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1.
Braz J Med Biol Res ; 52(11): e8899, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31664307

RESUMEN

Few behavioral tests allow measuring several characteristics and most require training, complex analyses, and/or are time-consuming. We present an apparatus based on rat exploratory behavior. Composed of three different environments, it allows the assessment of more than one behavioral characteristic in a short 3-min session. Factorial analyses have defined three behavioral dimensions, which we named Exploration, Impulsivity, and Self-protection. Behaviors composing the Exploration factor were increased by chlordiazepoxide and apomorphine and decreased by pentylenetetrazole. Behaviors composing the Impulsivity factor were increased by chlordiazepoxide, apomorphine, and both acute and chronic imipramine treatments. Behaviors composing the Self-protection factor were decreased by apomorphine. We submitted Wistar rats to the open-field test, the elevated-plus maze, and to the apparatus we are proposing. Measures related to exploratory behavior in all three tests were correlated. Measures composing the factors Impulsivity and Self-protection did not correlate with any measures from the two standard tests. Also, compared with existing impulsivity tests, the one we proposed did not require previous learning, training, or sophisticated analysis. Exploration measures from our test are as easy to obtain as the ones from other standard tests. Thus, we have proposed an apparatus that measured three different behavioral characteristics, was simple and fast, did not require subjects to be submitted to previous learning or training, was sensitive to drug treatments, and did not require sophisticated data analyses.


Asunto(s)
Ansiedad/psicología , Conducta Animal/fisiología , Investigación Conductal/instrumentación , Conducta Exploratoria/fisiología , Miedo/fisiología , Conducta Impulsiva/fisiología , Animales , Ansiolíticos/farmacología , Antidepresivos Tricíclicos/farmacología , Apomorfina/farmacología , Conducta Animal/efectos de los fármacos , Clordiazepóxido/farmacología , Agonistas de Dopamina/farmacología , Conducta Exploratoria/efectos de los fármacos , Miedo/efectos de los fármacos , Antagonistas del GABA/farmacología , Conducta Impulsiva/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Modelos Animales , Pentilenotetrazol/farmacología , Ratas Wistar , Factores de Tiempo
2.
Behav Processes ; 165: 1-3, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31185264

RESUMEN

The nematode Phasmarhabditis hermaphrodita can infect and kill many species of slugs and has been formulated into a biological control agent for farmers and gardeners. P. hermaphrodita can manipulate the behaviour of slugs, making those infected move to areas where the nematode is present. Research suggests P. hermaphrodita uses manipulation of biogenic amines to achieve this, however the exact role of serotonin and dopamine needs further elucidation. Here we fed slugs Deroceras invadens (uninfected and infected with P. hermaphrodita) apomorphine, sertraline and haloperidol and observed their behaviour when given a choice between a P. hermaphrodita infested habitat, or a parasite free area of soil. In contrast to their usual P. hermaphrodita avoidance behaviour, uninfected D. invadens fed sertraline were attracted to the nematodes and conversely those fed haloperidol avoided the nematodes. D. invadens fed apomorphine were recorded equally on the control and nematode side. D. invadens pre-infected with P. hermaphrodita fed sertraline and apomorphine were found significantly more on the side with the nematodes. However, suppressing dopaminergic signalling through feeding with haloperidol abrogated this attraction and slugs were found on both sides. These results demonstrate that serotonin and dopamine are potential regulators of behavioural manipulation by P. hermaphrodita.


Asunto(s)
Reacción de Prevención/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Agentes de Control Biológico/farmacología , Gastrópodos/efectos de los fármacos , Gastrópodos/parasitología , Rhabditoidea , Animales , Apomorfina/farmacología , Reacción de Prevención/fisiología , Dopamina/fisiología , Haloperidol/farmacología , Serotonina/fisiología , Sertralina/farmacología , Suelo/parasitología
3.
Sensors (Basel) ; 19(9)2019 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-31071987

RESUMEN

An optical probe was developed to measure the change of oxy-hemoglobin (OHb), deoxy- hemoglobin (RHb), and total hemoglobin (THb) along with temperature from the vaginal wall of female rats. Apomorphine (APO, 80 µg/kg) was administered to elicit sexual arousal in female Sprague Dawley rats (SD, 180-200 g). The behavior changes caused by APO administration were checked before monitoring vaginal responses. The changes of oxy-, deoxy-, and total hemoglobin concentration and the temperature from the vaginal wall were monitored before, during, and after APO administration. Animals were under anesthesia during the measurement. After APO administration, the concentration of OHb (55 ± 29 µM/DPF), RHb (33 ± 25 µM/DPF), and THb (83 ± 59 µM/DPF) in the vaginal wall increased in a few min, while saline administration did not cause any significant change. In case of the vaginal temperature change, APO decreased the temperature slightly in the vaginal wall while saline administration did not show any temperature change in the vaginal wall. As the outcomes demonstrated, the developed probe can detect hemodynamic and temperature variation in the vaginal wall. The hemodynamic information acquired by the probe can be utilized to establish an objective and accurate standard of female sexual disorders.


Asunto(s)
Hemodinámica/fisiología , Monitoreo Fisiológico , Óptica y Fotónica/instrumentación , Conducta Sexual Animal/fisiología , Vagina/fisiología , Animales , Apomorfina/farmacología , Diseño de Equipo , Femenino , Oxihemoglobinas/metabolismo , Ratas Sprague-Dawley , Respiración
4.
Acta Neuropsychiatr ; 31(3): 143-150, 2019 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-30890202

RESUMEN

OBJECTIVES: NMDA antagonists and nitric oxide synthase (NOS) inhibitors induce antidepressant-like effects and may represent treatment options for depression. The behavioural effects of NMDA antagonists seem to depend on Tyrosine kinase B receptor (TrkB) activation by BDNF and on mechanistic target of rapamycin (mTOR), in the medial prefrontal cortex (mPFC). However, it is unknown whether similar mechanisms are involved in the behavioural effects of NOS inhibitors. Therefore, this work aimed at determining the role of TrkB and mTOR signalling in the prelimbic area of the ventral mPFC (vmPFC-PL) in the antidepressant-like effect of NOS inhibitors. METHODS: Pharmacological treatment with LY235959 or ketamine (NMDA antagonists), NPA or 7-NI (NOS inhibitors), BDNF, K252a (Trk antagonist) and rapamycin (mTOR inhibitor) injected systemically or into vmPFC-PL followed by behavioural assessment. RESULTS: We found that bilateral injection of BDNF into the vmPFC-PL induced an antidepressant-like effect, which was blocked by pretreatment with K252a and rapamycin. Microinjection of LY 235959 into the vmPFC-PL induced antidepressant-like effect that was suppressed by local rapamycin but not by K252a pretreatment. Microinjection of NPA induced an antidepressant-like effect insensitive to both K252a and rapamycin. Similarly, the antidepressant-like effects of a systemic injection of ketamine or 7-NI were not affected by blockade of mTOR or Trk receptors in the vmPFC-PL. CONCLUSION: Our data support the hypothesis that NMDA blockade induces an antidepressant-like effect that requires mTOR but not Trk signalling into the vmPFC-PL. The antidepressant-like effect induced by local NOS inhibition is independent on both Trk and mTOR signalling in the vmPFC-PL.


Asunto(s)
Antidepresivos/farmacología , Factor Neurotrófico Derivado del Encéfalo/farmacología , Óxido Nítrico Sintasa de Tipo I/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Animales , Antidepresivos/administración & dosificación , Apomorfina/administración & dosificación , Apomorfina/análogos & derivados , Apomorfina/farmacología , Factor Neurotrófico Derivado del Encéfalo/administración & dosificación , Carbazoles/administración & dosificación , Carbazoles/farmacología , Pérdida de Tono Postural/efectos de los fármacos , Indazoles/administración & dosificación , Indazoles/farmacología , Alcaloides Indólicos/administración & dosificación , Alcaloides Indólicos/farmacología , Isoquinolinas/administración & dosificación , Isoquinolinas/farmacología , Ketamina/administración & dosificación , Ketamina/farmacología , Locomoción/efectos de los fármacos , Masculino , Microinyecciones , Ornitina/administración & dosificación , Ornitina/farmacología , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Ratas , Receptor trkB/antagonistas & inhibidores , Receptor trkB/biosíntesis , Sirolimus/administración & dosificación , Sirolimus/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/biosíntesis
5.
Neuroimage Clin ; 22: 101724, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30822717

RESUMEN

Identification of Parkinson's disease at the earliest possible stage of the disease may provide the best opportunity for the use of disease modifying treatments. However, diagnosing the disease during the pre-symptomatic period remains an unmet goal. To that end, we used pharmacological MRI (phMRI) to assess the function of the cortico-basal ganglia circuit in a non-human primate model of dopamine deficiency to determine the possible relationships between phMRI signals with behavioral, neurochemical, and histological measurements. Animals with unilateral treatments with the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), that expressed stable, long-term hemiparkinsonism were challenged with the dopaminergic receptor agonist, apomorphine, and structure-specific phMRI blood oxygen level-dependent (BOLD) activation responses were measured. Behavioral, histopathological, and neurochemical measurements were obtained and correlated with phMRI activation of structures of the cortico-basal ganglia system. Greater phMRI activations in the basal ganglia and cortex were associated with slower movement speed, decreased daytime activity, or more pronounced parkinsonian features. Animals showed decreased stimulus-evoked dopamine release in the putamen and substantia nigra pars compacta and lower basal glutamate levels in the motor cortex on the MPTP-lesioned hemisphere compared to the contralateral hemisphere. The altered neurochemistry was significantly correlated with phMRI signals in the motor cortex and putamen. Finally, greater phMRI activations in the caudate nucleus correlated with fewer tyrosine hydroxylase-positive (TH+) nigral cells and decreased TH+ fiber density in the putamen. These results reveal the correlation of phMRI signals with the severity of the motor deficits and pathophysiological changes in the cortico-basal ganglia circuit.


Asunto(s)
Apomorfina/farmacología , Imagen por Resonancia Magnética/métodos , Corteza Motora/diagnóstico por imagen , Corteza Motora/metabolismo , Trastornos Parkinsonianos/diagnóstico por imagen , Trastornos Parkinsonianos/metabolismo , Animales , Agonistas de Dopamina/farmacología , Femenino , Macaca mulatta , Corteza Motora/efectos de los fármacos , Consumo de Oxígeno/efectos de los fármacos , Consumo de Oxígeno/fisiología , Trastornos Parkinsonianos/inducido químicamente
6.
Pak J Pharm Sci ; 32(1): 197-203, 2019 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-30772809

RESUMEN

Apomorphine is a classical psychostimulant and used throughout the world as prescribed medicine. Despite of their therapeutic effects, use of psychostimulants is restricted because some psychosis and impulse control disorders are the consequence of their long term use. Studies suggest that serotonin (5-Hydroxytryptamine; 5-HT) has a critical role in psychosis and drug abuse. Center of the present article is to assess the impacts of serotonin in the easing of misuse potential; the sensitization prompted by recommended psychostimulant apomorphine. We researched that whether Escitalopram can weaken apomorphine instigated behavioral sensitization. Rats treated with Escitalopram (10 mg/kg) daily for 7 days followed by apomorphine injections (1mg/kg) for next 7 days. Apomorphine increased motor activity after single injection and repeated injections produced a progressive sensitization of motor activity. Whereas, in rats pretreated with Escitalopram apomorphine induced behavioral sensitization did not occur. In this article, from the results of this study it is concluded that apomorphine induced behavioral sensitization was smaller in rats pretreated with SSRIs. It might be due to the desensitization of somatodendritic 5-HT-1A receptors.


Asunto(s)
Apomorfina/farmacología , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Sensibilización del Sistema Nervioso Central/efectos de los fármacos , Citalopram/farmacología , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Agonistas del Receptor de Serotonina 5-HT1/farmacología , Inhibidores de la Captación de Serotonina/farmacología , Animales , Encéfalo/metabolismo , Conducta Exploratoria/efectos de los fármacos , Masculino , Actividad Motora/efectos de los fármacos , Ratas Wistar , Receptor de Serotonina 5-HT1A/metabolismo , Factores de Tiempo
7.
Neurosci Lett ; 699: 71-76, 2019 04 23.
Artículo en Inglés | MEDLINE | ID: mdl-30716425

RESUMEN

The effects of melatonin and melatonin analogs in experimental Parkinson's disease (PD) models remain controversial. Agomelatine, a novel analog of melatonin, is both agonists for melatonin-1 and melatonin-2 receptors and antagonist of 5-HT2C receptors. While agomelatine has been commonly used as an anti-depressant and sleep drug, information about effects of agomelatine in PD are still lacking. Male Sprague-Dawley rats (220-260 g) were injected with rotenone (0.5 µg, n = 16) or vehicle (1 µl DMSO, n = 8) into the left substantia nigra (SN) and ventral tegmental area under stereotaxic surgery. After ten days, the rats were assessed for the confirmation of PD by the rotational test following apomorphine injection (2 mg/kg, i.p.). The confirmed rats were divided into two groups which received daily p.o. agomelatine (40 mg/kg, n = 8) or saline (2 ml/rat, n = 8) for consecutively 18 days. Twenty-four hours after the last drug administration, the rotational test was repeated and motor coordination was assesed just before the decapitation. Brain tissues were taken for biochemical, molecular and histopathological evaluations. Agomelatine treated animals showed augmented apomorphine-induced rotation response and impaired motor coordination compared to the rotenone group. Furthermore, agomelatine treatment significantly induced apoptosis with an increase in caspase-3 expression independent from PARP-1 activation. Agomelatine treatment caused increased protein oxidation levels, in addition to a decrease in neuron number in the striatum. Although we investigated the effects of the agomelatine in the manner of ameliorating the rotenone toxicity in animals, agomelatine exacerbates rotenone-induced toxicity which mimics Parkinson's disease pathology.


Asunto(s)
Acetamidas/farmacología , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/prevención & control , Rotenona , Animales , Apomorfina/farmacología , Apoptosis/efectos de los fármacos , Encéfalo/metabolismo , Recuento de Células , Cuerpo Estriado/patología , Hipocinesia/prevención & control , Masculino , Neuronas/patología , Oxidación-Reducción/efectos de los fármacos , Proteínas/metabolismo , Ratas , Prueba de Desempeño de Rotación con Aceleración Constante , Rotación
8.
J Neurol ; 266(3): 659-666, 2019 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-30617907

RESUMEN

INTRODUCTION: Deep brain stimulation (DBS) is an effective therapy for patients with advanced Parkinson's disease (PD). However, sometimes, it is not sufficient to adequately control motor symptoms. We describe our experience with continuous subcutaneous apomorphine infusion (APO) in patients with DBS. METHODS: We undertook a retrospective analysis of all patients treated with DBS and APO at our centre over 12 years. Subjects were allocated to four groups: (1) APO temporarily before DBS, (2) APO after DBS complications before a new DBS, (3) APO after definitive DBS removal, and (4) APO in patients with DBS and declining response. Motor state and other parameters were analysed and compared for the different treatments. RESULTS: Data for 71 patients were evaluated. Group 1: (n = 18) patients improved their motor function significantly with both APO and DBS (off-hours before APO 5.4 ± 1.4; after APO 1.4 ± 1.2, p > 0.001; after DBS 0.7 ± 0.8, p < 0.001). Group 2: (n = 11) patients were found to have mild but significant worsening of motor state between the first DBS treatment (off-hours 0.7 ± 1.0) and APO (2.2 ± 1.5, p = 0.02), and improvement between APO and the second DBS treatment (off-hours 0.6 ± 0.8, p = 0.03). Group 3: (n = 12) patients had mild but significant worsening of motor function between DBS (off-hours 1.1 ± 1.0) and APO (2.0 ± 0.9, p = 0.03). Group 4: (n = 13) significant improvement in motor function was observed between DBS alone (off-hours 3.9 ± 2.6) and DBS combined with APO (2.2 ± 1.3, p = 0.03). CONCLUSION: In advanced PD, DBS may be not sufficient or may fail to control motor symptoms adequately. In these cases, APO, whether alone or in combination with DBS, is a good choice to improve the disease control.


Asunto(s)
Apomorfina/farmacología , Estimulación Encefálica Profunda/métodos , Agonistas de Dopamina/farmacología , Enfermedad de Parkinson/terapia , Anciano , Apomorfina/administración & dosificación , Terapia Combinada , Agonistas de Dopamina/administración & dosificación , Humanos , Infusiones Subcutáneas , Persona de Mediana Edad , Enfermedad de Parkinson/tratamiento farmacológico , Estudios Retrospectivos
9.
Behav Pharmacol ; 30(1): 89-94, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-29847340

RESUMEN

The development of Parkinson's disease (PD) involves the degeneration of dopaminergic neurons caused by oxidative stress. Accumulating clinical evidence indicates that high blood levels of uric acid (UA), an intrinsic antioxidative substance, are associated with reduced risk of PD. However, this hypothesis has not been confirmed by in-vivo experiments. The present study investigated the effects of UA on behavioral abnormalities in the development of PD. We used unilateral 6-hydroxydopamine-lesioned mice, which were fed on a diet containing 1% UA and 2.5% potassium oxonate (an uricase inhibitor) to induce hyperuricemia. A significant elevation in UA levels was found in groups that were fed a UA diet. The 6-hydroxydopamine-lesioned mice showed impaired rotarod performance and increased apomorphine-induced contralateral rotations. These behavioral abnormalities were significantly reversed by feeding a UA diet for 1 week before and 5 weeks after surgery (subchronic hyperuricemia). These behavioral improvements occurred in parallel with recovery of tyrosine hydroxylase protein levels in the lesioned striatal side. The present study with a dietary hyperuricemia mice model confirms that UA exerts a neuroprotective effect on dopaminergic neuronal loss, improving motor dysfunction and ameliorating PD development.


Asunto(s)
Trastornos Mentales/sangre , Trastornos Mentales/etiología , Enfermedad de Parkinson Secundaria/complicaciones , Ácido Úrico/sangre , Adrenérgicos/toxicidad , Animales , Apomorfina/farmacología , Modelos Animales de Enfermedad , Hiperuricemia/sangre , Hiperuricemia/etiología , Masculino , Trastornos Mentales/dietoterapia , Ratones , Ratones Endogámicos ICR , Actividad Motora/efectos de los fármacos , Oxidopamina/toxicidad , Ácido Oxónico/administración & dosificación , Enfermedad de Parkinson Secundaria/inducido químicamente , Prueba de Desempeño de Rotación con Aceleración Constante , Tirosina 3-Monooxigenasa/metabolismo
10.
Psychopharmacology (Berl) ; 236(4): 1303-1312, 2019 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-30536080

RESUMEN

RATIONALE: The influence of the main dopaminergic brain regions controlling copulation, the medial preoptic area (mPOA) and the nucleus accumbens (NAcc), on male rat sexual behavior expression has not been fully established. OBJECTIVE: This work analyzes the sexual effects of dopamine (DA) receptor activation in the mPOA or the NAcc of sexually active male rats, with an intact (sexually experienced) or a reduced (sexually exhausted) sexual motivation. METHODS: The non-specific DA receptor agonist apomorphine and the D2-like receptor agonist quinpirole were infused into the mPOA or the NAcc of sexually experienced or sexually exhausted male rats and their sexual behavior recorded. RESULTS: DA receptor activation neither in the mPOA nor in the NAcc modified the copulatory behavior of sexually experienced male rats. DA receptor stimulation in the NAcc, but not in the mPOA, reversed the characteristic sexual inhibition of sexually satiated rats, and D2-like receptors were found to participate in this effect. CONCLUSION: The optimal sexual performance of sexually experienced male rats cannot be further improved by DA receptor activation at either brain region. In sexually satiated rats, which are sexually inhibited and have a diminished sexual motivation, NAcc DA receptor stimulation appears to play a key role in their capacity to respond to a motivational significant stimulus, the receptive female, with the participation of D2-like receptors. Activation of DA receptors with the same drug, at the same dose and in the same brain region, produces different effects on copulatory behavior that depend on the animal's sexual motivational state.


Asunto(s)
Agonistas de Dopamina/farmacología , Dopamina/metabolismo , Motivación/fisiología , Núcleo Accumbens/metabolismo , Saciedad/fisiología , Conducta Sexual Animal/fisiología , Animales , Apomorfina/farmacología , Copulación/efectos de los fármacos , Copulación/fisiología , Relación Dosis-Respuesta a Droga , Femenino , Masculino , Motivación/efectos de los fármacos , Núcleo Accumbens/efectos de los fármacos , Quinpirol/farmacología , Ratas , Ratas Wistar , Receptores Dopaminérgicos/metabolismo , Saciedad/efectos de los fármacos , Conducta Sexual Animal/efectos de los fármacos
11.
Colloids Surf B Biointerfaces ; 174: 174-180, 2019 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-30453136

RESUMEN

The present work reports the processing of laser irradiated Si arrays (LISi) and underlines their surface enhanced Raman scattering (SERS) functionality. A nanostructured Si/SiOx surface forms providing additional fluidic and photoprotective properties. Because of their optical and surface characteristics, the arrays exhibit a SERS analytical enhancing factor of 500, without any noble metals such as gold or silver. Micro-Raman maps allowed studying LISi properties, identifying maximum amplification in nanostructured areas characterized by the presence of 7 nm Si nanocrystals. These structures are confined by a SiOx layer as illustrated by XPS valence band measurements. The highly hydrophilic LISi areas allow a pre-concentration of target molecules prior to SERS analysis. A relevant application of LISi was found in the detection of apomorphine (APO), a drug used for the treatment of Parkinson's disease. In contrast with what is obtained by using gold SERS substrates, LISi allows the detection of APO with no sign of oxidation. This invites for the use of the Si/SiOx SERS detection in future systems for the personalized delivery of APO.


Asunto(s)
Apomorfina/análisis , Agonistas de Dopamina/análisis , Rayos Láser , Nanoestructuras/química , Silicio/química , Apomorfina/farmacología , Agonistas de Dopamina/farmacología , Oxidación-Reducción , Tamaño de la Partícula , Receptores Dopaminérgicos/metabolismo , Espectrometría Raman , Propiedades de Superficie
12.
Eur J Pharmacol ; 843: 66-79, 2019 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-30395851

RESUMEN

Apomorphine is a 150-year old nonspecific dopaminergic agonist, currently indicated for treating motor fluctuations in Parkinson's disease. At the era of drug repurposing, its pleiotropic biological functions suggest other possible uses. To further explore new therapeutic and diagnostic applications, the available literature up to July 2018 was reviewed using the PubMed and Google Scholar databases. As many of the retrieved articles consisted of case reports and preclinical studies, we adopted a descriptive approach, tackling each area of research in turn, to give a broad overview of the potential of apomorphine. Apomorphine may play a role in neurological diseases like restless legs syndrome, Huntington's chorea, amyotrophic lateral sclerosis, Alzheimer's disease and disorders of consciousness, but also in sexual disorders, neuroleptic malignant(-like) syndrome and cancer. Further work is needed in both basic and clinical research; current developments in novel delivery strategies and apomorphine derivatives are expected to open the way.


Asunto(s)
Apomorfina/uso terapéutico , Agonistas de Dopamina/uso terapéutico , Animales , Apomorfina/farmacología , Agonistas de Dopamina/farmacología , Reposicionamiento de Medicamentos , Humanos , Neoplasias/tratamiento farmacológico , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Disfunciones Sexuales Fisiológicas/tratamiento farmacológico
13.
Neurochem Int ; 122: 38-46, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30419255

RESUMEN

Parkinson's disease (PD) is a frequent neurodegenerative disease causing bradykinesia, tremor, muscle rigidity and postural instability. Although its main pathology is progressive dopaminergic (DArgic) neuron loss in the substantia nigra, motor deficits are thought not to become apparent until most DArgic neurons are lost, probably due to compensatory mechanisms that overcome the decline of DA level in the striatum. Even in animal PD models, it is difficult to detect motor deficits when most DArgic neurons are functional. In this study, we performed various behavioral tests (apomorphine-induced rotation, cylinder, forepaw adjustment steps (FAS), beam walking, rota-rod, and open-field), using 6-hydroxydopamine (OHDA) and lipopolysaccharide (LPS)-induced hemi-PD model rats with various striatal DA levels, to find the best way to predict the DA level from earlier disease stages. Different from the 6-OHDA-induced model, reduction in the striatal DA levels in the LPS-model was less significant. Among the behavioral tests, data from cylinder and FAS tests, which evaluate forelimb movements, best correlated with decline of the DA level. They also correlated well with decreased body weight gain. The beam and apomorphine tests showed less significant correlation than the cylinder and FAS tests. Open-field and rota-rod tests were not useful. Expressional levels of mRNA encoding tyrosine hydroxylase (TH), a marker of DArgic neurons, correlated well with the DA level. Metabotropic glutamate receptor 4 mRNA expression correlated with the striatal DA level and may be related to compensatory mechanisms. These results suggest that motor impairments of PD should be evaluated by forelimb movements, or hands and forearms in clinical settings, rather than movement of the body or large joints. The combination of cylinder and FAS tests may be the best to evaluate the rat PD models, in which many DArgic neurons survive.


Asunto(s)
Apomorfina/farmacología , Conducta Animal/efectos de los fármacos , Agonistas de Dopamina/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Animales , Escala de Evaluación de la Conducta , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Masculino , Actividad Motora/efectos de los fármacos , Degeneración Nerviosa/tratamiento farmacológico , Degeneración Nerviosa/metabolismo , Enfermedad de Parkinson/metabolismo , Ratas Wistar , Sustancia Negra/efectos de los fármacos , Sustancia Negra/metabolismo
14.
Behav Pharmacol ; 30(1): 59-66, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30299277

RESUMEN

The transient receptor potential vanilloid 1 (TRPV1) can modulate stress-related behaviours, thus representing an interesting target for new antidepressant drugs. TRPV1 can trigger glutamate release and nitric oxide synthesis in the brain, mechanisms also involved in the neurobiology of depression. However, it is not known if these mechanisms are involved in TRPV1-induced behavioural effects. Therefore, the aim of this study was to verify if the antidepressant-like effect induced by a TRPV1 antagonist in mice submitted to the forced swimming test (FST) would be facilitated by combined treatment with neuronal nitric oxide synthase (nNOS) inhibition and N-methyl-D-aspartate (NMDA) blockade. Male Swiss mice were given (intracerebroventricular) injections of capsazepine (CPZ) (TRPV1 antagonist - 0.05/0.1/0.3/0.6 nmol/µl), and AP7 (NMDA antagonist - 1/3/10 nmol/µl) or N-propyl-L-arginine (NPA, nNOS inhibitor - 0.001/0.01/0.1 nmol/µl), and 10 min later, submitted to an open field test, and immediately afterwards, to the FST. An additional group received coadministration of CPZ and AP7 or CPZ and NPA, in subeffective doses. The results demonstrated that CPZ (0.1 nmol/µl), AP7 (3 nmol/µl) and NPA (0.01/0.1 nmol/µl) induced antidepressant-like effects. Moreover, coadministration of subeffective doses of CPZ and AP7 or CPZ and NPA induced significant antidepressant-like effects. Altogether, the data indicate that blockade of TRPV1 receptors by CPZ induces antidepressant-like effects and that both nNOS inhibition and NMDA blockade facilitate CPZ effects in the FST.


Asunto(s)
Antidepresivos/uso terapéutico , Capsaicina/análogos & derivados , Depresión/tratamiento farmacológico , Ácido Glutámico/metabolismo , Óxido Nítrico/metabolismo , Natación/psicología , 2-Amino-5-fosfonovalerato/análogos & derivados , 2-Amino-5-fosfonovalerato/farmacología , Animales , Apomorfina/análogos & derivados , Apomorfina/farmacología , Arginina/farmacología , Capsaicina/uso terapéutico , GMP Cíclico/metabolismo , Depresión/metabolismo , Depresión/fisiopatología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Vías de Administración de Medicamentos , Inhibidores Enzimáticos/farmacología , Conducta Exploratoria/efectos de los fármacos , Masculino , Microinyecciones , Nitroprusiato/metabolismo , Ratas , Receptores de N-Metil-D-Aspartato/metabolismo , Estadísticas no Paramétricas
15.
Andrologia ; 51(1): e13160, 2019 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-30276840

RESUMEN

Nonorganic erectile dysfunction is a problem with unknown central mechanisms. Changes in brain activity in the amygdala have been observed in human patients. This study aimed to investigate the dopamine system in the basolateral amygdala of male rats with nonorganic erectile dysfunction. We applied chronic mild stress to induce nonorganic erectile dysfunction. After exposure to chronic mild stress, the sucrose consumption test, sexual behaviour test and apomorphine test were used to select depression-like rats with erectile dysfunction as nonorganic erectile dysfunction model rats. The sexual behaviour of these rats after central infusion of a dopamine D1/D2 receptor agonist/antagonist was observed. The expression levels of dopamine D1/D2 receptors and tyrosine hydroxylase in the basolateral amygdala were also measured. The result of the sucrose consumption test, sexual behaviour test and apomorphine test indicated a successful nonorganic erectile dysfunction model. Central infusion of a dopamine D2 receptor agonist increased intromission ratio in model rats. Lower expression levels of tyrosine hydroxylase and the dopamine D2 receptor in the basolateral amygdala were observed in rats with nonorganic erectile dysfunction. These results suggest that impairment of the dopamine D2 receptor pathway in the basolateral amygdala may contribute to the development of nonorganic erectile dysfunction.


Asunto(s)
Complejo Nuclear Basolateral/efectos de los fármacos , Disfunción Eréctil/metabolismo , Erección Peniana/efectos de los fármacos , Receptores de Dopamina D2/metabolismo , Conducta Sexual Animal/efectos de los fármacos , Animales , Apomorfina/farmacología , Complejo Nuclear Basolateral/metabolismo , Modelos Animales de Enfermedad , Agonistas de Dopamina/farmacología , Antagonistas de los Receptores de Dopamina D2/farmacología , Masculino , Ratas , Ratas Wistar , Conducta Sexual Animal/fisiología , Estrés Psicológico/metabolismo
16.
Neuropsychopharmacology ; 44(3): 572-580, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30267014

RESUMEN

Aripiprazole is an antipsychotic drug characterized by partial agonist activity at D2 receptors to normalize both hyperdopaminergic and hypodopaminergic states. Traditional D2 antagonist antipsychotic drugs have been shown previously to reduce dopamine neuron activity through action on D2 autoreceptors to produce an overexcitation-induced cessation of cell firing, referred to as depolarization block. It is unclear whether aripiprazole reduces dopamine neuron activity via inhibition or, as seen following D2 antagonist administration, depolarization block. The impact of acute and repeated aripiprazole treatment was examined in the methylazoxymethanol acetate (MAM) rodent model to observe its effects on a hyperdopaminergic system, compared to normal rats. We found that administration of aripiprazole acutely or after 1 or 7 days of withdrawal from 21-day repeated treatment led to a decrease in the number of spontaneously active dopamine neurons in MAM rats but not in controls. This reduction was not reversed by apomorphine (100-200 µg/kg i.p. or 20 µg/kg i.v.) administration, suggesting that it was not due to depolarization block. In contrast, 1 h after induction of depolarization block of dopamine neurons by acute haloperidol treatment (0.6 mg/kg i.p.), aripiprazole (1 mg/kg, i.p.) reversed the depolarization block state. Therefore, aripiprazole rapidly reduced the hyperdopaminergic activity selectively in MAM rats. The reduction is unlikely due to depolarization block and persists following 7-day withdrawal from repeated treatment. Aripiprazole also removes haloperidol-induced depolarization block in MAM rats, which may underlie the acute psychotic state often observed with switching to this treatment.


Asunto(s)
Aripiprazol/farmacología , Agonistas de Dopamina/farmacología , Antagonistas de Dopamina/farmacología , Neuronas Dopaminérgicas/efectos de los fármacos , Receptores de Dopamina D2/efectos de los fármacos , Área Tegmental Ventral/efectos de los fármacos , Animales , Apomorfina/farmacología , Modelos Animales de Enfermedad , Electroencefalografía , Haloperidol/farmacología , Masculino , Acetato de Metilazoximetanol/farmacología , Ratas , Ratas Sprague-Dawley
17.
Behav Brain Res ; 359: 771-782, 2019 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-30114434

RESUMEN

Morphine has potent pro-dopamine effects that can be manifested as hyper-locomotion and these behavioral effects can undergo conditioning and sensitization. The aim of the present study was to assess whether an inhibitory dopaminergic post-trial treatment (0.05 mg/kg apomorphine) given during re-consolidation could reduce morphine conditioning. To induce conditioned morphine hyperactivity and control for morphine exposure, a paired/unpaired Pavlovian conditioning protocol was used. The morphine paired groups received morphine in the open-field test arena and the unpaired groups received the same morphine (10 mg/kg) treatments but in a different environment. The morphine treatments were administered once per day for 5 days. With repeated treatments, the paired morphine groups developed a sensitized hyper-locomotion response whereas the unpaired morphine groups did not differ from vehicle groups. Subsequently, the paired, unpaired and vehicle groups were given four daily non-drug 5 min conditioning tests. In these conditioning tests, the paired but not the unpaired and vehicle groups exhibited a conditioned locomotor stimulant response. These groups were subdivided into matched groups and received either vehicle or 0.05 mg/kg apomorphine either during re-consolidation immediately post-test or after re-consolidation 15 min post-test. In the immediate post-trial treatment groups, the morphine conditioned response in the paired group was eliminated after only one post-trial apomorphine treatment. The same immediate 0.05 mg/kg apomorphine post-trial treatments had no effect on the unpaired morphine or vehicle groups. In the paired group that received vehicle immediately post-trial, the conditioned response remained robust and unchanged over the four conditioning tests. In the post-trial 15 min delay treatment groups, the post-trial apomorphine treatments had no effect on the morphine conditioned response. These results showed that the inhibition of dopamine activity by apomorphine during the re-consolidation of a cue activated morphine conditioned response eliminated morphine conditioned effects. In that morphine conditioned effects are important for the initiation of addiction and in triggering drug craving and relapse, this finding has potential relevance to opioid addiction treatment.


Asunto(s)
Analgésicos Opioides/farmacología , Apomorfina/farmacología , Condicionamiento Operante/efectos de los fármacos , Agonistas de Dopamina/farmacología , Hipercinesia/inducido químicamente , Hipercinesia/tratamiento farmacológico , Morfina/farmacología , Animales , Relación Dosis-Respuesta a Droga , Locomoción/efectos de los fármacos , Masculino , Ratas , Ratas Wistar , Estadísticas no Paramétricas , Factores de Tiempo
18.
Pak J Pharm Sci ; 31(6): 2561-2567, 2018 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-30473532

RESUMEN

Psychostimulants substances, some of which are abused by humans, are generally believed to produce sensitization effects when they are repeatedly administered to animals. Apomorphine, a non-narcotic derivative of morphine, having agonistic property for dopamine in order to produce psycho stimulant-like effects. Meanwhile, chronic administration leads to behavioral sensitization. Therefore, present study destine to produce desensitization in animals by the repeated administration of tryptophan (100 mg/kg), thereafter treated with apomorphine (1.0 mg/kg) to observe the intensity of sensitization in rats pre-treated with tryptophan. Apomorphine on acute administration known to increase motor activity whereas repeated treatment of apomorphine initiates the sensitization of motor behavior. It is expected that the intensity of apomorphine induced sensitization would be affected in tryptophan-treated rats. Present study provide the clear-cut evidence that chronic treatment of apomorphine arouses the motor behavior of animals in both novel and anxiolytic model over the saline treated animals, whereas hypo locomotive behavior was seen in animals pre-treated with tryptophan, provides the evidence that preliminary treatment of tryptophan perturbs the apomorphine induced sensitization in animals. The discoveries present an inventive methodology for amplifying the remedial utilization of apomorphine and traditional psychostimulants.


Asunto(s)
Apomorfina/farmacología , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Sensibilización del Sistema Nervioso Central/efectos de los fármacos , Agonistas del Receptor de Serotonina 5-HT1/farmacología , Triptófano/farmacología , Animales , Encéfalo/metabolismo , Locomoción/efectos de los fármacos , Aprendizaje por Laberinto/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Ratas Wistar , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Receptor de Serotonina 5-HT1A/metabolismo
19.
Pharmacol Biochem Behav ; 175: 108-115, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30267795

RESUMEN

This investigation was undertaken to compare the sensitization/conditioned effects induced by apomorphine given pre-trial versus administered immediately post-trial or 15 min post-trial. We measured the effects on locomotor activity of 5 daily apomorphine treatments induced by an inhibitory low auto-receptor dose (0.05 mg/kg) and a stimulatory high postsynaptic dose (2.0 mg/kg). Three sets of four groups were used and each set of four groups was comprised of two vehicle and two apomorphine groups (0.05/2.0 apomorphine). The only difference among the three sets of four groups was when the treatments were administered relative to placement in the novel environment. One set received the treatment pre-test, another set was injected immediately after and the third set injected 15 min after 5 min test sessions in a novel environment. The repeated pre and immediate post-test apomorphine treatments induced locomotor sensitization over the 5 days of treatment. The low dose pre and immediate post-test treatments progressively decreased locomotion and the high dose pre and immediate post-test progressively increased locomotion. Critically, the tests for the immediate post-test groups were non-drug and for both the pre-test and immediate post-test groups, sensitization effects did not occur until the second test day. To control for non-associative apomorphine effects, the same apomorphine treatments were given post-test after a 15 minute delay and were found to be equivalent to vehicle. In a subsequent conditioning test, both the pre and immediate post-test low dose apomorphine groups showed conditioned behavioral inhibition and the pre and immediate post-test high dose apomorphine groups showed conditioned behavioral stimulation. We propose that the inhibitory low dose apomorphine decreased the salience/incentive of the novel environment association and thereby decreased the behavioral response and conversely that the high dose excitatory apomorphine treatment increased the salience/incentive value of the novel environment association and potentiated the behavioral response.


Asunto(s)
Apomorfina/farmacología , Condicionamiento Clásico/efectos de los fármacos , Agonistas de Dopamina/farmacología , Animales , Apomorfina/administración & dosificación , Agonistas de Dopamina/administración & dosificación , Relación Dosis-Respuesta a Droga , Masculino , Ratas , Ratas Wistar
20.
J Neuroinflammation ; 15(1): 249, 2018 Aug 31.
Artículo en Inglés | MEDLINE | ID: mdl-30170624

RESUMEN

BACKGROUND: The deficiency in 1α, 25-dihydroxyvitamin D3 (VD3) seems to increase the risk for neurodegenerative pathologies, including Parkinson's disease (PD). The majority of its actions are mediated by the transcription factor, VD3 receptor (VD3R). METHODS: The neuroprotective effects of VD3 were investigated on a PD model. Male Wistar rats were divided into the following groups: sham-operated (SO), 6-OHDA-lesioned (non-treated), and 6-OHDA-lesioned and treated with VD3 (7 days before the lesion, pre-treatment or for 14 days after the 6-OHDA striatal lesion, post-treatment). Afterwards, the animals were subjected to behavioral tests and euthanized for striatal neurochemical and immunohistochemical assays. The data were analyzed by ANOVA and the Tukey test and considered significant for p < 0.05. RESULTS: We showed that pre- or post-treatments with VD3 reversed behavioral changes and improved the decreased DA contents of the 6-OHDA group. In addition, VD3 reduced the oxidative stress, increased (TH and DAT), and reduced (TNF-alpha) immunostainings in the lesioned striata. While significant decreases in VD3R immunoreactivity were observed after the 6-OHDA lesion, these changes were blocked after VD3 pre- or post-treatments. We showed that VD3 offers neuroprotection, decreasing behavioral changes, DA depletion, and oxidative stress. In addition, it reverses partially or completely TH, DAT, TNF-alpha, and VD3R decreases of immunoreactivities in the non-treated 6-OHDA group. CONCLUSIONS: Taken together, VD3 effects could result from its anti-inflammatory and antioxidant actions and from its actions on VD3R. These findings should stimulate translational research towards the VD3 potential for prevention or treatment of neurodegenerative diseases, as PD.


Asunto(s)
Neuronas Dopaminérgicas/efectos de los fármacos , Encefalitis/etiología , Encefalitis/patología , Estrés Oxidativo/efectos de los fármacos , Trastornos Parkinsonianos/complicaciones , Vitamina D/farmacología , Animales , Apomorfina/farmacología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Dopamina/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Conducta Exploratoria/efectos de los fármacos , Peroxidación de Lípido/efectos de los fármacos , Masculino , Oxidopamina/toxicidad , Trastornos Parkinsonianos/inducido químicamente , Ratas , Ratas Wistar , Conducta Estereotipada/efectos de los fármacos , Natación/fisiología , Simpaticolíticos/toxicidad , Tirosina 3-Monooxigenasa/metabolismo
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