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1.
Prog Urol ; 33(2): 66-72, 2023 Feb.
Artículo en Francés | MEDLINE | ID: mdl-36207246

RESUMEN

OBJECTIVE: The objective of this sub-analysis of the PERSAT study was to evaluate the efficacy of hexanic extract of S. Repens (HESr) and alpha-blockers (AB), at 6 months in patients with moderate to severe LUTS/BPH. METHODS: The PERSAT observational study was conducted in France by general practitioners on patients with BPH with an IPSS≥12 score. The primary endpoint was the percentage of responders (decrease in total IPSS score ≥ 3) at 6 months. Improvement in quality of life (IPSS-QoL) as well as patient satisfaction were also measured. RESULTS: Of the 759 patients in the study, 324 treated with HESr and 309 with AB were reviewed at 6 months, with no change in treatment during follow-up. Characteristics at inclusion were globally similar with a mean IPSS of 18.2±4.9. The response rates at 6 months (IPSS-total decrease ≥ 3) were 93.7% and 94.8% for patients treated with HESr and AB, with a mean decrease in IPSS score of 10.1±5.6 points, which reached 13.6 and 14.8 points respectively, in severe patients (IPSS>19), without major difference between groups. More than 95% of HESr or AB patients reported a significant overall improvement in their LUTS/BPH. The most frequently reported adverse events with AB were ejaculation disorders (4.9%) and hypotension (4.2%) and with HESr digestive disorders (1.5%). CONCLUSION: This sub-analysis of the PERSAT cohort reported the clinical efficacy of HESr and AB as a first-line treatment in the management of moderate or severe LUTS/BPH patients.


Asunto(s)
Síntomas del Sistema Urinario Inferior , Hiperplasia Prostática , Masculino , Humanos , Hiperplasia Prostática/tratamiento farmacológico , Calidad de Vida , Fitoterapia , Síntomas del Sistema Urinario Inferior/tratamiento farmacológico , Extractos Vegetales/uso terapéutico , Antagonistas Adrenérgicos alfa/uso terapéutico , Resultado del Tratamiento
2.
Pharmacology ; 106(1-2): 114-118, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-32950991

RESUMEN

Obsessive compulsive disorder (OCD) is a psychiatric disorder characterized by excessive and repetitive thoughts and gestures, mainly treated pharmacologically with selective serotonin reuptake inhibitors (SSRIs). The marble burying test in mice is commonly used to model OCD and has been shown to be sensitive to SSRIs, which decrease burying behavior. The activity of SSRIs in this model is mediated through activation of 5-hydroxytryptamine (5-HT) 1A receptors, but the respective implication of pre- versus postsynaptic 5-HT1A receptors has not been elucidated. Here, we investigated marble burying behavior by male NMRI mice following acute administration of 3 biased agonists, which preferentially activate presynaptic 5-HT1A receptors (F13714) or postsynaptic receptors (NLX-101) or which exhibit balanced activation of both pre- and postsynaptic 5-HT1A receptors (NLX-112). When administered at the dose of 2.5 mg/kg i.p., all 3 biased agonists completely or nearly completely abolished marble burying behavior. However, they varied in their potency with minimal effective doses of 0.16, 0.63, and 2.5 mg/kg i.p., for F13714, NLX-112, and NLX-101, respectively. The selective 5-HT1A receptor antagonist, WAY100,635 was inactive up to 2.5 mg/kg. These results suggest that marble burying behavior in male NMRI mice is preferentially sensitive to activation of pre- versus postsynaptic 5-HT1A receptors. Moreover, they suggest that targeting 5-HT1A receptors with biased agonists could provide an innovative therapeutic approach to combat OCD.


Asunto(s)
Conducta Animal/efectos de los fármacos , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Receptores Presinapticos/efectos de los fármacos , Agonistas del Receptor de Serotonina 5-HT1/administración & dosificación , Agonistas del Receptor de Serotonina 5-HT1/farmacología , Aminopiridinas/administración & dosificación , Aminopiridinas/farmacología , Animales , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Inyecciones Intraperitoneales , Masculino , Ratones Endogámicos , Trastorno Obsesivo Compulsivo/tratamiento farmacológico , Piperazinas/administración & dosificación , Piperazinas/farmacología , Piperidinas/administración & dosificación , Piperidinas/farmacología , Piridinas/administración & dosificación , Piridinas/farmacología , Pirimidinas/administración & dosificación , Pirimidinas/farmacología , Antagonistas de la Serotonina/administración & dosificación , Antagonistas de la Serotonina/farmacología , Sinapsis/efectos de los fármacos
3.
Neurobiol Dis ; 65: 55-68, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24423646

RESUMEN

Null mutations in the gene encoding the major myelin protein of the central nervous system, proteolipid protein 1 (PLP1), cause an X-linked form of spastic paraplegia (SPG2) associated with axonal degeneration. While motor symptoms are the best known manifestations of this condition, its somatosensory disturbances have been described but poorly characterized. We carried out a longitudinal study in an animal model of SPG2 - mice carrying a deletion of the Plp1 gene (Plp-null mice). Plp-null mice exhibited severe early-onset thermal hyperalgesia, in the absence of thermal allodynia. We first performed an electrophysiological testing which showed an early decrease in peripheral and spinal conduction velocities in Plp null mice. Such as the abnormal sensitive behaviors, this slowing of nerve conduction was observed before the development of myelin abnormalities at the spinal level, from 3months of age, and without major morphological defects in the sciatic nerve. To understand the link between a decrease in nerve velocity and an increased response to thermal stimuli before the appearance of myelin abnormalities, we focused our attention on the dorsal horn of the spinal cord, the site of integration of somatosensory information. Immunohistochemical studies revealed an early-onset activation of astrocytes and microglia that worsened with age, associated later in age with perturbation of the expression of the sensory neuropeptides calcitonin-gene-related peptide and galanin. Taken together, these results represent complementary data supporting the hypothesis that Plp-null mice suffer from ganglionopathy associated with late onset central demyelination but with few peripheral nerve alterations, induced by the glial-cell-mediated sensitization of the spinal cord. The mechanism suggested here could underlie pain experiments in other leukodystrophies as well as in other non-genetic demyelinating diseases such as multiple sclerosis.


Asunto(s)
Sensibilización del Sistema Nervioso Central/genética , Hiperalgesia/genética , Proteína Proteolipídica de la Mielina/deficiencia , Umbral del Dolor/fisiología , Eliminación de Secuencia/genética , Factores de Edad , Animales , Condicionamiento Operante/fisiología , Potenciales Evocados Motores/genética , Potenciales Evocados Somatosensoriales/genética , Reflejo H/genética , Calor/efectos adversos , Hiperalgesia/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Actividad Motora/genética , Proteína Proteolipídica de la Mielina/genética , Conducción Nerviosa/genética , Nervio Ciático/patología , Nervio Ciático/fisiopatología , Médula Espinal/patología
4.
J Opioid Manag ; 20(4): 269-274, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39321046

RESUMEN

BACKGROUND: NLX-112 (a.k.a. F13640, befiradol) is a highly selective and fully efficacious agonist at 5-hydroxytryptamine (5-HT1A) receptors. It has been shown to be robustly and potently active in nociceptive, neuropathic and traumatic pain models in rats and mice. In particular, NLX-112 decreases oral fentanyl self-administration (FSA) in polyarthritic rats, ie, it has opioid dose-sparing effects. OBJECTIVE: To examine if the dose-sparing effects of NLX-112 in polyarthritic rats are shared by other 5-HT1A ligands: the prototypical 5-HT1A receptor agonist 8-HYDROXY-2-(DI-n-PROPYLAMINO)TETRALIN ((±)8-OH-DPAT), and the 5-HT1A receptor partial agonist and weak dopamine D2 receptor blocker, -buspirone. DESIGN: Polyarthritis was induced by inoculating rats with heat-killed Mycobacterium butyricum. They then had access to either a fentanyl (0.008 mg/mL) or a sweetened solution in their home cage. NLX-112, (±)8-OH-DPAT, or buspirone was administered via an osmotic minipump (5 µL/h) during a 2-week infusion period from day 14 to day 28 post-inoculation with Mycobacterium butyricum. Control infusions consisted of sterile 0.9 percent NaCl. RESULTS: NLX-112 (0.63 mg/day) significantly decreased FSA by 47 percent and increased total fluid consumption (TFC) by 7 percent (vehicle-loaded minipumps as controls). Both (±)8-OH-DPAT and buspirone (0.63 and 2.5 mg/day, respectively) failed to reduce FSA; (±)8-OH-DPAT did not modify TFC, while buspirone significantly decreased it by 17 percent. CONCLUSIONS: These results suggest that oral FSA dose-sparing effect, in this rat polyarthritis pain model, requires high efficacy activation of 5-HT1A receptors, such as that afforded by NLX-112. By contrast, the agonist efficacy of (±)8-OH-DPAT and buspirone seems insufficient for FSA dose-sparing.


Asunto(s)
8-Hidroxi-2-(di-n-propilamino)tetralin , Buspirona , Fentanilo , Receptor de Serotonina 5-HT1A , Agonistas del Receptor de Serotonina 5-HT1 , Animales , Buspirona/farmacología , Buspirona/administración & dosificación , Agonistas del Receptor de Serotonina 5-HT1/farmacología , Agonistas del Receptor de Serotonina 5-HT1/administración & dosificación , Receptor de Serotonina 5-HT1A/metabolismo , Receptor de Serotonina 5-HT1A/efectos de los fármacos , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , 8-Hidroxi-2-(di-n-propilamino)tetralin/administración & dosificación , Masculino , Fentanilo/administración & dosificación , Fentanilo/farmacología , Ratas , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/farmacología , Ratas Sprague-Dawley , Relación Dosis-Respuesta a Droga , Artritis Experimental/tratamiento farmacológico , Artritis/tratamiento farmacológico , Piperidinas , Piridinas
5.
Behav Pharmacol ; 22(5-6): 390-404, 2011 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-21808193

RESUMEN

Serotonin [5-hydroxytryptamine (5-HT)] in the central nervous system and in the periphery has long been considered to have an important role in the control of pain, for example, through descending inhibition. In recent years, considerable research efforts have focused on the role played by 5-HT on acute or chronic pain states as well as on the identification of the respective 5-HT receptors involved. However, preclinical studies have reported conflicting observations, and numerous important questions remain unanswered. The purpose of this study is to provide an analysis of the recent developments in understanding the role of 5-HT both within the periphery and at the level of the spinal dorsal horn. We discuss the inhibitory or facilitatory influences exerted by 5-HT, through the descending 5-HT pathway, on spinal processing of nociceptive information in pathological pain states. Evidence with regard to the possible implication of the 5-HT(1A), 5-HT(2A), 5-HT(3), and 5-HT(7) receptors in pain modulation is also reviewed. Recent studies (both behavioral and clinical, relevant to these targets) have indeed demonstrated that 5-HT(1A) and 5-HT(7) receptor agonists or 5-HT(2A) and 5-HT(3) receptor antagonists may be promising therapeutic agents for the treatment of pain states.


Asunto(s)
Dolor Crónico/tratamiento farmacológico , Receptores de Serotonina/efectos de los fármacos , Serotonina/metabolismo , Animales , Dolor Crónico/fisiopatología , Humanos , Células del Asta Posterior/metabolismo , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología
6.
Behav Pharmacol ; 22(5-6): 599-606, 2011 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-21841543

RESUMEN

Milnacipran, a serotonin and noradrenalin reuptake inhibitor (SNRI), is efficacious in rodents in various models of acute or chronic pain (traumatic, neuropathic, inflammatory, visceral). However, its activity against arthritic pain has never been explored. Here, we assessed the activity of acute treatment with milnacipran in a polyarthritic rat model. Rats were injected in the tail base with complete Freund's adjuvant to induce a state of polyarthritis. Analgesic effects of acute treatment with intraperitoneal administration of milnacipran were then evaluated, using the Randall-Selitto model, against two levels of pressure applied to both hind paws (a lower one, addressing mechanical allodynia and a higher one, addressing mechanical hyperalgesia). The other SNRI duloxetine and the nonsteroidal anti-inflammatory drug indomethacin were tested as positive controls. Milnacipran was significantly and dose dependently active against the decrease of paw withdrawal threshold produced by complete Freund's adjuvant for low (minimum effective dose=5 mg/kg, range tested: 2.5-10 mg/kg) and high (minimum effective dose=10 mg/kg, range tested: 5-20 mg/kg)-pressure levels. Duloxetine (20 mg/kg, intraperitoneally) was significantly active against low pressure only. Indomethacin (3 mg/kg per os) was efficacious against both pressure levels. These rodent data suggest that milnacipran should be efficacious in painful conditions associated with chronic inflammatory states, such as arthritis.


Asunto(s)
Artritis Experimental/tratamiento farmacológico , Ciclopropanos/farmacología , Indometacina/farmacología , Tiofenos/farmacología , Inhibidores de Captación Adrenérgica/administración & dosificación , Inhibidores de Captación Adrenérgica/farmacología , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/farmacología , Artritis Experimental/fisiopatología , Ciclopropanos/administración & dosificación , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Clorhidrato de Duloxetina , Indometacina/administración & dosificación , Masculino , Milnaciprán , Ratas , Ratas Wistar , Tiofenos/administración & dosificación
7.
Int J Neuropsychopharmacol ; 13(10): 1285-98, 2010 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-20059805

RESUMEN

F15599 is a novel agonist with high selectivity and efficacy at serotonin 5-HT(1A) receptors (5-HT(1A)Rs). In signal transduction, electrophysiological and neurochemical tests, F15599 preferentially activates post-synaptic 5-HT(1A)Rs in rat frontal cortex. Such a profile may translate to an improved profile of therapeutic activity for mood disorders. The in-vivo effects of F15599 were therefore compared with those of a related compound, F13714, in rat models of antidepressant activity and 5-HT(1A)R activation: forced swimming test (FST), conditioned stress-induced ultrasonic vocalization, 5-HT syndrome, plasma corticosterone and body temperature. Acute administration of F15599 or F13714 reduced immobility in the FST at low doses; these effects were long lasting and the effects of F15599 were maintained after repeated (5 d, p.o.) administration. Both compounds decreased ultrasonic vocalization duration at low doses. In contrast, higher doses of F15599 were required to induce lower lip retraction, elements of the 5-HT behavioural syndrome, hypothermia and to increase plasma corticosterone levels. Notably, there was a greater separation of ED50 between FST and other effects for F15599 than for F13714. Thus, the in-vivo potency of F15599 in models of antidepressant/anti-stress activity is similar to that of F13714, despite the fact that the latter has an in-vitro potency two orders of magnitude greater. In contrast F15599 has a lower propensity than F13714 to induce other serotonergic signs. The distinctive pharmacological profile of F15599 suggests that preferential targeting of post-synaptic 5-HT(1A)Rs constitutes a promising strategy for improved antidepressant therapy.


Asunto(s)
Aminopiridinas/farmacología , Antidepresivos/farmacología , Depresión/tratamiento farmacológico , Terapia Molecular Dirigida , Piperidinas/farmacología , Agonistas del Receptor de Serotonina 5-HT1/uso terapéutico , Animales , Corticosterona/sangre , Corticosterona/metabolismo , Hipotermia/inducido químicamente , Masculino , Modelos Animales , Actividad Motora/efectos de los fármacos , Piperidinas/uso terapéutico , Corteza Prefrontal/efectos de los fármacos , Pirimidinas/uso terapéutico , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Serotonina/farmacología , Estrés Fisiológico/efectos de los fármacos , Natación/fisiología
8.
Behav Pharmacol ; 20(4): 303-11, 2009 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-19584712

RESUMEN

Dopamine (DA) is implicated in penile erection (PE) and yawning (YA) in rats through activation of D2-like receptors. However, the exact role of each subtype (D2, D3 and D4) of this receptor family in PE/YA is still not clearly elucidated. We recorded concomitantly PE and YA after treatment with agonists with various levels of selectivity for the different subtypes of D2-like receptors. In addition, we investigated the efficacy of antagonists with selective or preferential affinity for each of the three receptor subtypes to prevent apomorphine-induced PE and YA. Wistar rats were more sensitive than Long-Evans rats to the erectogenic activity of the nonselective DA agonist apomorphine (0.01-0.08 mg/kg), whereas Sprague-Dawley rats were insensitive. However, all the three strains were equally sensitive to apomorphine-induced YA. In Wistar rats, apomorphine (0.01-0.63 mg/kg), the D2/D3 agonists quinelorane and (+)7-OH-DPAT (0.000625-10 mg/kg) or PD 128,907 (0.01-10 mg/kg), but not the D4 agonists PD-168,077, RO-10-5824 and ABT-724 (0.04-0.63 mg/kg), produced PE and YA with bell-shaped dose-response curves. Similarly, ABT-724 and CP226-269 (another D4 agonist) failed to elicit PE and YA in Sprague-Dawley rats. Furthermore, in Wistar rats, PE and YA elicited by apomorphine (0.08 mg/kg) were not modified by selective D3 (S33084 and SB-277011, 0.63-10 mg/kg) or D4 (L-745,870 and RBI-257, 0.63-2.5 mg/kg) antagonists, but were prevented by the preferential D2 blocker L-741,626 (near-full antagonism at 2.5 mg/kg). The present data do not support a major implication of either DA D3 or D4 receptors in the control of PE and YA in rats, but indicate a preponderant role of DA D2 receptors.


Asunto(s)
Agonistas de Dopamina/farmacología , Erección Peniana/efectos de los fármacos , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D3/agonistas , Receptores de Dopamina D4/agonistas , Bostezo/efectos de los fármacos , Animales , Apomorfina/farmacología , Antagonistas de los Receptores de Dopamina D2 , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Masculino , Ratas , Ratas Long-Evans , Ratas Sprague-Dawley , Ratas Wistar , Receptores de Dopamina D3/antagonistas & inhibidores , Receptores de Dopamina D4/antagonistas & inhibidores , Especificidad de la Especie
9.
ACS Chem Neurosci ; 10(7): 3101-3107, 2019 07 17.
Artículo en Inglés | MEDLINE | ID: mdl-30929419

RESUMEN

When placed in an unfamiliar and brightly lit open-field, two adult male rats that have not previously interacted display a low level of social interaction (SI) attributed to an anxiety-like state. The SI test has therefore been used to explore anxiolytic/antistress activity. Here, we investigated the effects of serotonin 5-HT1A receptor agonists displaying various activity profiles, i.e. partial vs full agonist efficacy and pre- versus postsynaptic 5-HT1A receptor preferential activation by "biased agonists". Adult male Sprague-Dawley rats were housed singly before starting the social interaction session. At 30 min before being placed in an open-field, both rats of the dyad were injected (i.p or s.c.) with either vehicle, diazepam (as a reference compound), or one of six 5-HT1A receptor agonists: NLX-101 (a.k.a. F15599), F13714, S15535, flesinoxan, 8-OH-DPAT, and buspirone. Time spent in SI (following, sniffing, playing) was recorded for 10 min. Time spent in SI was inversely correlated with light intensity, with values dropping nearly by half (212.6 ± 18.8 vs 113.7 ± 7.0 s) between 10 and 300 lx (measured at floor level). Under the high light intensity conditions (300 lx), diazepam showed a bell-shaped curve, significantly increasing SI (78% increase in interaction time above control) at 1 mg/kg i.p. only. In the case of 5-HT1A receptor ligands, full agonists, whether nonpreferential (flesinoxan, (±)8-OH-DPAT) or preferential for presynaptic receptors (F13714), showed the strongest activity in this model. The preferential presynaptic receptor partial agonist, S15535, was also active over a wide dose-range, although with lower efficacy than F13714. In contrast, NLX-101, a high-efficacy biased agonist that preferentially activates postsynaptic 5-HT1A receptors, exhibited little activity. The clinical anxiolytic, buspirone, showed a marked effect likely due to its partial agonist activity at 5-HT1A presynaptic receptors. These data support the hypothesis that enhancement of SI in this model is mediated by preferential agonist activation of presynaptic 5-HT1A receptors, and confirm previous studies using local microinjections of (±)8-OH-DPAT. They further support the utility of noninvasive administration of biased agonists for exploring the activity of 5-HT1A receptor subpopulations.


Asunto(s)
Ansiedad/tratamiento farmacológico , Conducta Animal/efectos de los fármacos , Relaciones Interpersonales , Agonistas del Receptor de Serotonina 5-HT1/farmacología , Conducta Social , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , 8-Hidroxi-2-(di-n-propilamino)tetralin/uso terapéutico , Aminopiridinas/farmacología , Aminopiridinas/uso terapéutico , Animales , Buspirona/farmacología , Buspirona/uso terapéutico , Modelos Animales de Enfermedad , Masculino , Piperazinas/farmacología , Piperazinas/uso terapéutico , Piperidinas/farmacología , Piperidinas/uso terapéutico , Piridinas/farmacología , Piridinas/uso terapéutico , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Ratas , Ratas Sprague-Dawley , Agonistas del Receptor de Serotonina 5-HT1/uso terapéutico
10.
Eur J Pharmacol ; 597(1-3): 34-8, 2008 Nov 12.
Artículo en Inglés | MEDLINE | ID: mdl-18773888

RESUMEN

Small rodents (mice, rats) are the species of choice for evaluating the pharmacology of centrally acting compounds, such as antipsychotics, whereas toxicology data are routinely obtained from other species (rabbits, dogs, monkeys). Whilst there is a substantial number of "therapeutically relevant" pharmacological models for "antipsychotic-like" activity in small rodents, based on hyperdopaminergic or hypoglutamatergic/NMDA approaches, there is a remarkable paucity of such models in other species. Here, we compared the efficacy and potency of reference and new generation dopamine D2/5-HT(1A) putative antipsychotics, administered orally, against apomorphine-induced emesis in dogs, a model of central D2 receptor activation that can be implemented with relative ease. Risperidone potently and fully (10 microg/kg) prevented emesis/retching induced by 0.1 mg/kg s.c. apomorphine. SLV313 and F15063 (D2 receptor antagonists/5-HT(1A) receptor agonists) also abolished emesis/retching, albeit less potently than risperidone (minimal effective dose, MEDs: 10 and 40 microg/kg, respectively). The D2 receptor partial agonists/5-HT(1A) receptor agonists aripiprazole and bifeprunox, (up to 80 microg/kg) only partially attenuated emesis, as did the peripheral D2 receptor antagonist domperidone. Under the present experimental conditions, haloperidol was only efficacious at the highest dose tested (320 microg/kg). To summarize, dogs are very sensitive to the dopaminergic blocking effects of antipsychotics in this model of D2 receptor activation. This model can thus be advantageously used to investigate the pharmacological activity of novel D2 receptor antagonists/partial agonists in dogs.


Asunto(s)
Antieméticos/farmacología , Antipsicóticos/farmacología , Antagonistas de Dopamina/farmacología , Antagonistas de los Receptores de Dopamina D2 , Agonistas del Receptor de Serotonina 5-HT1 , Agonistas de Receptores de Serotonina/farmacología , Vómitos/prevención & control , Animales , Apomorfina , Modelos Animales de Enfermedad , Perros , Relación Dosis-Respuesta a Droga , Agonismo Parcial de Drogas , Masculino , Receptor de Serotonina 5-HT1A/metabolismo , Receptores de Dopamina D2/metabolismo , Vómitos/inducido químicamente , Vómitos/metabolismo
11.
Eur J Pharmacol ; 592(1-3): 160-6, 2008 Sep 11.
Artículo en Inglés | MEDLINE | ID: mdl-18640111

RESUMEN

Several novel antipsychotics activate serotonin 5-HT1A receptors as well as antagonising dopamine D2/3 receptors. Such a pharmacological profile is associated with a lowered liability to produce extrapyramidal side effects and enhanced efficacy in treating negative and cognitive symptoms of schizophrenia. However, 5-HT1A receptor agonists increase plasma corticosterone and many antipsychotics disturb the regulation of glucose. Here, we compared the influence on plasma glucose and corticosterone of acute treatments with 'new generation' antipsychotics which target dopamine D2/3 receptors and 5-HT1A receptors, with that of atypical antipsychotics, and with haloperidol. Olanzapine and clozapine, antipsychotics that are known to produce weight gain and diabetes in humans, both at 10 mg/kg p.o., substantially increased plasma glucose (from 0.8 to 1.7 g/l) at 1 h after administration, an effect that returned to control levels after 4 h. In comparison, F15063 (40 mg/kg p.o.) was without effect at any time point. Olanzapine and clozapine dose-dependently increased plasma glucose concentrations as did SLV313 and SSR181507. Haloperidol and risperidone had modest effects whereas aripiprazole, ziprasidone and bifeprunox, antipsychotics that are not associated with metabolic dysfunction in humans, and F15063 had little or no influence on plasma glucose. The same general pattern of response was found for plasma corticosterone levels. The present data provide the first comparative study of conventional, atypical and 'new generation' antipsychotics on glucose and corticosterone levels in rats. A variety of mechanisms likely underlie the hyperglycemia and corticosterone release observed with clozapine and olanzapine, whilst the balance of dopamine D2/3/5-HT1A interaction may contribute to the less favourable impact of SLV313 and SSR181507 compared with that of bifeprunox and F15063.


Asunto(s)
Antipsicóticos/farmacología , Benzodiazepinas/farmacología , Glucemia/metabolismo , Clozapina/farmacología , Corticosterona/metabolismo , Animales , Aripiprazol , Benzofuranos/farmacología , Benzoxazoles/farmacología , Bencilaminas/farmacología , Ciclopentanos/farmacología , Antagonistas de los Receptores de Dopamina D2 , Relación Dosis-Respuesta a Droga , Haloperidol/farmacología , Masculino , Olanzapina , Piperazinas/farmacología , Quinolonas/farmacología , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Receptores de Dopamina D2/efectos de los fármacos , Tiazoles/farmacología
12.
Naunyn Schmiedebergs Arch Pharmacol ; 375(4): 241-50, 2007 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-17453175

RESUMEN

F15063 (N-[(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)ethyl]-3-(cyclopent-1-enyl)-benzylamine fumarate salt) is a novel potential antipsychotic with dopamine D(2)/D(3) blocking properties and agonist activity at 5-HT(1A) and D(4) receptors. The pertinent parameter for pharmacological activity of antipsychotics appears to be central D2-like receptor occupancy. However, its duration is not necessarily correlated with drug plasma levels, on which clinical dosing regimens are often based. Thus, we compared in mice the duration of actions of F15063 and haloperidol to (1) inhibit apomorphine-induced climbing and sniffing (behavioural measures of D2-like receptor antagonism) and (2) occupy D2-like receptors in vivo in the striatum and olfactory tubercles (inhibition of [(3)H]nemonapride binding). Finally, we measured plasma levels of F15063. D2-like receptor occupancy in the striatum remained elevated at 1, 4 and 8 h postadministration, with both F15063 (ID(50): 7.1, 3.6 and 16.5 mg/kg p.o., respectively) and the typical antipsychotic, haloperidol (ID(50): 1.4, 0.52 and 0.53 mg/kg p.o., respectively). This was paralleled by a protracted inhibition of apomorphine-induced climbing (ED(50): 0.9, 2.8 and 3.6 mg/kg p.o., and 0.21, 0.37 and 0.87 mg/kg p.o., respectively, for F15063 and haloperidol). In contrast, after administration of 10 mg/kg p.o. of F15063, its plasma levels decreased rapidly: 15.2, 2.1 and 0.6 ng/ml, 1, 4 and 8 h after administration, respectively. A similar pattern of results was observed when F15063 and haloperidol were administered i.p. and s.c., respectively. To summarise, the time-course of D2-like receptor occupancy and inhibition of apomorphine-climbing (and sniffing) behaviours was similarly long lasting with F15063 and haloperidol. In addition, the durations of action of F15063 and haloperidol in a behavioural model of antipsychotic-like activity were closely correlated to their occupancy of central D2-like receptors, and much longer than their presence in plasma.


Asunto(s)
Antipsicóticos/farmacología , Benzofuranos/farmacología , Bencilaminas/farmacología , Ciclopentanos/farmacología , Antagonistas de Dopamina/farmacología , Antagonistas de los Receptores de Dopamina D2 , Receptores de Dopamina D3/antagonistas & inhibidores , Receptores de Dopamina D4/agonistas , Agonistas del Receptor de Serotonina 5-HT1 , Agonistas de Receptores de Serotonina/farmacología , Animales , Antipsicóticos/sangre , Apomorfina/farmacología , Benzamidas/metabolismo , Benzofuranos/sangre , Bencilaminas/sangre , Ciclopentanos/sangre , Haloperidol/farmacología , Masculino , Ratones
13.
Neuropsychopharmacology ; 31(9): 1869-79, 2006 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-16237379

RESUMEN

A new generation of proven or potential antipsychotics, including aripiprazole, bifeprunox, SSR181507 and SLV313, exhibit agonist actions at serotonin 5-HT1A receptors, but little comparative data are available on their pharmacological profiles. Here, we compared in mice the in vivo antipsychotic-like vs cataleptogenic activities of these compounds with those of drugs that exhibit little interaction at 5-HT1A receptors, such as haloperidol, olanzapine and risperidone. All the drugs dose-dependently reduced apomorphine-induced climbing or sniffing and, with the exception of ziprasidone, produced complete suppression of these responses. In the bar catalepsy test, when administered alone, haloperidol, olanzapine and risperidone produced marked catalepsy, whereas, at doses up to 40 mg/kg, aripiprazole, SLV313, SSR181507, and sarizotan produced little or no catalepsy. The latter compounds, therefore, displayed a large separation between doses with 'antipsychotic-like' and those with cataleptogenic actions. When 5-HT1A receptors were blocked by pretreatment with WAY100635 (2.5 mg/kg, s.c.), cataleptogenic properties of SSR181507 and sarizotan were unmasked, and the catalepsy induced by bifeprunox was enhanced. In the case of aripiprazole and SLV313, although WAY100635 produced upward shifts in their dose-response, the magnitude of catalepsy appeared to reach an asymptotic plateau, suggesting that other mechanisms may be involved in their low cataleptogenic liability. The present data confirm that 5-HT1A receptor activation reduces or even completely prevents the cataleptogenic potential of novel antipsychotic agents. Further, they indicate that the balance of affinity and/or efficacy between D2 and 5-HT1A receptors profoundly influences their pharmacological activities, and will likely impact their therapeutic profiles.


Asunto(s)
Antipsicóticos/farmacología , Catalepsia/inducido químicamente , Antagonistas de Dopamina/farmacología , Antagonistas de los Receptores de Dopamina D2 , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Agonistas de Receptores de Serotonina/farmacología , Animales , Apomorfina/farmacología , Agonistas de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Piperazinas/farmacología , Piridinas/farmacología , Antagonistas de la Serotonina/farmacología , Conducta Estereotipada/efectos de los fármacos
14.
Eur J Pharmacol ; 523(1-3): 29-39, 2005 Oct 31.
Artículo en Inglés | MEDLINE | ID: mdl-16226246

RESUMEN

F 13640 is a newly discovered high-efficacy 5-HT(1A) receptor agonist that produces exceptional analgesia in animal models of tonic and chronic, nociceptive and neuropathic pains by novel molecular and neuroadaptive mechanisms. Here we examined the effects of F 13640 and remifentanil (0.63 mg/kg with either compound) when injected i.p. either before or 15 min after rats underwent orthopedic surgery. Surgery consisted of the drilling of a hole in the calcaneus bone and of an incision of the skin, fascia and plantar muscle of one foot. During surgery, the concentration of volatile isoflurane was progressively incremented depending on the animal's response to surgical maneuvers. Other experiments examined the dose-dependent effects of F 13640 (0.04 to 0.63 mg/kg) on surgical pain as well as on the Minimum Alveolar Concentration of isoflurane. Both F 13640 and remifentanil markedly reduced the intra-operative isoflurane requirement. F 13640 also reduced measures of postoperative pain (i.e., paw elevation and flexion). With these postoperative measures, remifentanil produced short-lived analgesia followed by hyperalgesia. F 13640 significantly reduced both surgical pain and the isoflurane Minimum Alveolar Concentration from 0.16 mg/kg onward. F 13640 produced powerful intra- and postoperative analgesia in rats undergoing orthopedic surgery. Unlike the opioid, remifentanil, F 13640 caused no hyperalgesia with ongoing postoperative pain, and should remain effective with protracted postoperative use.


Asunto(s)
Analgésicos no Narcóticos/farmacología , Dolor Postoperatorio/prevención & control , Dolor/prevención & control , Piperidinas/farmacología , Piridinas/farmacología , Analgesia , Analgésicos no Narcóticos/administración & dosificación , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/efectos adversos , Analgésicos Opioides/farmacología , Análisis de Varianza , Anestésicos por Inhalación/administración & dosificación , Anestésicos por Inhalación/farmacocinética , Anestésicos por Inhalación/farmacología , Animales , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Hiperalgesia/inducido químicamente , Isoflurano/administración & dosificación , Isoflurano/farmacocinética , Isoflurano/farmacología , Masculino , Monitoreo Intraoperatorio , Procedimientos Ortopédicos/efectos adversos , Dolor/etiología , Dimensión del Dolor/métodos , Umbral del Dolor/efectos de los fármacos , Dolor Postoperatorio/etiología , Piperazinas/farmacología , Piperidinas/administración & dosificación , Piperidinas/efectos adversos , Alveolos Pulmonares/metabolismo , Piridinas/administración & dosificación , Ratas , Ratas Sprague-Dawley , Remifentanilo , Antagonistas de la Serotonina/farmacología , Vocalización Animal/efectos de los fármacos
15.
Eur J Pain ; 8(3): 253-61, 2004 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-15109976

RESUMEN

We here studied the involvement of spinally located 5-HT(1A) and opioid receptors, in the paradoxical effects that their activation can produce on nociception. Intrathecal (i.t.) injection of the 5-HT(1A) receptor agonist 8-hydroxy-2-[di-n-propylamino] tetralin (8-OH-DPAT) (1-10 microg) induced analgesic effects in the formalin model of tonic pain whereas in the paw pressure test, it decreased the vocalization threshold. In this latter test, i.t. 8-OH-DPAT also markedly reduced the analgesic effect of systemic morphine (5-10 mg/kg, s.c.). At 10 microg, 8-OH-DPAT totally abolished the effect of 5 mg/kg of morphine; this inhibitory effect was antagonized by pre-treatment with 0.63 mg/kg of the 5-HT(1A) antagonist WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl]-N-(2-pyridinyl)-cyclohexanecarboxamide-trihydrochloride). In contrast, the i.t. injection of WAY-100635 (1-10 microg) dose-dependently potentiated the antinociceptive activity of a dose of morphine (2.5 mg/kg, s.c.). Furthermore, WAY-100635 (10 microg, i.t.) potentiated morphine analgesia in morphine-tolerant rats. These findings demonstrate that 5-HT(1A) receptor agonists can act in the spinal cord to produce both hyper- and hypo-algesic effects and play a major role in the opioid analgesia and tolerance.


Asunto(s)
Vías Aferentes/efectos de los fármacos , Morfina/farmacología , Dolor/tratamiento farmacológico , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Médula Espinal/efectos de los fármacos , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Vías Aferentes/citología , Vías Aferentes/metabolismo , Analgésicos Opioides/farmacología , Animales , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas/fisiología , Tolerancia a Medicamentos/fisiología , Inyecciones Espinales , Masculino , Dolor/metabolismo , Dolor/fisiopatología , Dimensión del Dolor/efectos de los fármacos , Umbral del Dolor/efectos de los fármacos , Umbral del Dolor/fisiología , Piperazinas/farmacología , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT1A/metabolismo , Receptores Opioides/efectos de los fármacos , Receptores Opioides/metabolismo , Antagonistas de la Serotonina/farmacología , Médula Espinal/fisiopatología
16.
Eur J Pharmacol ; 672(1-3): 83-7, 2011 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-21996314

RESUMEN

The role of antidepressants in the treatment of visceral pain has not been extensively examined. Milnacipran, a serotonin/noradrenalin reuptake inhibitor, has recently been approved in the USA for fibromyalgia, a chronic pathology characterized by diffused/chronic musculoskeletal pain, and a high prevalence of irritable bowel syndrome. Here, we determined its antinociceptive efficacy in two visceral pain tests in rodents: the acetic acid-induced writhing model in mice and the butyrate/colonic distension assay in rats, a model of irritable bowel syndrome. Acute milnacipran (5-40 mg/kgi.p.) significantly and dose-dependently reduced writhing (72.2 ± 3.2 versus 17.0 ± 4.1 writhes at 40 mg/kg). Following repeated administration (40 m/kgi.p. for 5 days), milnacipran preserved its ability to significantly reduce writhing (76 ± 8.3 versus 21.1 ± 6.7 writhes). Similarly, in the butyrate model, acute milnacipran (17.5 and 35 mg/kg, i.p.) significantly and dose-dependently increased cramps induction thresholds (from 45.7 ± 5.7 to 66.3 ± 4.8 and 75.6 ± 2.9 mm Hg, for 17.5 and 35 mg/kg, respectively) and reduced the number of cramps (from 3.0 ± 0.8 to 1.2 ± 0.8 and 0.3 ± 0.3 following inflation of an intra-rectal balloon. To summarise, milnacipran was efficacious in the writhing test, after acute and semi-chronic administration. This effect was confirmed after acute administration in a more specific model of colonic hypersensitivity induced by butyrate. This suggests that milnacipran has potential clinical application in the treatment of visceral pain, such as in irritable bowel syndrome, highly co-morbid with fibromyalgia.


Asunto(s)
Dolor Abdominal/tratamiento farmacológico , Analgésicos/farmacología , Ciclopropanos/farmacología , Síndrome del Colon Irritable/tratamiento farmacológico , Dolor Visceral/tratamiento farmacológico , Dolor Abdominal/inducido químicamente , Ácido Acético/efectos adversos , Analgésicos/administración & dosificación , Analgésicos/uso terapéutico , Animales , Butiratos/efectos adversos , Ciclopropanos/administración & dosificación , Ciclopropanos/uso terapéutico , Modelos Animales de Enfermedad , Esquema de Medicación , Síndrome del Colon Irritable/inducido químicamente , Masculino , Ratones , Milnaciprán , Ratas , Dolor Visceral/inducido químicamente
17.
Eur J Pharmacol ; 655(1-3): 46-51, 2011 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-21277295

RESUMEN

Milnacipran, a serotonin/norepinephrine reuptake inhibitor (SNRI), has shown efficacy against several chronic pain conditions, including fibromyalgia. Here, we evaluated, in rats, its anti-allodynic effects following acute or sub-chronic treatment in a model of neuropathic pain (chronic constriction injury, CCI, of the sciatic nerve). Amitriptyline, a tricyclic antidepressant active pre-clinically and clinically against neuropathic pains, was added as a comparison compound. Upon acute i.p. administration, milnacipran was potently efficacious in the CCI model. It significantly reduced thermal allodynia in the cold (4°C) plate test (MED=2.5mg/kg), and attenuated mechanical allodynia in the von Frey filaments test (MED=10mg/kg). Given sub-chronically (7day, b.i.d.), milnacipran was effective at 10mg/kgi.p. in both tests. Acute amitriptyline (10mg/kgi.p.) was efficacious against mechanical, but less so against cold allodynia; under sub-chronic conditions, it was only active against mechanical allodynia. These data show that milnacipran is as efficacious as the reference compound amitriptyline in a pre-clinical model of injury-induced neuropathy, and demonstrate for the first time that it is active acutely and sub-chronically against cold allodynia. They also suggest that milnacipran has the potential to alleviate allodynia associated with nerve compression-induced neuropathic pain in the clinic (for example following discal hernia, avulsion or cancer-induced tissue damage).


Asunto(s)
Amitriptilina/farmacología , Analgésicos/farmacología , Frío , Ciclopropanos/farmacología , Hiperalgesia/tratamiento farmacológico , Neuralgia/tratamiento farmacológico , Analgésicos/administración & dosificación , Analgésicos/efectos adversos , Analgésicos/uso terapéutico , Animales , Conducta Animal/efectos de los fármacos , Constricción , Ciclopropanos/administración & dosificación , Ciclopropanos/efectos adversos , Ciclopropanos/uso terapéutico , Modelos Animales de Enfermedad , Milnaciprán , Ratas , Nervio Ciático/efectos de los fármacos , Nervio Ciático/lesiones , Factores de Tiempo
18.
Eur Neuropsychopharmacol ; 20(9): 641-54, 2010 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-20488670

RESUMEN

We assessed the activity of F15599, a selective and high efficacy 5-HT(1A) agonist that preferentially activates post- versus pre-synaptic receptors, in rat cognition/memory models. F15599 (0.16 mg/kg i.p.) partially alleviated detrimental effects of phencyclidine on working and reference memory deficit in a hole-board model. It also attenuated phencyclidine-induced deficit of cognitive flexibility in a reversal learning task, without effects of its own. F13714 (0.04 mg/kg) a chemical congener of F15599, and 8-OH-DPAT (0.01 or 0.16), were inactive against these phencyclidine-induced deficits, and/or even worsened basal performances. F15599 (0.04-2.5) was less disruptive than F13714 (0.005-0.16) or 8-OH-DPAT (0.01-0.63), on basal performance in models of attention (5-choice serial reaction time task) and working memory (delayed non-matching to position). Finally, unlike either comparator, F15599 reduced PPI with modest potency and only partially. To conclude, F15599, in models of memory/cognition, has a more favourable profile than F13714 and 8-OH-DPAT. This suggests that preferential activation of post-synaptic 5-HT(1A) receptors could prove useful in pathologies characterized by cognitive/memory deficiencies, such as schizophrenia and depression.


Asunto(s)
Cognición/efectos de los fármacos , Piperidinas/farmacología , Pirimidinas/farmacología , Receptor de Serotonina 5-HT1A/metabolismo , Agonistas del Receptor de Serotonina 5-HT1/farmacología , 8-Hidroxi-2-(di-n-propilamino)tetralin/metabolismo , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Aminopiridinas/metabolismo , Aminopiridinas/farmacología , Animales , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Masculino , Memoria a Corto Plazo/efectos de los fármacos , Fenciclidina/farmacología , Piperidinas/metabolismo , Ratas , Ratas Sprague-Dawley , Reflejo de Sobresalto/efectos de los fármacos , Transducción de Señal
19.
Behav Pharmacol ; 19(2): 145-52, 2008 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-18332679

RESUMEN

Antipsychotics constitute efficacious augmenting agents in the treatment of anxiety disorders, including refractory obsessive-compulsive disorder. We examined the effects of 36 compounds, including typical, atypical and novel antipsychotics with dual dopamine D2/5-hydroxytryptamine 1A (D2/5-HT1A) actions on marble burying behavior in mice, a putative preclinical test for anxiety disorders. One hour after drug administration, male NMRI mice were placed individually in cages containing 20 marbles, and the total number of marbles buried after 30 min was counted. The selective serotonin reuptake inhibitors, citalopram (2.5-40 mg/kg), fluoxetine (2.5-10 mg/kg) and the benzodiazepine diazepam (2.5-10 mg/kg), reduced the number of buried marbles. The atypical antipsychotic, clozapine (0.16-10 mg/kg), but not its congener olanzapine, was effective in this test. Haloperidol, a typical antipsychotic, also reduced the number of buried marbles, albeit not in a dose-dependent manner. The atypical risperidone was partially active (0.16-0.63 mg/kg), as was the benzamide derivative, amisulpride, albeit at high (10-40 mg/kg) doses. Among the 'third-generation' antipsychotics possessing combined D2/5-HT1A properties, bifeprunox was active at 0.0025 mg/kg, whereas SLV313 and aripiprazole were active only at the highest doses (2.5 and 10 mg/kg, respectively). SSR181507, F15063 and the antidyskinetic agent, sarizotan, were without any effect. Among a series of receptor subtype-selective ligands, only the 5-HT1A agonist, (+)-8-OH-DPAT (0.63-2.5 mg/kg) and the 5-HT2A/2B/2C antagonist, ritanserin (0.63-2.5 mg/kg) were active. Among novel antipsychotics with dual D2/5-HT1A properties, only bifeprunox was able to potently reduce the number of buried marbles. Inhibition of marble burying behavior may result from the interplay of several receptor systems, including 5-HT2 receptor blockade, dopamine D2 partial agonism and serotonin 5-HT1A agonism.


Asunto(s)
Antipsicóticos/farmacología , Nivel de Alerta/efectos de los fármacos , Encéfalo/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Receptores de Dopamina D2/efectos de los fármacos , Conducta Estereotipada/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Relación Estructura-Actividad
20.
Behav Pharmacol ; 18(2): 103-18, 2007 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-17351418

RESUMEN

Combining antagonist/partial agonist activity at dopamine D2 and agonist activity at serotonin 5-HT1A receptors is one of the approaches that has recently been chosen to develop new generation antipsychotics, including bifeprunox, SSR181507 and SLV313. There have been, however, few comparative data on their pharmacological profiles. Here, we have directly compared a wide array of these novel dopamine D2/5-HT1A and conventional antipsychotics in rat models predictive of antipsychotic activity. Potency of antipsychotics to antagonize conditioned avoidance, methylphenidate-induced behaviour and D-amphetamine-induced hyperlocomotion correlated with their affinity at dopamine D2 receptors. Potency against ketamine-induced hyperlocomotion was independent of affinity at dopamine D2 or 5-HT1A receptors. Propensity to induce catalepsy, predictive of occurrence of extrapyramidal side effects, was inversely related to affinity at 5-HT1A receptors. As a result, preferential D2/5-HT1A antipsychotics displayed a large separation between doses producing 'antipsychotic-like' vs. cataleptogenic actions. These data support the contention that 5-HT1A receptor activation greatly reduces or prevents the cataleptogenic potential of novel antipsychotics. They also emphasize that interactions at 5-HT1A and D2 receptors, and the nature of effects (antagonism or partial agonism) at the latter has a profound influence on pharmacological activities, and is likely to affect therapeutic profiles.


Asunto(s)
Antipsicóticos/farmacología , Conducta Animal/efectos de los fármacos , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Receptores de Dopamina D2/efectos de los fármacos , Animales , Reacción de Prevención/efectos de los fármacos , Catalepsia/inducido químicamente , Catalepsia/psicología , Estimulantes del Sistema Nervioso Central/farmacología , Dextroanfetamina/farmacología , Relación Dosis-Respuesta a Droga , Electrochoque , Antagonistas de Aminoácidos Excitadores/farmacología , Inyecciones Intraperitoneales , Ketamina/farmacología , Masculino , Metilfenidato/farmacología , Actividad Motora/efectos de los fármacos , Ratas , Ratas Sprague-Dawley
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