This study investigated if bone marrow cell therapy would be able to modify the behavioral effects of lesions in the hippocampus. Bone marrow mononuclear cells labeled with the enhanced green fluorescent protein (EGFP) were transplanted into C57BL/6 mice which had the dorsal hippocampus damaged by bilateral electrolytic lesion. The results of the behavioral assessment in the elevated plus-maze showed that the hippocampal lesion produced anxiolysis, an effect that was attenuated in transplanted animals. Immunohistochemical analysis of brain tissue revealed, however, a limited presence of EGFP+ cells into the brains of injured animals. Given the non-recovery of the tissue cytoarchitecture, it is believed that the observed benefits on the behavior resulted from a paracrine effect of the mononuclear cells, which possibly helped in the action of endogenous mechanisms for partial reimbursement of the hippocampal functions.