The mesolimbic dopamine system, including dopaminergic projections from the ventral tegmental area (VTA) to nucleus accumbens (NAc), is critically involved in the development of addiction to many drugs of abuse, including cocaine (CA). Although there is an attractive hypothesis that the modifications of mesolimbic reward circuit following repeated drug exposure are responsible for cocaine-addicted causes behaviors change, however, our understanding in the underlying molecular mechanisms at the neural circuit level is still in its infancy. It has been suggested PKMzeta, a constitutively active atypical isoform of PKC, plays a critical role in spatial memory formation and long-term synaptic potentiation in hippocampus. To define the relationship among PKMzeta, CA-induced synaptic long-term potentiation and CA addiction, we examined the regulation of PKMzeta after CA administration in Sprague-Dawley rat. We found single CA injection elicits an increase in PKMzeta protein expression in the VTA region. The increase was first observed 10 min after CA administration and lasted for 7 days, the longest sampling time point of our experimental design. The PKMzeta protein expression can also be induced in 10 minutes while incubating the acute isolated brain slice with CA, the expression within 1 hr can be eliminated at the present of Chelerythrine (PKC inhibitor) and ZIP (PKMzeta inhibitor) suggests a positive feedback loop. The PKMzeta mRNA expression can be induced within 1 hr, and Actinomycin d (transcription inhibitor) had no effect on the PKMzeta protein expression indicating CA increases PKM£a translation from preexisting PKM£a mRNA. Furthermore,real time PCR-based analysis showed resembling increase profile ofPKM£a mRNA after single CA injection, suggesting a co-upregulation of transcription and translation of PKM£a after CA administration in VTA. Eticlopride (dopamine receptor D2-subtype antagonist) ¡BSCH-23390(dopamine receptor D1-subtype antagonist)¡BH-89 (PKA inhibitor)¡B Wortmannin (PI3K inhibitor)¡BPD98059 (MEK1 inhibitor) decreasedcocaine-induced PKM£a expression within 1 hr in VTA. On the contrary, KN-62 (CaMK II inhibitor) has no obvious effect on PKM£a expression. CA challenge not only induces the PKM£a expression in the VTA region but also in the NAc and hippocampus region. The CA-induced PKM£a expression is more obvious in elder group (>45 days in age) than younger group (18~30 days in age), similar results also showed in the locomotor activity assay. Prenatal CA exposure decreased the postnatal CA-induced PKM£a expression and the locomotor sensitivity in younger group. Overall, results from our current experiments have raised the possibility of PKM£a involvement in CA addiction. How CA regulates PKM£a expression and the context dependence between PKM£a and CA-induced behavior change and synaptic long-term potentiation remains further elucidation.

Addiction is a chronic disease that characterize as habitual or compulsive involvement in an activity despite it¡¦s bring negative consequences. Some of psystimulants such as cocaine or amphetamine cause a strong reinforcing effects even after prolonged abstinence periods. Such illegal drugs not only hurt on the adult health but also result in fetal physiological damage. For example, that babies born to mothers who abuse with cocaine bring prematurely delivered, low birth weights, smaller head circumferences and increased heart disease in adult offspring. Mesolimbic dopamine system include nucleus accumbens (NAc) and ventral tegmental area (VTA) are critical regions for the neural adaptations that contribute to addiction. VTA that receives inputs from a large number of brain regions. For example, it receives glutamatergic inputs from prefrontal cortex, or GABAergic inputs from NAc. It has been known that VTA play a major role in the acquisition and expression of learned addictive behaviors. Results from many neuropharmacological studies in animal models indicate that exposure to cocaine or some other drugs of abuse seems to induce long-term potentiation (LTP) ¢w like changes of synaptic plasticity among neurons in VTA region. LTP was first described in hippocampus, a region that associated with memory formation, and were found widespread events in many mammalian brain sites. In the present time, theories and investigation indicated that memory and addiction might shared the similar neural circuitry and signal pathways. In general, LTP can be separate into two main phases : induction and maintenance phases. Many of molecules participate in induction phase such as calcium/calmodulin-dependent protein kinase II (CaMKII), cyclic AMP (cAMP), phosphatidylinositol 3-kinases (PI3K) and protein kinase C (PKC). However, until now there was only one molecule has been found associated with LTP maintenance¡Xprotein kinase M£a (PKM£a). PKM£a is a brain specific, constitutively active form of PKC that does not need Ca2+ or diacylglycerol (DAG) for its activation. Molecular evidences showed that PKM£a is translated uniquely by PKM£a mRNA which is generated under the control of an internal promoter in the PKC£a gene. Recently, investigators introduced a PKM£a selective inhibitor¡XZIP, to hippocampus or insular cortex both successful to eliminate long-term spatial memory or conditioned taste aversion (CTA) behavior, respectively, on rat. Therefore, exclude PKM£a by specific inhibitors and then result in abolish long-term synaptic potentiation which had already established seem to be a leading candidate for cure addiction. Here we showed that blocked of PKM£a activity in VTA dopaminergic neuron eliminated mEPSCs or AMPAR/NMDAR ratio increment elicited by cocaine. Otherwise, our results also presented that myristoylatedinhibitory peptide¢wZIP had no effect on spike timing-dependent long-term potentiation in rats previously injected with saline but remarkably restored spike timing-dependent long-term potentiation in VTA dopamine neurons in slices prepared from rats that received single or multiple cocaine exposure. Furthermore, our western blot analyses showed that both single and five consecutive cocaine injections induced a significant increase in PKM£a level in VTA or NAc. Moreover, our ex vivo cocaine incubation results indicated that multiple kinases activation or de novo protein synthesis was required for PKM£a increment. The most important, our data provided the first physiological evidence between PKM£a and drug addiction when intracranial administered specific PKM£a inhibitors to VTA reversed cocaine-induced conditioned-place preference (CPP) behavior. Finally, we investigated the behavioral effect of cocaine-induced locomotor sensitization in an open field apparatus. Our data showed that peri-adolescent (P21) rats exhibited prominently increased in either acute or repeated cocaine-induced locomotor activity than mid-adolescent (P28) and post-adolescent (P41). Interestingly, applied to high dosage cocaine (30 mg/kg) rescued the acute locomotor response in P28 rats but not behavioral sensitization. We further examined the locomotion on rats that were exposed to cocaine in utero after single or multiple cocaine injection. However, cocaine-induced increase in locomotor activity was lower in P21 rats which exposed to cocaine during pregnancy but no significantly difference in P28 rats. Surprisingly, single high dose cocaine treatment caused a marked reduction in locomotor activity on P21 rats prenatally exposed to cocaine. Otherwise, we also provided the first evidences that repeated cocaine injection in pregnant rats induced a significant decreased to KCC2 level in PFC regions prepared from P20 rat. In conclusion, results from our current studies demonstrate for the first time that persistently active PKM£a is necessary in (1) mEPSC facilitation induced by single cocaine exposure; (2) cocaine-induced enhancement in AMPAR/NMDAR ratio; (3) single or repeated cocaine-induced LTP but not in LTP induced by spike-timing stimulation; and (4) cocaine conditioned place preference in the VTA. In addition, our results also present evidence that the expression of PKM£a is increased by either single or repeated cocaine exposure. Furthermore, our behavioral or Western blotting consequence of cocaine treatment in utero was reflected by the diminishion in the sensitivity of locomotor activity in postnatal rats to cocaine and KCC2 level in PFC regions.

Thesis (Ph. D.)--University of Washington, 2002. / Vita. Includes bibliographical references (leaves 67-89).

No description available.

Darbo tikslas - nustatyti nenutrūkstamų izometrinių susitraukimų tikslumo ir stabilumo valdymo ypatumus. Tyrimo metu kelti šie uždaviniai: 1) nustatyti ir palyginti vaizdinės grįžtamosios informacijos (VGI) ir skirtingos procentinės jėgos (SPJ) įtaką nenutrūkstamo izometrinio susitraukimo tikslumui, stabilumui ir raumenų (agonisto ir antagonisto) elektriniam aktyvumui; 2) nustatyti ir palyginti mokymosi ir potencijuojamojo krūvio įtaką nenutrūkstamo izometrinio susitraukimo tikslumui ir stabilumui. Buvo tiriami jauni, fiziškai aktyvūs vyrai (n = 8; amžius 20,0 ± 1,5 m, ūgis 182,4 ± 6,5 cm; kūno masė 73,0 ± 5,7 kg, KMI kūno masės indeksas 22,0 ± 1,7 kg/m2 (vid. ± S). Pirmojo tyrimo metu tiriamieji atliko 20%, 50% ir 70% nuo MVJ nenutrūkstamus izometrinius susitraukimus (NIS). Tiriamieji atliko 2 NIS su ir be VGI. NIS truko 13 s, tačiau buvo analizuojami tik paskutinių 10 s duomenys, nes per pirmas 3 s tiriamiesiems buvo leidžiama pasiekti reikiamą jėgą nuo MVJ ir ją išlaikyti likusias 10 s. Antrojo tyrimo metu tiriamieji atliko tokius pačius NIS kaip ir pirmojo tyrimo metu 20% jėga nuo MVJ. Tiriamieji po su VGI ir be jos atliktų NIS atliko rankos raumenų potenciaciją, kurios metu turėjo padidinti rankos lenkimo jėgą iki maksimumo ir ją išlaikyti 10 s. Pailsėję 10 s vėl atliko NIS be VGI. Visas tyrimas buvo pakartotas po 9 - erių mokymosi pratybų, kai per pratybas tiriamieji buvo mokomi atlikti greitus ir tikslius izometrinius susitraukimus 20% jėga nuo MVJ kas antrą dieną su... [toliau žr. visą tekstą] / Research aim was to establish the peculiarities of control of the accuracy and the stability of continuous isometric muscle contractions. Objectives: 1) to establish and compare effect of visual feedback on the accuracy, stability and muscle activity of continuous isometric contractions performed with different strength; 2) to establish and compare effect of learning on the dependence of accuracy and stability of a continuous isometric contraction on muscle potentiation. The subjects studied were healthy, physically active men (n = 8; age 20.0 ± 1.5 m, height 182.4 ± 6.5 cm; body mass 73.0 ± 5.7 kg, body mass index 22.0 ± 1.7 kg/m2 ( ±SD). In experiment 1, the subjects performed CIC at 20%, 50% and 70% force of MVC. The subjects performed two series of CIC – first with visual feedback information (VFI), second – without VFI. The duration of each series was 13 sec. In experiment 2, the subjects performed the same CIC at 20% force of MVC. The subjects after two series of CIC (first with VFI, second – without VFI), done potentiation load (PL), when they had to achieve maximal force and it maintain 10 sec. After 10 sec rest the subjects performed CIC without VFI. All the experiment was repeated after 9 training series. In training series, they were learning speeds – accuracy isometric contractions at 20% force of MVC. Absence of visual feedback information worsening in the accuracy of performing CIC at all forces of MVC. We have established that there is a significant... [to full text]

We have recently established that aberrant alkylacylglycerophosphocholine metabolism results in the increased tissue concentration of platelet activating factors (PAFs) in the temporal cortex of Alzheimer Disease (AD) patients and in TgCRND8 mice over-expressing mutant human amyloid precursor protein. PAF lipids activate a G-protein coupled receptor (PAFR) reported to be expressed by microglia and subsets of neurons in rat. It is not known whether this same expression pattern is recapitulated in mice however, as the expression has only been inferred by use of pharmacological PAFR antagonists, many of which impact on both PAFR-dependent and PAFR-independent signalling pathways. PAFR plays a role in long term potentiation (LTP) induction in rats. PAFR has also been implicated in behavioural indices of spatial learning and memory in rats. Contradictory reports using mice provide ambiguity regarding the role of PAFR in LTP induction in mice. To assess whether PAFR is expressed in murine neurons, I localized PAFR mRNA in wild-type C57BL/6 mice using PAFR KO mice as a negative control. I further showed that the loss of PAFR did not impair learning and memory although this assessment must be considered preliminary as the behavioural test employed was not optimized to detect changes in learning and memory of C57BL/6 mice over time adequately.Finally, I showed that the loss of PAFR in TgCRND8 mouse model of AD had no impact upon Aβ plaque number. My observations suggest that PAFR is restricted to microglial-like cells in mouse hippocampus and as such, it may not play a role in learning and memory.

The short-term enhancement of physical performance known as post-activation potentiation could be exploited in the design of sport-specific training sessions. The purpose of this study was to compare the potentiation of softball throwing velocity following two kinds of resistance-training session: a control session consisting of traditional heavy-load sets, and an experimental "Pmax" session consisting of sets of loads selected to maximise the mean power output during explosive bench presses. Both sessions included plyometric medicine ball chest passes. Eight male softball players of premier grade, with at least 2 yr experience of resistance training, performed the two sessions in a crossover fashion, with 30 min recovery between sessions. Softball throwing velocity was measured with a radar gun immediately before and at 2-min intervals 4-10 min after each session. Percent effects on throwing speed were analyzed via log transformation, and t statistics were used to make magnitude-based inferences with respect to the smallest important change of 2%. The average throwing velocity increased between pre and post tests for both treatments; the average increase was a substantial 2.3% (0.5 to 4.1%). Throwing velocity after Pmax training was a trivial 0.4% slower relative to that after heavy-load training (90% confidence limits -1.2 to 1.9%). There was a greater change in throwing velocity by 10 min post treatment than by 4 min post treatment; the change by 10 min was 5.0% (3.2 to 6.7%) for the Pmax training session and 5.3% (2.1 to 8.6%) for the heavy-load session. These effects were almost certainly beneficial for throwing speed, but the difference between them was unclear (-0.3%; -3.7 to 3.1%). The mean change between 4 and 10 min for both treatments combined was 5.1% (90% confidence limits 3.6 to 6.7%). The short-term enhancement of throwing performance following heavy-load and Pmax training sets has implications for the design of softball warm-up routines. There is also the potential for softball players to use such training to improve their throwing velocity during games.

Diss. (sammanfattning) Göteborg : Göteborgs universitet, 2006. / Härtill 4 uppsatser.

Thesis (Ph. D.)--University of Washington, 2004. / Vita. Includes bibliographical references (leaves 94-116).

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No. of bitstreams: 1 poli_rab_me_bauru.pdf: 2546681 bytes, checksum: 7ecb5edb5c025ff32bea79318c106654 (MD5) Previous issue date: 2018-08-20 / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / O objetivo do presente estudo foi investigar os efeitos da potenciação pós ativação (PAP) induzida por drop jumps no tempo até a exaustão a 115% da intensidade associada ao consumo máximo de oxigênio (("iV" ) ̇"O" _"2max" ) em ciclo ergômetro, em aspectos neuromusculares da fadiga (central e periférica) e sobre as vias metabólicas não oxidativas (capacidade anaeróbia, via glicolítica e dos fosfagênios). Para isso, o projeto foi dividido em dois estudos independentes. No Estudo A, 14 ciclistas recreacionais do sexo masculino (34 ± 4 anos) foram submetidos a 5 sessões de avaliações. Na primeira sessão realizaram teste incremental até exaustão (TInc), na segunda e terceira avaliações realizaram familiarização ao esforço supramáximo a 115% da ("iV" ) ̇"O" _"2max" , enquanto que na quarta e quinta sessões os participantes realizaram de maneira randomizada o esforço supramáximo a 115% da ("iV" ) ̇"O" _"2max" com e sem PAP (controle). Como esforço indutor da PAP, foram realizados 5 drop jumps (15s de intervalo entre eles) antes do esforço supramáximo. Nas sessões 4 e 5, a fadiga neuromuscular foi avaliada por meio de contrações voluntárias máximas (CVM) de extensão do joelho e estimulação elétrica periférica (PNS) realizadas antes e após o esforço supramáximo. Além disso, a eletromiografia de superfície foi realizada durante o esforço supramáximo para mensuração da roots mean square (EMGRMS) e a frequência mediana (EMGFM) e analisadas de forma estratificada a cada 25% de tempo total de esforço (0-25%, 25-50%, 50-75% e 75-100%). No Estudo B, 16 ciclistas recreacionais do sexo masculino (33 ± 6 anos) realizaram desenho experimental semelhante ao estudo A, entretanto na quarta e quinta sessões, as contribuições dos sistemas metabólicos foram mensuradas pelo componente rápido do excesso de consumo de oxigênio pós exercício (EPOC) (via dos fosfagênios) e pelo delta de lactato (via glicolítica), assumindo a soma das contribuições dessas vias como capacidade anaeróbia (AC[La-]+EPOCrápido), além disso a capacidade anaeróbia também foi mensurada pelo déficit máximo de oxigênio acumulado. Como resultados, no estudo A foi verificado uma melhora do significativa desempenho no esforço supramáximo após a realização da PAP (p=0,02; Δ%=+9,85%). Ambas condições (controle e PAP) apresentaram quedas significativas na força pico medidas durante a CVM e na força evocada pelo estímulo elétrico duplo na musculatura em repouso (p<0,01 e p<0,01, respectivamente) quando comparado o momento pré e pós esforço, indicando uma fadiga periférica causada pelo esforço. Entretanto não houve interação entre as condições (F=4,19; p=0,06 e F=3,03; p=0,09, respectivamente). A EMGRMS e a EMGFM do último quarto de esforço (75-100%) foi significativamente maior que os momentos 0-25%, 25-50%, 50-75%, para ambas as condições (p<0,02), entretanto não houve interação entre grupos (p<0,05). No Estudo B o desempenho no esforço supramáximo foi significativamente maior na condição PAP (p=0,05; Δ%=+7,44%). A contribuição glicolítica e a capacidade anaeróbia mensurada pelo AC[La-]+EPOCrápido foram maiores após a PAP (p=0,002; Δ%= +9,09% e p=0,04; Δ%= +7,75%, respectivamente), entretanto, a contribuição dos fosfagênios não apresentou diferenças significativas entre condições (p=0,35). Portanto, a PAP foi efetiva em melhorar o desempenho em um esforço supramáximo em ciclo ergômetro, tendo sua melhora acompanhada por um aumento da participação glicolítica e da capacidade anaeróbia, além de causar uma “preservação” do aparato neuromuscular durante o esforço para o vasto lateral e o glúteo máximo. / The aim of the present study was investigating the effects of post activation potentiation (PAP) induced by drop jumps in performance during a supramaximal effort at 115% of the intensity associated with maximal oxygen uptake (iV̇ O2max) on a cycle ergometer, also investigating the influence of PAP on neuromuscular fatigue (central and peripheral) and, on the non-oxidative metabolic pathways (anaerobic capacity, glycolytic pathway and phosphagen). Therefore, the project was divided in two independent studies. In Study A, 14 recreational male cyclists (34 ± 4 years) underwent 5 sessions of evaluations, in the first session they performed a graded exercise test (GXT), in the second and third evaluations they performed familiarization to the supramaximal effort to 115% of the iV̇ O2max. In the fourth and fifth sessions, the participants randomly performed the supramaximal effort at 115% of the iV̇ O2max with PAP and without PAP (control). To induce PAP, the volunteers performed 5 drop jumps (15s interval between them) 2 minutes before the supramaximal effort. In sessions 4 and 5, neuromuscular fatigue was assessed by maximal voluntary contractions (CVM) of knee extension with peripheral electrical stimulation (SNP) performed before and after the supramaximal effort. In addition, surface electromyography was performed during the supramaximal effort to measure roots mean square (EMGRMS) and the median frequency (EMGFM) for every 25% of total effort time (0-25%, 25-50%, 50-75% and 75-100% %). In Study B, 14 male recreational cyclists (33 ± 6 years) performed experimental design similar to study A, however in the fourth and fifth session, the contributions of the non-oxydative metabolic systems were measured by the fast component of the excess post-exercise oxygen consumption (EPOC) and the lactate delta (glycolytic pathway), assuming the sum of the contributions of these pathways as anaerobic capacity (AC[La -] + EPOCfast). In addition, the anaerobic capacity was also measured by the maximum accumulated oxygen deficit (MAOD). In study A, an improvement in the supramaximal effort was observed after PAP (p=0.02, Δ%=+9.85%). Both conditions (control and PAP) showed significant decrease in the peak force measured during the CVM and in the force evoked by the double electric stimulus in the resting muscles (p<0.01 and p <0.01, respectively) when compared to the pre and post moments, indicating peripheral fatigue caused by the supramaximal effort. However, ere was no interaction between the conditions (F=4.19, p=0.06 and F=3.03, p=0.09, respectively). The EMGRMS and EMGFM of the last quarter of effort (75- 100%) was significantly higher than the 0-25%, 25-50%, 50-75%, moments for both conditions (p <0.02), however there was no interaction between groups (p<0.05). In Study B, performance on supramaximal effort was significantly higher in the PAP condition (p=0.05, Δ%=+7.44%). The glycolytic contribution and the anaerobic capacity measured by AC[La -] + EPOCfast was higher after PAP (p=0,002; Δ%= +9,09% e p=0,04; Δ%= +7,75%, respectively), however, the contribution of the phosphagen pathway did not show significant differences between conditions (p = 0.35). Therefore, the PAP was effective in improving the performance in a supramáximo effort in cycle ergometer, having its improvement accompanied by an increase in the glycolytic participation and in anaerobic capacity, in addition to causing a "preservation" of the neuromuscular apparatus during the effort for the vastus lateralis and gluteus maximus / FAPESP: 2016/17836-2