Oral edaravone ameliorates behavioral deficits and pathologies in a valproic acid-induced rat model of autism spectrum disorder.

Autism spectrum disorder (ASD) is neurodevelopmental disorder with a high incidence rate, characterized by social deficits and repetitive behaviors. There is currently no effective management available to treat the core symptoms of ASD; however, oxidative stress has been implicated in its pathogenesis. Edaravone (EDA), a free-radical scavenger, is used to treat amyotrophic lateral sclerosis (ALS) and acute ischemic stroke (AIS). Here, we hypothesized that an oral formula of EDA may have therapeutic efficacy in the treatment of core ASD symptoms. A rat model of autism was established by prenatal exposure to valproic acid (VPA), and the offsprings were orally treated with EDA at low (3 mg/kg), medium (10 mg/kg), and high (30 mg/kg) doses once daily for 28 days starting from postnatal day 25 (PND25). Oral EDA administration alleviated the core symptoms in VPA rats in a dose-dependent manner, including repetitive stereotypical behaviors and impaired social interaction. Furthermore, oral administration of EDA significantly reduced oxidative stress in a dose-dependent manner, as evidenced by a reduction in oxidative stress markers and an increase in antioxidants in the blood and brain. In addition, oral EDA significantly attenuated downstream pathologies, including synaptic and mitochondrial damage in the brain. Proteomic analysis further revealed that EDA corrected the imbalance in brain oxidative reduction and mitochondrial proteins induced by prenatal VPA administration. Overall, these findings demonstrate that oral EDA has therapeutic potential for ASD by targeting the oxidative stress pathway of disease pathogenesis and paves the way towards clinical studies.

Adolescent chemogenetic activation of dopaminergic neurons leads to reversible decreases in amphetamine-induced stereotypic behavior.

Chronic perturbations of neuronal activity can evoke homeostatic and new setpoints for neurotransmission. Using chemogenetics to probe the relationship between neuronal cell types and behavior, we recently found reversible decreases in dopamine (DA) transmission, basal behavior, and amphetamine (AMPH) response following repeated stimulation of DA neurons in adult mice. It is unclear, however, whether altering DA neuronal activity via chemogenetics early in development leads to behavioral phenotypes that are reversible, as alterations of neuronal activity during developmentally sensitive periods might be expected to induce persistent effects on behavior. To examine the impact of developmental perturbation of DA neuron activity on basal and AMPH behavior, we expressed excitatory hM3D(Gq) in postnatal DA neurons in TH-Cre and WT mice. Basal and CNO- or AMPH-induced locomotion and stereotypy was evaluated in a longitudinal design, with clozapine N-oxide (CNO, 1.0 mg/kg) administered across adolescence (postnatal days 15-47). Repeated CNO administration did not impact basal behavior and only minimally reduced AMPH-induced hyperlocomotor response in adolescent TH-CrehM3Dq mice relative to WThM3Dq littermate controls. Following repeated CNO administration, however, AMPH-induced stereotypic behavior robustly decreased in adolescent TH-CrehM3Dq mice relative to controls. A two-month CNO washout period rescued the diminished AMPH-induced stereotypic behavior. Our findings indicate that the homeostatic compensations that take place in response to chronic hM3D(Gq) stimulation during adolescence are temporary and are dependent on ongoing chemogenetic stimulation.

Effects of association between resveratrol and ketamine on behavioral and biochemical analysis in mice.

Resveratrol (3,5,4'-trihydroxy-trans-stilbene), a phenol commonly found in grapes and wine, has been associated as protective in experimental models involving alterations in different neurotransmitter systems. However, studies are reporting that resveratrol could have adverse effects. This study evaluated if the association of a low dose of ketamine and resveratrol could induce behavioral manifestations associated with biochemical alterations. Moreover, the effects of treatment with resveratrol and/or ketamine on monoamine oxidase (MAO) activity, oxidative stress markers, and IL-6 levels in the brain were also investigated. Male Swiss mice received a low dose of ketamine (20 mg/kg) for 14 consecutive days, and resveratrol (10, 30, or 100 mg/kg) from day 8 up to day 14 of the experimental period, intraperitoneally. Locomotor, stereotyped behavior, Y-maze, novel recognition object test (NORT), and social interaction were quantified as well as ex vivo analysis of MAO activity, IL-6 levels, and oxidative stress markers (TBARS and total thiol levels) in brain tissues. Ketamine per se reduced the number of bouts of stereotyped behavior on day 8 of the experimental period. Resveratrol per se reduced the locomotor and exploratory activity in the open field, the time of exploration of new objects in the NORT, MAO-A activity in the striatum and increased the IL-6 levels in the cortex. These effects were attenuated when the mice were co-treated with ketamine and resveratrol. There was a decrease in MAO-A activity in the cortex of mice treated with ketamine + resveratrol 100 mg/kg. No significant alterations were found in oxidative stress markers. Resveratrol does not appear to cause summative effects with ketamine on behavioral alterations. However, the effect of resveratrol per se, mainly on locomotor and exploratory activity, should be better investigated.

Comparison of predictive validity of two autism spectrum disorder rat models: Behavioural investigations.

The valproic acid model has been shown to reproduce ASD-like behaviours observed in patients and is now widely validated for construct, face, and predictivity as ASD model in rat. The literature agrees on using a single exposition to 500 mg/kg of VPA at gestational day 12 to induce ASD phenotype with the intraperitoneal route being the most commonly used. However, some studies validated this model with repeated exposure by using oral route. The way of administration may be of great importance in the induction of the ASD phenotype and a comparison is greatly required. We compared two ASD models, one induced by a unique IP injection of 500 mg/kg of body weight at GD12 and the other one by repeated PO administration of 500 mg/kg of body weight/day between GD11 and GD13. The behavioural phenotypes of the offspring were assessed for the core signs of ASD (impaired social behaviour, stereotypical/repetitive behaviours, sensory/communication deficits) as well as anxiety as comorbidity, at developmental and juvenile stages in both sexes. The VPA IP model induced a more literature-compliant ASD phenotype than the PO one. These results confirmed that the mode of administration as well as the window of VPA exposure are key factors in the ASD-induction phenotype. Interestingly, the effects of VPA administration were similar at the developmental stage between both sexes and then tended to differ later in life.

Characterization of the Neurochemical and Behavioral Effects of the Phenethylamine 2-Cl-4,5-MDMA in Adolescent and Adult Male Rats.

BACKGROUND: The proliferation of novel psychoactive substances (NPS) in the drug market raises concerns about uncertainty on their pharmacological profile and the health hazard linked to their use. Within the category of synthetic stimulant NPS, the phenethylamine 2-Cl-4,5-methylenedioxymethamphetamine (2-Cl-4,5-MDMA) has been linked to severe intoxication requiring hospitalization. Thereby, the characterization of its pharmacological profile is urgently warranted. METHODS: By in vivo brain microdialysis in adolescent and adult male rats we investigated the effects of 2-Cl-4,5-MDMA on dopamine (DA) and serotonin (5-HT) neurotransmission in two brain areas critical for the motivational and rewarding properties of drugs, the nucleus accumbens (NAc) shell and the medial prefrontal cortex (mPFC). Moreover, we evaluated the locomotor and stereotyped activity induced by 2-Cl-4,5-MDMA and the emission of 50-kHz ultrasonic vocalizations (USVs) to characterize its affective properties. RESULTS: 2-Cl-4,5-MDMA increased dialysate DA and 5-HT in a dose-, brain area-, and age-dependent manner. Notably, 2-Cl-4,5-MDMA more markedly increased dialysate DA in the NAc shell and mPFC of adult than adolescent rats, while the opposite was observed on dialysate 5-HT in the NAc shell, with adolescent rats being more responsive. Furthermore, 2-Cl-4,5-MDMA stimulated locomotion and stereotyped activity in both adolescent and adult rats, although to a greater extent in adolescents. Finally, 2-Cl-4,5-MDMA did not stimulate the emission of 50-kHz USVs. CONCLUSIONS: This is the first pharmacological characterization of 2-Cl-4,5-MDMA demonstrating that its neurochemical and behavioral effects may differ between adolescence and adulthood. These preclinical data could help understanding the central effects of 2-Cl-4,5-MDMA by increasing awareness on possible health damage in users.

The effect of visitor number and spice provisioning in pacing expression by jaguars evaluated through a case study / O efeito do número de visitantes e do provisionamento de especiaria na expressão do pacing por onças-pintadas avaliado por estudo de caso

Abstract Captive animals exhibit stereotypic pacing in response to multiple causes, including the inability to escape from human contact. Environmental enrichment techniques can minimize pacing expression. By using an individual-based approach, we addressed whether the amount of time two males and a female jaguar (Panthera onca) devote to pacing varied with the number of visitors and tested the effectiveness of cinnamon and black pepper in reducing pacing. The amount of time that all jaguars engaged in pacing increased significantly with the number of visitors. Despite the difference between the males regarding age and housing conditions, both devoted significantly less time to pacing following the addition of both spices, which indicates their suitability as enrichment techniques. Mean time devoted to pacing among the treatments did not differ for the female. Our findings pointed out to the validity of individual-based approaches, as they can reveal how suitable olfactory stimuli are to minimizing stereotypies irrespective of particular traits.

Resumo Animais cativos exibem a estereotipia pacing em resposta a múltiplos fatores, os quais incluem a incapacidade de escapar da exposição ao público. As técnicas de enriquecimento ambiental podem minimizar a expressão do pacing. Usando uma abordagem individual, nós investigamos se a extensão de tempo que dois machos e uma fêmea de onça-pintada (Panthera onca) dispendem com pacing variou em função do número de visitantes e testamos a eficácia da canela e da pimenta-do-reino na redução do pacing. A extensão de tempo em pacing aumentou significativamente com o número de visitantes para todos os indivíduos. Apesar da diferença entre os machos com relação à idade e às condições no cativeiro, ambos devotaram ao pacing menos tempo após a administração das duas especiarias, o que indica a adequabilidade dessas como técnicas de enriquecimento. Para a fêmea, o tempo médio dispendido com pacing não variou entre os tratamentos. Nossos resultados respaldam a validade da realização de abordagens individuais, uma vez que essas podem revelar o grau de eficácia dos estímulos olfativos na minimização de estereotipias independentemente de características particulares.

Novedosos agentes dopaminérgicos centrales derivados del 2-aminoindano-4,7 disustituido atípico. Síntesis y perfil farmacológico central / Novel central dopaminergic agents derived from atypical di-substituted 2-aminoindane-4, 7. Synthesis and central pharmacological profile

En las últimas décadas son muchos los compuestos con actividad dopaminérgica central que se han diseñado, sintetizado y evaluado farmacológicamente. A pesar de ello, no se ha logrado obtener un fármaco capaz de mejorar o curar las patologías que involucran la regulación dopaminérgica en el sistema nervioso central tales como la Enfermedad de Parkinson y la esquizofrenia, entre otras. Tomando en consideración el término de “farmacóforo atípico” y a partir del compuesto 5, se incorporó el fragmento aralquil y se sintetizaron los compuestos 10, 11, 13a-h y 14a-h. Tanto los compuestos 10 y 13a-h bajo su forma metoxilada como los compuestos 11 y 14a-h bajo su forma fenólica, fueron evaluados farmacológicamente para determinar su actividad agonística y antagonística sobre el sistema dopaminérgico central. Para ello se determinó el efecto de la inyección intracerebroventricular de dichos compuestos sobre el balance hidromineral y la conducta estereotipada en ratas. Los resultados de la evaluación farmacológica preliminar muestran una acción central a través de mecanismos dopaminérgicos, siendo que los compuestos 10, 11, 13d-h y 14a mostraron respuestas como agonistas, mientras que los compuestos 14b-h, tuvieron respuestas como antagonistas.

In recent decades, many compounds with central dopaminergic activity have been designed, synthesized and evaluated pharmacologically. However, it has not been possible to obtain a drug able to improve or cure diseases involving dopaminergic regulation in the central nervous system, such as Parkinson’s disease and schizophrenia, among others. Taking into consideration the term “atypical pharmacophore” and from the compound 5, the aralkyl fragment was incorporated, and the compounds 10, 11, 13a-h and 14a-h were synthesized. Both the compounds 10 and 13a-h under its methoxylated form and the compounds 11 and 14a-h under the phenolic form, were evaluated to determine their pharmacologically agonistic and antagonistic effects on central dopaminergic activity. For this, the effect of intracerebroventricular injection of said compounds on the hydromineral balance and stereotyped behavior in rats, was determined. The results of the preliminary pharmacological evaluation show a centrally acting action through dopamine mechanisms, in which the compounds 10, 11, 13d-h and 14a showed responses as agonists, whereas compounds 14b-h, had responses as antagonists.

Behavioral effects of endogenous or exogenous estradiol and progesterone on cocaine sensitization in female rats

Cocaine sensitization is a marker for some facets of addiction, is greater in female rats, and may be influenced by their sex hormones. We compared the modulatory effects of endogenous or exogenous estradiol and progesterone on cocaine-induced behavioral sensitization in 106 female rats. Ovariectomized female rats received progesterone (0.5 mg/mL), estradiol (0.05 mg/mL), progesterone plus estradiol, or the oil vehicle. Sham-operated control females received oil. Control and acute subgroups received injections of saline, while the repeated group received cocaine (15 mg/kg, ip) for 8 days. After 10 days, the acute and repeated groups received a challenge dose of cocaine, after which locomotion and stereotypy were monitored. The estrous cycle phase was evaluated and blood was collected to verify hormone levels. Repeated cocaine treatment induced overall behavioral sensitization in female rats, with increased locomotion and stereotypies. In detailed analysis, ovariectomized rats showed no locomotor sensitization; however, the sensitization of stereotypies was maintained. Only females with endogenous estradiol and progesterone demonstrated increased locomotor activity after cocaine challenge. Estradiol replacement enhanced stereotyped behaviors after repeated cocaine administration. Cocaine sensitization of stereotyped behaviors in female rats was reduced after progesterone replacement, either alone or concomitant with estradiol. The behavioral responses (locomotion and stereotypy) to cocaine were affected differently, depending on whether the female hormones were of an endogenous or exogenous origin. Therefore, hormonal cycling appears to be an important factor in the sensitization of females. Although estradiol increases the risk of cocaine sensitization, progesterone warrants further study as a pharmacological treatment in the prevention of psychostimulant abuse.

Behavior study of ketamine-induced symptoms similar to schizophrenia in mice / 法医学杂志

OBJECTIVE@#To observe the symptoms similar to schizophrenia in mice after ketamine single or continuous injection and to evaluate the feasibility of schizophrenia model injected with different dose of ketamine.@*METHODS@#A total of 40 male mice were randomly divided into 4 groups, which were injected intraperitoneally with physiological saline (control group), 25 mg/kg ketamine (low dose group), 50 mg/kg ketamine (middle dose group), and 100 mg/kg ketamine (high dose group) qd for 7 days continuously. The behavior changes of mice were observed.@*RESULTS@#Hyperactivity, stereotyped behavior and ataxia (P < 0.01) were observed in high dose group after single injection. After continuous injection of ketamine for 7 days, the middle dose group showed hyperactivity, stereotyped behavior and ataxia (P < 0.05), stereotyped behavior and ataxia were more significant in high dose group (P < 0.01).@*CONCLUSION@#Ketamine can induce the symptoms similar to schizophrenia in mice after single or continuous injection. The symptoms induced by high dose ketamine will be more prominent and stable after continuous injection.

Establishment and evaluation of animal model with methamphetamine poisoning / 法医学杂志

Amphetamine-type stimulants (ATS) is the most widespread narcotics in the 21st century. The methamphetamine's intoxication mechanism, psychological dependence, drug resistance and therapeutic drug development are the hot spots in current research. Establishment of animal model with methamphetamine poisoning is the basic for the relative studies, the normalization and standardization of the animal model settles the foundation for methamphetamine's further research. This article reviews the animal model of methamphetamine poisoning in China and abroad, the brief history of the acute, subacute and chronic animal model of methamphetamine poisoning, as well as the principles and methods of the animal model establishment and its evaluation criteria. The necessity, significance and its scientific expansion of performing experimental research on the methamphetamine poisoning animal model are also discussed.

Perfil neurofarmacológico del Echinodorus berteroi (spreng): Fasset var. berteroi (Llantén cimarrón) / Neuropharmacological profile of Echinodorus berteroi (spreng): Fasset var. berteroi (Llantén cimarrón)

Se estudia el perfil neurofarmacológico de la decocción de las raíces secas de E. berteroi mediante su administración aguda en la prueba de Irwin, la conducta exploratoria, los modelos de estereotipias inducidas por anfetamina y apomorfina, así como en las pruebas de analgesia. Los extractos de la planta (D1, D5 y D30) afectaron el perfil conductual, manifestado por un aumento de la pasividad y una atenuación de la respuesta al dolor; además, se afectó el perfil neurológico en el cual se evidencia una relajación muscular, sin sufrir variación el perfil autonómico. Las decocciones D5 y D30 produjeron una disminución significativa en la conducta exploratoria y D5, en las estereotipias inducidas por anfetamina, sin producir cambios en las estereotipias inducidas por apomorfina. Las decocciones de la planta (D1, D5 y D30) produjeron una atenuación de la respuesta nociceptiva durante la prueba del ácido acético, sin afectar la prueba del plato caliente. Los resultados demuestran que el extracto acuoso de la planta posee un efecto depresor de tipo sedante, un efecto analgésico de acción periférica y una acción neuroléptica

Intracerebroventricular administration of cholecystokinin reduces stereotypy in dopamine supersensitive rats

Cholecystokinin (CCK-8) coexists with dopamine in some neurons and modulates dopaminergic neurotransmission. In the present study we determined the effect of CCK-8 on stereotyped behavior in supersensitive dopaminergic system. Adult male Wistar rats, weighing 200-250 g, were used. Dopaminergic supersensitivity was induced by long-term haloperidol (HAL) treatment (30 days: 1.0 mg/kg twice a day). Seventy-two hours after HAL withdrawal animals received CCK-8 (14.5 nmol/5 µl) or saline intracerebroventricularly (icv) before being tested for apomorphine (APO, 0.6 mg/kg, sc)-induced stereotyped behavior. experimental groups were: long-term HAL-treated rats that received saline (HSAL, N = 9) or CCK-8 (HCCK, N = 11) icvand long-term saline-treated rats that received CCK-8(SCCK,N = 9) or saline (SSAL, N = 8) icv. As expected, HSAL rats showed statistically significant higher stereotypy scores than SSAL rats (42 + or - 1.7 vs 31 + or - 1.6; P<0.05) and CCK-8 icv reduces stereotypy in dopaminergic-supersensitive rats, and suggest that the dopamine supersensitivity phenomenon can be modulated by CCK-8

Effect of manipulation of the GABA system on dopamine-related behaviors

The interaction between GABAergic and dopaminergic system within the central nervous system was investigated in rats using the open-field apparatus and apomorphine-induced stereotypy, and in mice using haloperidol-induced catalepsy. The single intraperitoneal adminsitration of baclofen 3.0 mg/kg, 4,5,6,7-tetrahydroisoxasolo-(5,4-c) piridin-3-ol (THIP) 10.0 mg/kg and picrotoxin 2.0 mg/kg decreased both ambulation and rearing frequencies of the rats in the open-field; only the GABA agonists increased the duration of animal immobility. THIP (10.0 mg/kg) increased the duration of haloperidol-induced catalepsy. For apomorphine-induced stereotypy, baclofen 3.0 mg/kg and picrotoxin 1.0 mg/kg induced a significant leftward displacement of the control dose-response curve constructed for apomorphine (0.1-10 mg/kg) in relation to the control. In addition, baclofen, THIP, picrotoxin and 3-mercaptopropionic acid (3-MPA) 10.0 mg/kg decreased both rearing and sniffing behaviors elicited by apomorphine and increased licking and/ or gnawing. Different mechanisms seem to be involved in the similar effects induced by GABA agonists and antagonists. Picrotoxin induced stereotyped movements per se with a dose-dependent effect, but baclofen and THIP did not. The present data suggest that GABA manipulation facilitates the progressive activation of the different dopaminergic pathways involved in stereotyped behaviors, thus increasing those stereotyped components (gnawing and licking) that appear after a high level of activation of dopaminergic pathways

Effects of single and long-term administration of nifedipine on nociception and stereotyped behavior of rats

In the present investigation, nociception and stereotyped behavior were evaluated in 3-month old male Wistar rats after a single nifedipine dose (2.5 and 5.0 mg/kg, ip, 1 h before testing, 6-7 rats per group for stereotypy studies and 15 animals per group for nociception experiments) or after long-term nifedipine treatment (2.5 mg/kg, ip, twice daily for 30 days, with testing performed 72 or 96 h after the last injection, 7 rats per group for stereotypy studies and 14-16 animals per group for nociception experiments). Stereotypy was induced with 2.5 mg/kg amphetamine, ip, and nociception was measured by the tail-immersion test. Administration of a single nifedipine dose did not modify nociception or amphetamine-induced stereotypy (with a mean +/- SEM tail-withdrawal latency of 4.5 +/- 0.5 s for control, 4.4 +/- 0.3 s for 2.5 mg/kg nifedipine and 4.7 +/- 0.7 s for 5.0 mg/kg nifedipine and with mean +/- SEM sum of stereotypy scores of 32.5 +/- 1.6 for control, 29.1 +/- 1.0 for 2.5 mg/kg nifedipine and 29.1 +/- 1.6 for 5.0 mg/kg nifedipine). Withdrawal from long-term nifedipine treatment did not affect stereotyped behavior (with mean +/- SEM sum of stereotypy scores of 28.7 +/- 1.6 for control and 30.7 +/- 1.3 for nifedipine-treated rats) but significantly increased tail-withdrawal latencies (with a mean +/- SEM tail-withdrawal latency of 4.1 +/- 0.3 s for control and 6.4 +/- 0.6 s for nifedipine-treated rats). Therefore, long-term nifedipine treatment induced plastic modifications in nociception but not in stereotyped behavior.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of single and long-term administration of nifedipine on dopamine-related behaviors

The effects of single (2.5 and 5.0 mg/kg) and long-term (2.5 mg/kg, twice daily, for 30 days) ip administration of nifedipine on open-field and apomorphine-induced stereotyped behavior were evaluated in young male Wistar rats (12-16 animals per group for the open-field studies and 7 animals per group for the stereotypy experiments). Administration of a single dose of nifedipine produced no changes in ambulation or rearing frequencies or in immobility duration in the open-field compared to controls. Similarly, treatment with a single dose of nifedipine did not modify apomorphine-induced stereotypy. Withdrawal from long-term nifedipine administration caused a significant increase only in rearing frequency 24 h after the last drug injection (with a mean +/- SEM frequency of 23.2 +/- 2.8 for the nifedipine group and of 14.7 +/- 2.0 for control rats, after 6-min observation). This enhancement of rearing frequency was no longer observed 48 h after abrupt nifedipine withdrawal (means +/- SEM: 15.0 +/- 2.2 and 19.6 +/- 2.7 for nifedipine-treated and control rats, respectively). The other open-field behavioral parameters and apomorphine-induced stereotypy (which was observed 96 h after nifedipine withdrawal) were not affected by long-term nifedipine treatment; for example, the sum of stereotypy scores (mean +/- SEM) was 26.9 +/- 3.0 for nifedipine-treated rats and 25.5 +/- 2.2 for vehicle-treated animals. The possible mechanisms underlying these results are discussed in light of the changes in dopaminergic neurotransmission induced by dihydropyridine calcium channel blockers

Effects of a single administration of buspirone on catalepsy, yawning and stereotypy in rats

In the present study, the effects of a single administration of buspirone (0.1, 0.3, 1.0, and 3.0 mg/kg sc-30 min before testing) on three dopamine-related behaviors were evaluated in 4-month old male Wistar rats (7-10 animals per group). Buspirone decreased haloperidol (2.0 mg/kg ip)-induced catalepsy in a dose-dependent manner (from 7.30 to 5.09 1n of s compared to the untreated control group). Apomorphine (0.06 mg/kg sc)-induced yawning was also dose-dependently reduced (from 26.7 to 0.9 yawns in 30 min) and so was apomorphine (1.0 mg/kg sc)-induced stereotypy (from 32.9 to 5.9, sum of scores). The present results indicate that buspirone presents unique pharmacological effects related to dopaminergic transmission not only in biochemical but also in behavioral terms

Behavioral and biochemical effects of Xylazine: possible interactions between central noradrenergic-dopaminergic systems

Alguns efeitos comportamentais e bioquímicos da xilazina foram estudados em ratos e camundongos. Os resultados mostraram que a xilazina: a)diminuiu a atividade geral de ratos e camundongos observados em campo-aberto; b) foi incapaz de produzir catatonia e suprimiu este comportamento induzido pelo haloperidol em camundongos; c) potencializou o comportamento estereotipado induzido pela apomorfina em ratos; d) aumentou os nívei cerebrais de noradrenalina, porém näo alterou aqueles de dopamina. Estes resultados foram discutidos considerando-se açäo da xilazina em sistemas noradrenérgicos centrais e da interaçäo entre sistemas noradrenérgicos e dopaminérgicos centrais

A study on the action of two calcium channel blockers (verapamil and flunarizine) upon an experimental model of tardive dyskinesia in rats

A discinesia tardia (DT) é complicaçäo decorrente do uso prolongado de neurolépticos. Até o presente, nenhum tratamento provou ser eficaz na DT. Evidências indiretas apontam para a açäo de drogas bloqueadoras de canais de cálcio (BCC) em algumas vias neurais. A açäo de duas dessas drogas, varapamil e flunarizina, foi testada em modelo experimental de DT em rato, neste estudo. O haloperidol foi administrado por 21 dias e induçäo de movimentos estereotipados era obtida no 24§ dia, com a injeçäo de apomorfina. As drogas BCC foram administradas por uma vez no 28§ dia (experimento agudo) e por 8 dias, após o 25§ dia (experimento crônico). A flunarizina näo induziu modificaçäo no padräo de estereotipia dos animais, mas o verapamil levou a aumento no experimento agudo e a diminuiçäo no experimento crônico. Estes achados indicam que as drogas BCC podem ter alguma açäo sobre a DT e que ensaios clínicos devem ser feitos para se comprovar se tal açäo ocorre no homem

Mesolimbic deficits exacerbate amphetamine treatment: clinical implications for drug abusers

Amphetamine, a common drug used by abusers, is able to produce a schizophreniform psychosis in man. The experiment reported here examined amphetamine in relation to its role in the nucleus accumbens septi (NAS) and the globus pallidus. The effects produced by apomorphine, a direct dopamine (DA) agonist, were compared with those of amphetamine, a known indirect DA agonist. The data revealed that amphetamine in NAS-lesioned animals produced very active stereotypy which intensified with time. This effect was blocked by pallidal lesioning. Apomorphine in pallidectomised rats produced persistent stereotypy, but of diminished intensity. The results are discussed in terms of the mediating roles of the NAS and globus pallidus on behavioural sequelae. (AU)