RESUMEN
Serotonin plays a pivotal role in the initiation and modulation of locomotor behavior in the intact animal, as well as following spinal cord injury. Quipazine, a serotonin 2 receptor agonist, has been used successfully to initiate and restore motor behavior in rodents. Although evidence suggests that the effects of quipazine are spinally mediated, it is unclear whether intrathecal (IT) quipazine administration alone is enough to activate locomotor-like activity or whether additional stimulation is needed. Thus, the current study examined the effects of IT administration of quipazine in postnatal day 1 rats in two separate experiments. In experiment 1, quipazine (0.1, 0.3, or 1.0 mg/kg) was dissolved in saline and administered via IT injection to the thoracolumbar cord. There was no significant effect of drug on hindlimb alternating stepping. In experiment 2, quipazine (0.3 or 1.0 mg/kg) was dissolved in a polysorbate 80-saline solution (Tween 80) and administered via IT injection. Polysorbate 80 was used to disrupt the blood-brain barrier to facilitate absorption of quipazine. The injection was followed by tail pinch 5 minutes post-injection. A significant increase in the percentage of hindlimb alternating steps was found in subjects treated with 0.3 mg/kg quipazine, suggesting that IT quipazine when combined with sensory stimulation to the spinal cord, facilitates locomotor-like behavior. These findings indicate that dissolving the drug in polysorbate 80 rather than saline may heighten the effects of IT quipazine. Collectively, this study provides clarification on the role of quipazine in evoking spinally-mediated locomotor behavior.
Asunto(s)
Barrera Hematoencefálica/efectos de los fármacos , Inyecciones Espinales/métodos , Cinesis , Actividad Motora/efectos de los fármacos , Polisorbatos/farmacología , Quipazina , Animales , Animales Recién Nacidos , Disponibilidad Biológica , Cinesis/efectos de los fármacos , Cinesis/fisiología , Quipazina/administración & dosificación , Quipazina/farmacocinética , Ratas , Receptores de Serotonina 5-HT2/metabolismo , Agonistas del Receptor de Serotonina 5-HT2/administración & dosificación , Agonistas del Receptor de Serotonina 5-HT2/farmacocinética , Solventes/farmacología , Traumatismos de la Médula Espinal/fisiopatologíaRESUMEN
Pharmacological neuromodulation of swallowing may represent a promising therapeutic option to treat dysphagia. Previous studies suggested a serotonergic control of swallowing, but mechanisms remain poorly understood. Here, we investigated the effects of the serotonergic agonist quipazine on swallowing, using the arterially perfused working heart-brainstem (in situ) preparation in rats. Systemic injection of quipazine produced single swallows with motor patterns and swallow-breathing coordination similar to spontaneous swallows, and increased swallow rate with moderate changes in cardiorespiratory functions. Methysergide, a 5-HT2 receptor antagonist, blocked the excitatory effect of quipazine on swallowing, but had no effect on spontaneous swallow rate. Microinjections of quipazine in the nucleus of the solitary tract were without effect. In contrast, similar injections in caudal medullary raphe nuclei increased swallow rate without changes in cardiorespiratory parameters. Thus, quipazine may exert an excitatory effect on raphe neurons via stimulation of 5-HT2A receptors, leading to increased excitability of the swallowing network. In conclusion, we suggest that pharmacological stimulation of swallowing by quipazine in situ represents a valuable model for experimental studies. This work paves the way for future investigations on brainstem serotonergic modulation, and further identification of neural populations and mechanisms involved in swallowing and/or swallow-breathing interaction.
Asunto(s)
Deglución/efectos de los fármacos , Quipazina/farmacología , Núcleos del Rafe/efectos de los fármacos , Agonistas de Receptores de Serotonina/farmacología , Animales , Inyecciones Intraarteriales , Quipazina/administración & dosificación , Núcleos del Rafe/fisiología , Ratas , Ratas Wistar , Respiración/efectos de los fármacos , Agonistas de Receptores de Serotonina/administración & dosificaciónRESUMEN
Quipazine is a 5-HT2A-receptor agonist that has been used to induce motor activity and promote recovery of function after spinal cord injury in neonatal and adult rodents. Sensory stimulation also activates sensory and motor circuits and promotes recovery after spinal cord injury. In rats, tail pinching is an effective and robust method of sacrocaudal sensory afferent stimulation that induces motor activity, including alternating stepping. In this study, responsiveness to a tail pinch following treatment with quipazine (or saline vehicle control) was examined in spinal cord transected (at midthoracic level) and intact neonatal rats. Rat pups were secured in the supine posture with limbs unrestricted. Quipazine or saline was administered intraperitoneally and after a 10-min period, a tail pinch was administered. A 1-min baseline period prior to tail-pinch administration and a 1-min response period postpinch was observed and hind-limb motor activity, including locomotor-like stepping behavior, was recorded and analyzed. Neonatal rats showed an immediate and robust response to sensory stimulation induced by the tail pinch. Quipazine recovered hind-limb movement and step frequency in spinal rats back to intact levels, suggesting a synergistic, additive effect of 5-HT-receptor and sensory stimulation in spinal rats. Although levels of activity in spinal rats were restored with quipazine, movement quality (high vs. low amplitude) was only partially restored. (PsycINFO Database Record
Asunto(s)
Actividad Motora/efectos de los fármacos , Quipazina/administración & dosificación , Receptor de Serotonina 5-HT2A/fisiología , Agonistas del Receptor de Serotonina 5-HT2/administración & dosificación , Traumatismos de la Médula Espinal/fisiopatología , Tacto , Animales , Animales Recién Nacidos , Femenino , Masculino , Ratas , Ratas Sprague-Dawley , Traumatismos de la Médula Espinal/prevención & control , Cola (estructura animal)RESUMEN
Activity-based interventions such as locomotor training or passive cycling have a positive influence on the spinal circuitry and recovery following a spinal cord injury (SCI). The use of quipazine in combination with exercise training has demonstrated a greater functional recovery than has exercise training alone. However, the influence of exercise or training on the responsiveness of the spinal cord to quipazine has not been examined following a chronic spinal transection. The purpose of this study was to characterize the flexor and extensor monosynaptic reflex (MSR) response pre- and post-quipazine in chronic complete spinally transected rats that either underwent daily passive cycling for 3 months or did not receive passive cycling. Following a chronic spinal transection, the extensor MSR demonstrated a hyperreflexive response (fivefold increase) to afferent stimuli, and did not respond to quipazine injection. With daily passive cycling, the extensor MSR hyperexcitability was attenuated, and the MSR amplitude increased 72% following quipazine injection (p<0.004), which was comparable to the extensor MSR response (94%) in the control group. For both chronic spinal transection groups, the flexor MSR amplitudes were not altered following quipazine injection, whereas in the control group the flexor MSR amplitude increased 86% in response to quipazine (p<0.004). These results demonstrate that passive cycling attenuates the hyperreflexive response of the extensor MSR following a chronic SCI, and restores the MSR response to quipazine.
Asunto(s)
Terapia por Ejercicio/métodos , Quipazina/farmacología , Recuperación de la Función/fisiología , Reflejo Monosináptico/fisiología , Agonistas de Receptores de Serotonina/farmacología , Traumatismos de la Médula Espinal/terapia , Animales , Terapia Combinada , Modelos Animales de Enfermedad , Femenino , Quipazina/administración & dosificación , Ratas , Ratas Sprague-Dawley , Recuperación de la Función/efectos de los fármacos , Reflejo Monosináptico/efectos de los fármacos , Agonistas de Receptores de Serotonina/administración & dosificación , Traumatismos de la Médula Espinal/tratamiento farmacológicoRESUMEN
RATIONALE: The serotonin (5-HT) system is involved in pain modulation, and 5-HT receptor agonists can enhance antinociceptive effects of mu opioid receptor agonists. Less is known about the actions of 5-HT receptor agonists on other effects of opioids. OBJECTIVE: This study examined the effects of non-contingent and contingent administration of the 5-HT(2A) receptor agonists DOM and quipazine on i.v. heroin self-administration in rhesus monkeys. RESULTS: Heroin (0.0001-0.1 mg/kg/infusion) generated an inverted U-shaped dose-response function. Non-contingent administration of DOM (0.1-0.32 mg/kg) flattened the dose-response function in three monkeys and eliminated heroin self-administration in a fourth monkey. Contingent DOM (0.0032-0.032 mg/kg/infusion) alone did not maintain responding above that maintained by saline, and, when added to self-administered heroin, monkeys responded less than for the same unit doses of heroin alone. Non-contingent (0.32-3.2 mg/kg) and contingent (0.0032-0.56 mg/kg/infusion) administration of quipazine flattened the dose-response function in two monkeys, increasing responding maintained by small unit doses of heroin and saline, but failed to enhance responding for heroin in two other monkeys. CONCLUSION: This study shows that DOM does not enhance, and might attenuate, the positive reinforcing effects of the mu opioid receptor agonist heroin. Quipazine increased responding for saline and small doses of heroin; those effects were modest and observed in only two subjects. Taken together, these data suggest that 5-HT(2A) receptor agonists do not significantly enhance the reinforcing effectiveness of mu opioid receptor agonists and support the view that administering 5-HT drugs in combination with opioids to treat pain might not enhance abuse liability.
Asunto(s)
2,5-Dimetoxi-4-Metilanfetamina/farmacología , Heroína/administración & dosificación , Quipazina/farmacología , Agonistas del Receptor de Serotonina 5-HT2/farmacología , 2,5-Dimetoxi-4-Metilanfetamina/administración & dosificación , Animales , Relación Dosis-Respuesta a Droga , Femenino , Macaca mulatta , Masculino , Quipazina/administración & dosificación , Esquema de Refuerzo , Autoadministración , Agonistas del Receptor de Serotonina 5-HT2/administración & dosificaciónRESUMEN
BACKGROUND: Liver disease is commonly seen in the clinic and its pathological characteristic is combined hepatocellular death and apoptosis. Promoting hepatocyte regeneration is one of the main methods of treating liver disease. Serotonin (5-HT) is an important compound which participates in various life process, and 95% of it is carried by platelets in the blood. A recent finding showed that platelet-derived serotonin is the key factor in liver regeneration, which fails without serotonin. This study aimed to investigate the effects of quipazine, a selective 5-HT receptor agonist, on proliferation and apoptosis in the human hepatocyte strain L-02. METHODS: L-02 cells were cultured in medium with 5-HT and quipazine, and samples were collected at 24, 48, and 72 hours. The methyl thiazolyl tetrazolium (MTT) method was used to test viability, flow cytometry to assess the cell cycle, the Annexin-V/PI method to evaluate apoptosis, and immunohistochemistry to detect proliferating cell nuclear antigen (PCNA). RESULTS: Compared with the control group, the viability of L-02 cells was improved in the 10, 50, and 250 microg/ml quipazine groups (P<0.05); the percentage of S-phase and PCNA-positive cells were increased in the 2, 10, 50, and 250 microg/ml quipazine groups (P>0.05); and no difference in the percentage of apoptotic cells was found between the 50 microg/ml quipazine and control groups (P>0.05). CONCLUSION: Quipazine improves proliferation of a human hepatocyte strain in vitro, and this is not based on the inhibition of apoptosis.
Asunto(s)
Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Hepatocitos/citología , Hepatocitos/fisiología , Quipazina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Línea Celular , Relación Dosis-Respuesta a Droga , Hepatocitos/metabolismo , Humanos , Antígeno Nuclear de Célula en Proliferación/metabolismo , Quipazina/administración & dosificación , Fase S/efectos de los fármacos , Serotonina/farmacología , Serotoninérgicos/farmacología , Agonistas de Receptores de Serotonina/administración & dosificaciónRESUMEN
Epidural electrical stimulation (ES) at spinal cord segment L2 can produce coordinated step-like movements in completely spinalized adult rats [R.M. Ichiyama, Y.P. Gerasimenko, H. Zhong, R.R. Roy, V.R. Edgerton, Hindlimb stepping movements in complete spinal rats induced by epidural spinal cord stimulation, Neurosci. Lett. 383 (2005) 339-344]. Plantar placement of the paws, however, was rarely observed. Here, we sought to determine the dose dependence of a 5-HT agonist (quipazine) on stepping kinematics when administered in combination with ES. Six adult female Sprague-Dawley rats received a complete mid-thoracic spinal cord transection and were implanted with epidural electrodes at the L2 spinal cord level. Quipazine (i.p.) was tested at doses of 0.1, 0.2, 0.3, 0.4, and 0.5 mg/kg. Rats were placed in a body weight support system, allowing them to walk bipedally on a moving treadmill belt (7 cm/s). 3D step kinematics analysis revealed that coordinated alternating bilateral stepping was induced by L2 stimulation (50 Hz) alone and by quipazine alone. Furthermore, the combination treatment produced significantly greater numbers of plantar steps and improved quality of stepping compared to either intervention alone. Both number and quality of stepping peaked at the intermediate dose of 0.3-0.4 mg/kg. The results indicate that quipazine and ES can have complementary effects on spinal circuits and that quipazine dosage is an important factor in differentially modulating these circuitries to improve the quality of the bipedal stepping on a treadmill belt.
Asunto(s)
Terapia por Estimulación Eléctrica , Locomoción , Quipazina/administración & dosificación , Agonistas de Receptores de Serotonina/administración & dosificación , Traumatismos de la Médula Espinal/fisiopatología , Traumatismos de la Médula Espinal/terapia , Animales , Conducta Animal/efectos de los fármacos , Conducta Animal/efectos de la radiación , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Espacio Epidural , Femenino , Locomoción/efectos de los fármacos , Locomoción/fisiología , Locomoción/efectos de la radiación , Extremidad Inferior/fisiopatología , Extremidad Inferior/efectos de la radiación , Región Lumbosacra , Desempeño Psicomotor/efectos de los fármacos , Desempeño Psicomotor/efectos de la radiación , Ratas , Ratas Sprague-DawleyRESUMEN
We hypothesized that epidural spinal cord stimulation (ES) and quipazine (a serotonergic agonist) modulates the excitability of flexor and extensor related intraspinal neural networks in qualitatively unique, but complementary, ways to facilitate locomotion in spinal cord-injured rats. To test this hypothesis, we stimulated (40 Hz) the S(1) spinal segment before and after quipazine administration (0.3 mg/kg, ip) in bipedally step-trained and nontrained, adult, complete spinal (mid-thoracic) rats. The stepping pattern of these rats was compared with control rats. At the stimulation levels used, stepping was elicited only when the hindlimbs were placed on a moving treadmill. In nontrained rats, the stepping induced by ES and quipazine administration was non-weight bearing, and the cycle period was shorter than in controls. In contrast, the stepping induced by ES and quipazine in step-trained rats was highly coordinated with clear plantar foot placement and partial weight bearing. The effect of ES and quipazine on EMG burst amplitude and duration was greater in flexor than extensor motor pools. Using fast Fourier transformation analysis of EMG bursts during ES, we observed one dominant peak at 40 Hz in the medial gastrocnemius (ankle extensor), whereas there was less of dominant spectral peak in the tibialis anterior (ankle flexor). We suggest that these frequency distributions reflect amplitude modulation of predominantly monosynaptic potentials in the extensor and predominantly polysynaptic pathways in the flexor muscle. Quipazine potentiated the amplitude of these responses. The data suggest that there are fundamental differences in the circuitry that generates flexion and extension during locomotion.
Asunto(s)
Terapia por Estimulación Eléctrica , Locomoción , Quipazina/administración & dosificación , Agonistas de Receptores de Serotonina/administración & dosificación , Traumatismos de la Médula Espinal/terapia , Médula Espinal , Animales , Conducta Animal , Fenómenos Biomecánicos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Electrodos Implantados , Electromiografía/métodos , Espacio Epidural , Femenino , Locomoción/efectos de los fármacos , Locomoción/fisiología , Locomoción/efectos de la radiación , Actividad Motora/efectos de los fármacos , Actividad Motora/efectos de la radiación , Ratas , Ratas Sprague-Dawley , Reflejo/efectos de los fármacos , Reflejo/efectos de la radiación , Análisis Espectral , Médula Espinal/efectos de los fármacos , Médula Espinal/fisiología , Médula Espinal/efectos de la radiaciónRESUMEN
The purpose of this study was to determine if robotic-assisted treadmill training improved hindlimb stepping in complete spinal cord transected (ST) rats. In addition, we examined whether chronic quipazine treatment would enhance the effectiveness of robotic-assisted training. Hindlimb stepping was examined in four groups of ST rats: trained + quipazine; trained + vehicle; untrained + quipazine; and untrained + vehicle. To train the rats to step, a robotic device was used that moved the hindlimbs in a semi-fixed trajectory during treadmill stepping. The robotic device was also used to assess treadmill stepping. Quipazine or vehicle was administered to the lumbar spinal cord using an intrathecal cannula. The groups that received robotic-assisted training performed more stepping movements on the treadmill than the untrained groups 10 weeks after ST. However, no differences were found between the robotic-assisted and untrained groups 16 weeks after ST. Kinematic analyses revealed that abnormally small step cycles were performed by all of the groups of ST rats. There was no significant effect of combining robotic-assisted training and quipazine treatment on stepping recovery. These data suggest that robotic-assisted training may generate hindlimb sensory stimuli that are effective in enhancing the ability of the lumbar spinal cord to generate hindlimb stepping. However, the effectiveness of robotic-assisted training may be limited to the early stages of recovery following spinal cord transection.
Asunto(s)
Prueba de Esfuerzo/métodos , Miembro Posterior/fisiología , Quipazina/administración & dosificación , Robótica/métodos , Traumatismos de la Médula Espinal/rehabilitación , Caminata/fisiología , Animales , Prueba de Esfuerzo/instrumentación , Femenino , Miembro Posterior/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Robótica/instrumentación , Traumatismos de la Médula Espinal/tratamiento farmacológico , Traumatismos de la Médula Espinal/fisiopatología , Factores de TiempoRESUMEN
In the present study, we investigated the effect of central serotonergic pathway activation achieved through third ventricle injections of quipazine, a serotonergic agonist, on plasma glucose levels of fasted and fed adult Wistar male rats, whose third ventricles were canulated 7 days before the experiments. Central quipazine administration induced a significant increase in plasma glucose levels in fasted animals, but was unable to modify plasma glucose concentrations in fed rats. Pretreatment with alpha-helical CRH, a CRH antagonist, significantly attenuated quipazine-induced hyperglycemia. Pretreatment with two different 5-HT3 receptor antagonists, LY-278,584 and ondansetron, was also able to produce a significant reduction in the hyperglycemic response evoked by central administration of quipazine. None of the antagonists used was capable of modifying plasma glucose concentrations when injected alone into the third ventricle. Quipazine-treated, hyperglycemic animals did not show any increase in plasma insulin levels. We conclude that acute pharmacological serotonergic stimulation by quipazine produces hyperglycemia by mechanisms that require the functional integrity of both CRH and 5-HT3 receptors, and that impairment in insulin secretion and/or activity may explain hyperglycemia induced by third ventricle injections of quipazine.
Asunto(s)
Hiperglucemia/sangre , Agonistas del Receptor de Serotonina 5-HT3 , Antagonistas del Receptor de Serotonina 5-HT3 , Antagonistas de la Serotonina/administración & dosificación , Agonistas de Receptores de Serotonina/administración & dosificación , Animales , Glucemia/efectos de los fármacos , Hormona Liberadora de Corticotropina/administración & dosificación , Hiperglucemia/inducido químicamente , Indazoles/administración & dosificación , Insulina/sangre , Masculino , Ondansetrón/administración & dosificación , Quipazina/administración & dosificación , Ratas , Ratas Wistar , Tropanos/administración & dosificaciónRESUMEN
In chronic spinal rats, long-term stimulation of 5-HT receptors with quipazine or 8-OHDPAT by means of daily injection, promotes robust locomotor recovery. The question of a possible potentiation between treatments when applied together was addressed. Daily injections of both 8-OHDPAT and quipazine, were performed for a month in spinal animals. Animals were placed on a treadmill and the bipedal hindlimb locomotion was tested. Motor performances (behavioural test) and locomotor parameters (EMG and kinematic) were analysed weekly during the treatment. Furthermore, the locomotor performances were evaluated during two supplemental months following the end of the treatment. Our results suggest that association of both agonists induced long-lasting positive effects on locomotor function. Motor performances were significantly better after combined injection of both drugs than when the agonists were used separately. But, the most significant and new result is that the locomotor scores did not decrease during the weeks that followed the end of the treatment. These results suggests a long-lasting and 5-HT-dependent reorganisation of spinal networks.
Asunto(s)
8-Hidroxi-2-(di-n-propilamino)tetralin/administración & dosificación , Actividad Motora/efectos de los fármacos , Quipazina/administración & dosificación , Recuperación de la Función/efectos de los fármacos , Agonistas de Receptores de Serotonina/administración & dosificación , Traumatismos de la Médula Espinal/tratamiento farmacológico , Animales , Conducta Animal/efectos de los fármacos , Enfermedad Crónica , Vías de Administración de Medicamentos , Esquema de Medicación , Quimioterapia Combinada , Electromiografía/métodos , Femenino , Locomoción/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Traumatismos de la Médula Espinal/fisiopatología , Factores de TiempoRESUMEN
RATIONALE: Temporal differentiation refers to animals' ability to regulate their behaviour during an ongoing interval. Striatal dopaminergic mechanisms are purported to be involved in temporal differentiation, and recent evidence also implicates 5-hydroxytryptaminergic (5-HTergic) mechanisms, possibly mediated by 5-HT(2A) receptors. There is evidence that 5-HT(3) receptors contribute to the regulation of dopamine release in the basal ganglia; however, it is not known whether 5-HT(3) receptor stimulation can influence temporal differentiation. OBJECTIVE: We examined the effects of a selective 5-HT(3) receptor agonist m-CPBG, a mixed 5-HT(2A/3) receptor agonist quipazine, and selective 5-HT(3) and 5-HT(2A) receptor antagonists (MDL-72222 and ketanserin, respectively) on temporal differentiation in a free-operant psychophysical procedure. METHODS: Twenty-four rats were trained to respond on two levers (A and B) under a free-operant psychophysical schedule, in which sucrose reinforcement (0.6 M: , 50 microl) was provided intermittently for responding on A during the first half and on B during the second half of 50-s trials. Logistic psychometric functions were fitted to the relative response rate data [percent responding on B (%B) vs time from trial onset (t)], and quantitative indices of timing performance [T (50) (value of t corresponding to %B=50), Weber fraction, and mean time of switching from A to B, S (50)] were derived. RESULTS: Quipazine (0.5, 1, and 2 mg kg(-1)) altered timing performance, dose-dependently reducing T (50) and S (50); m-CPBG (2.5, 5, and 10 mg kg(-1)) had no significant effect. The effect of quipazine was antagonized by ketanserin (2 mg kg(-1)), but not by MDL-72222 (1 mg kg(-1)). CONCLUSIONS: The present results provide no evidence for the involvement of 5-HT(3) receptors in temporal differentiation and indicate that the effect of quipazine on performance was mediated by 5-HT(2A) receptor stimulation. The results are consistent with previous evidence for the involvement of 5-HT(2A) receptors in interval timing behaviour.
Asunto(s)
Biguanidas/farmacología , Quipazina/farmacología , Análisis y Desempeño de Tareas , Percepción del Tiempo/efectos de los fármacos , Animales , Biguanidas/administración & dosificación , Condicionamiento Operante/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Inyecciones Intraperitoneales , Inyecciones Subcutáneas , Ketanserina/administración & dosificación , Ketanserina/farmacología , Psicometría/métodos , Quipazina/administración & dosificación , Ratas , Ratas Wistar , Receptor de Serotonina 5-HT2A/fisiología , Receptores de Serotonina 5-HT3/fisiología , Agonistas del Receptor de Serotonina 5-HT2 , Antagonistas del Receptor de Serotonina 5-HT2 , Agonistas del Receptor de Serotonina 5-HT3 , Antagonistas del Receptor de Serotonina 5-HT3 , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/administración & dosificación , Agonistas de Receptores de Serotonina/farmacología , Percepción del Tiempo/fisiología , Tropanos/administración & dosificación , Tropanos/farmacologíaRESUMEN
The aim of this study was to examine the effects of different doses of typical antipsychotics, chlorpromazine (0.25-1 mg/kg) and haloperidol (0.25-1 mg/kg), and atypical antipsychotics, clozapine (0.5-2 mg/kg), olanzapine (0.25-1 mg/kg), risperidone (0.5-2 mg/kg), sulpiride (10-40 mg/kg) and dopamine D1 antagonist, SCH 23390 (0.25-1 mg/kg) on feeding behavior at different time intervals after acute administration. The study further investigated the central dopamine and serotonergic receptor involvement in clozapine-induced hyperphagia using SKF 38393, quinpirole and quipazine. Then, the authors also examined the effect of subchronic treatment for 21 days with fluoxetine on clozapine-induced hyperphagia and modulation of body weight and fat pad weights. The feeding behavior was assessed in nondeprived mice by presenting the palatable chow to different groups of mice in glass petri dishes and recording the food consumed at different time intervals. After acute administration, significant (P<.05) increase in food intake was observed at different time intervals with different doses of both typical and atypical antipsychotics. Further, clozapine-induced hyperphagia was significantly (P<.05) reversed after treatment with SKF 38393 (dopamine D1 agonist), quinpirole (dopamine D2 agonist) and quipazine (5-HT1B, 5-HT2 and 5-HT3 agonist). In subchronic study, treatment with fluoxetine (10 mg/kg) significantly (P<.05) antagonized the increase in body weight and food intake induced by clozapine (2 mg/kg). The current investigations underscore the reported increases in food intake and body weight gain observed with antipsychotics. The study further confirms the involvement of dopamine D1, D2 and serotonergic receptor involvement in clozapine-mediated hyperphagia. Further, the serotonergic agents may prove useful to counteract antipsychotic-induced obesity.
Asunto(s)
Antipsicóticos/farmacología , Conducta Alimentaria/efectos de los fármacos , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/administración & dosificación , Tejido Adiposo/efectos de los fármacos , Animales , Peso Corporal/efectos de los fármacos , Clozapina/administración & dosificación , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Conducta Alimentaria/fisiología , Femenino , Fluoxetina/administración & dosificación , Hiperfagia/inducido químicamente , Hiperfagia/prevención & control , Ratones , Ratones Endogámicos , Tamaño de los Órganos/efectos de los fármacos , Quinpirol/administración & dosificación , Quipazina/administración & dosificación , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Aumento de Peso/efectos de los fármacos , Aumento de Peso/fisiologíaRESUMEN
We have studied the effect of acute trazodone (3--20 mg kg(-1)) and quipazine (1--3 mg kg(-1)) treatment on the apomorphine-induced (1 mg kg(-1), once daily over 2 weeks) aggressive behaviour in male Wistar rats. All doses of trazodone and quipazine tested attenuated the aggressiveness as evidenced by the abolished intensity of aggressive behaviour and increased time of latency before the first attack. The acute trazodone (3--10 mg kg(-1)) or quipazine (1--3 mg kg(-1)) treatment had no or only a minor effect on rat behaviour in the elevated plus-maze, open field, and forced swimming test. Concomitant apomorphine (1 mg kg(-1)) plus trazodone (3 mg kg(-1)), but not apomorphine (1 mg kg(-1)) plus quipazine (1 mg kg(-1)), treatment slowed the development of aggressive behaviour. Repeated apomorphine treatment moderately reduced the dopamine post mortem and increased the DOPAC and HVA contents in striatum. Other monoamines or their metabolites were unchanged. Neither trazodone and quipazine treatment nor forced swimming stress induced any changes in the monoamine contents. In conclusion, our results indicate that acute trazodone and quipazine treatment attenuates the apomorphine-induced aggressive behaviour in male rats, but this phenomenon cannot be implicated in the changes in emotional and motivational behaviour, or in changes of monoamine content post mortem.
Asunto(s)
Agresión/efectos de los fármacos , Antidepresivos de Segunda Generación/farmacología , Apomorfina/antagonistas & inhibidores , Monoaminas Biogénicas/metabolismo , Emociones/efectos de los fármacos , Quipazina/farmacología , Trazodona/farmacología , Animales , Antidepresivos de Segunda Generación/administración & dosificación , Apomorfina/farmacología , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Cromatografía Líquida de Alta Presión , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Motivación , Cambios Post Mortem , Quipazina/administración & dosificación , Ratas , Ratas Wistar , Estrés Fisiológico , Natación , Factores de Tiempo , Trazodona/administración & dosificaciónRESUMEN
1. The effects of injections i.c.v. of quipazine, (2 micromol kg-1) and 1-(2,5-di-methoxy-4-iodophenyl)-2-aminopropane (DOI; 2 micromol kg-1) on renal sympathetic and phrenic nerve activity, mean arterial blood pressure (MAP) and heart rate were investigated in alpha-chloralose anaesthetized rats pretreated with a peripherally acting 5-HT2 receptor antagonist. 2. Quipazine or DOI caused a rise in MAP which was associated with a tachycardia and renal sympathoinhibition in rats pretreated (i.c.v.) with the antagonist vehicle 10% PEG. These effects of quipazine were completely blocked by pretreatment with cinanserin (a 5-HT2 receptor antagonist) and attenuated by spiperone (a 5-HT2A receptor antagonist). However, pretreatment with SB200646A (a 5-HT2B/2C receptor antagonist) only blocked the sympathoinhibition, while pretreatment with SB204741 (a 5-HT2B receptor antagonist) reversed the sympathoinhibition to excitation as it also did for DOI. Quipazine also caused renal sympathoexcitation in the presence (i.v.) of a vasopressin V1 receptor antagonist. 3. Injection (i.v.) of the V1 receptor antagonist at the peak pressor response evoked by quipazine alone and in the presence of SB204741 caused an immediate fall in MAP. For quipazine alone the renal sympathoinhibition was slowly reversed to an excitation, while the renal sympathoexcitation observed in the presence of SB204741 was potentiated. In both, the quipazine-evoked tachycardia was unaffected. 4. The data indicate that cardiovascular responses caused by i.c.v. quipazine and DOI are primarily due to activation of central 5-HT2A receptors, which causes the release of vasopressin and a tachycardia. This released vasopressin appears to suppress a 5-HT2A receptor-evoked central increase in sympathetic outflow, which involves the activation of central 5-HT2B receptors indirectly by the released vasopressin.
Asunto(s)
Fenómenos Fisiológicos Cardiovasculares , Receptores de Serotonina/fisiología , Amidinas/administración & dosificación , Amidinas/farmacología , Anfetaminas/administración & dosificación , Anfetaminas/farmacología , Animales , Antagonistas de los Receptores de Hormonas Antidiuréticas , Derivados de Atropina/administración & dosificación , Derivados de Atropina/farmacología , Presión Sanguínea/efectos de los fármacos , Cinanserina/administración & dosificación , Cinanserina/farmacología , Inyecciones Intraventriculares , Masculino , Polietilenglicoles/farmacología , Quipazina/administración & dosificación , Quipazina/farmacología , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT2A , Receptor de Serotonina 5-HT2B , Antagonistas de la Serotonina/farmacología , Espiperona/administración & dosificación , Espiperona/farmacologíaRESUMEN
Nonphotic stimuli can reset and entrain circadian activity rhythms in hamsters and mice, and serotonin is thought to be involved in the phase-resetting effects of these stimuli. In the present study, the authors examined the effect of the serotonin agonist quipazine on circadian activity rhythms in three inbred strains of rats (ACI, BH, and LEW). Furthermore, they investigated the effect of quipazine on the expression of c-Fos in the mammalian circadian pacemaker, the suprachiasmatic nucleus (SCN). Quipazine reduced the amount of running wheel activity for 3 h after treatment, however, no long-term changes in tau and in the activity level were observed. More important, quipazine induced significant phase advances of the activity rhythm and c-Fos production in the SCN at the end of the subjective night (Circadian Time [CT] 22), whereas neither phase shifts nor c-Fos induction were observed during the subjective day. Quipazine injections also resulted in moderate phase delays at the beginning of the subjective night (CT 14). A similar phase-response characteristic typically can be observed for photic stimuli. By contrast, nonphotic stimuli normally produce phase advances during the subjective day. The present results suggest species differences between the hamster and the rat with respect to the serotonergic action on circadian timekeeping and indicate that serotonergic pathways play a role in the transmission of photic information to the SCN of rats.
Asunto(s)
Ritmo Circadiano/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Quipazina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Núcleo Supraquiasmático/metabolismo , Animales , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Inmunohistoquímica , Masculino , Actividad Motora/efectos de los fármacos , Estimulación Luminosa , Quipazina/administración & dosificación , Ratas , Ratas Endogámicas , Núcleo Supraquiasmático/citología , Núcleo Supraquiasmático/efectos de los fármacos , Factores de TiempoRESUMEN
The purposes of this study were to determine: first, if animals could be trained to discriminate a serotonin (5-HT)2 receptor agonist from a 5-HT2 receptor antagonist; second, which 5-HT2 receptor subtype was mediating the cues; and third, the usefulness of this model for studying adaptive changes in the 5-HT2 receptor system. Rats were trained to discriminate quipazine (0.5 mg/kg) from ketanserin (1.0 mg/kg) on a variable interval-20 schedule of reinforcement. After acquisition, the quipazine and ketanserin dose-response curves were found to be orderly and reproducible. Additional 5-HT2 receptor agonists (2,5-dimethoxy-4-iodoamphetamine and MK 212) and antagonists (pizotifen, mianserin, pirenperone and MDL 100,907) were tested for generalization and found to substitute for the quipazine and ketanserin cues, respectively. In antagonist studies, MDL 100,907 potently blocked quipazine discrimination. Results of ex vivo binding studies designed to estimate occupancy of 5-HT2A and 5-HT2C receptors suggested that the training dose of ketanserin blocked only 5-HT2A receptors and not 5-HT2C receptors. The combined results from the substitution, antagonism and ex vivo receptor autoradiographic studies suggest that the discriminative stimuli of quipazine and ketanserin are mediated at least in part by the 5-HT2A receptor. Additional experiments were designed to study adaptive changes in the 5-HT2A receptor. A single large dose of quipazine produced a rebound ketanserin-like effect at 20 hr after administration; however, a single large dose of ketanserin (10 mg/kg) did not produce a rebound quipazine-like effect.
Asunto(s)
Ketanserina/farmacología , Quipazina/farmacología , Receptores de Serotonina/efectos de los fármacos , Animales , Mapeo Encefálico , Aprendizaje Discriminativo/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Fluorobencenos/farmacología , Ketanserina/administración & dosificación , Masculino , Piperidinas/farmacología , Quipazina/administración & dosificación , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT2A , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacologíaRESUMEN
Growth stimulation of a variety of cell types by the neurotransmitter serotonin has been reported. We have examined the effects of three serotonin-uptake inhibitors, 6-nitroquipazine, zimelidine and fluoxetine (Prozac, Eli Lilly Co., Indianapolis, Indiana) on human prostate carcinoma cell lines. In vitro, all 3 of these compounds inhibited the proliferation of PC-3, DU-145 and LNCaP cells in a dose-dependent manner. Also, all 3 compounds blocked the uptake of a radiolabeled analog of serotonin by the prostate carcinoma cell lines. The order of potency for inhibition of growth as well as for serotonin uptake was fluoxetine > zimelidine > 6-nitroquipazine. The growth of subcutaneous, PC-3 xenografts in athymic nude mice was significantly inhibited by fluoxetine. These results implicate biogenic amines such as serotonin in the growth of prostate carcinoma cells and indicate the potential use of serotonin-uptake inhibitors for the treatment of prostate cancer.
Asunto(s)
Carcinoma/patología , Neoplasias de la Próstata/patología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Animales , Carcinoma/tratamiento farmacológico , Carcinoma/fisiopatología , División Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Fluoxetina/administración & dosificación , Fluoxetina/farmacología , Fluoxetina/uso terapéutico , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos , Ratones Desnudos , Trasplante de Neoplasias , Neoplasias de la Próstata/fisiopatología , Quipazina/administración & dosificación , Quipazina/análogos & derivados , Quipazina/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Trasplante Heterólogo , Células Tumorales Cultivadas , Zimeldina/administración & dosificación , Zimeldina/farmacologíaRESUMEN
The selective NK3 tachykinin agonist senktide evokes in rodents 5-HT mediated behaviors, including 5-HT2 receptor-mediated wet dog shakes (WDS) and head shakes (HS). It was observed previously that genetically selected Sardinian alcohol-preferring (sP) rats show a small number of WDS and HS following intracerebroventricular (ICV) injection of senktide. The present study was aimed at confirming these observations and at providing information on the reasons accounting for the anomalous response of sP rats. Senktide (500-2000 ng/rat, ICV) produced a much lower number of WDS and HS in sP rats than in nonselected Wistar (nsW) rats. Both behaviors were suppressed by the 5-HT2 antagonist ritanserin (1 mg/kg, subcutaneously), confirming that 5-HT2 receptors mediate the response. HS induced by the ICV injection of 5-HT agonists endowed with marked activity at 5-HT2 receptors, such as quipazine (1500-6000 ng/rat) or DOI (500-3500 ng/rat), were much less pronounced in sP rats than in nsW rats. Moreover, WDS following peripheral injection of 5-hydroxytryptophan, 25-100 mg/kg, and carbidopa, 12.5 mg/kg, were less intense in sP and in ethanol-naive sP rats than in nsW and in Sardinian alcohol-nonpreferring rats. These findings suggest that sP rats have an inherent different regulation of central 5-HT2 mechanisms.
Asunto(s)
Consumo de Bebidas Alcohólicas/psicología , Conducta Animal/efectos de los fármacos , Receptores de Serotonina/efectos de los fármacos , Serotoninérgicos/farmacología , 5-Hidroxitriptófano/administración & dosificación , 5-Hidroxitriptófano/farmacología , Consumo de Bebidas Alcohólicas/genética , Anfetaminas/administración & dosificación , Anfetaminas/farmacología , Animales , Carbidopa/administración & dosificación , Carbidopa/farmacología , Relación Dosis-Respuesta a Droga , Inyecciones Intraperitoneales , Inyecciones Intraventriculares , Inyecciones Subcutáneas , Masculino , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/farmacología , Quipazina/administración & dosificación , Quipazina/farmacología , Ratas , Ratas Endogámicas , Ritanserina/administración & dosificación , Ritanserina/farmacología , Serotoninérgicos/administración & dosificación , Agonistas de Receptores de Serotonina/administración & dosificación , Agonistas de Receptores de Serotonina/farmacología , Sustancia P/administración & dosificación , Sustancia P/análogos & derivados , Sustancia P/farmacologíaRESUMEN
The purpose of this experiment was to examine the effects of administration of serotonergic (5-HT) agonist and antagonist drugs on run-time to exhaustion (RUN-EXH) in male and female rats. RUN-EXH was reduced (p < 0.05) in a dose related manner by increasing dosages of quipazine dimaleate (QD: general 5-HT agonist) (0-5 mg.kg-1 i.p.) administered immediately prior to exercise (treadmill running at 20 m.min-1 and 5% grade). Conversely, RUN-EXH was increased (p < 0.05) by the greatest dosage of LY 53,857 (LY: 5-HT1C and 5-HT2 antagonist) (1.5 mg.kg-1 i.p.). Drug effects were similar in male and female rats. The negative effects of QD administration on RUN-EXH were not attenuated by administration of the peripherally restricted antagonist, xylamidine tosylate (up to 200 ug.kg-1 i.p.). The results of this investigation indicated that fatigue during prolonged exercise can be influenced by direct pharmacological administration of a serotonergic agonist and antagonist and that the mechanisms underlying these effects are likely to be central (brain) in nature.