RESUMEN
Background: The term Behavioral and Psychological Symptoms of Dementia (BPSD) covers a group of phenomenologically and medically distinct symptoms that rarely occur in isolation. Their therapy represents a major unmet medical need across dementias of different types, including Alzheimer's disease. Understanding of the symptom occurrence and their clusterization can inform clinical drug development and use of existing and future BPSD treatments. Objective: The primary aim of the present study was to investigate the ability of a commonly used principal component analysis to identify BPSD patterns as assessed by Neuropsychiatric Inventory (NPI). Methods: NPI scores from the Aging, Demographics, and Memory Study (ADAMS) were used to characterize reported occurrence of individual symptoms and their combinations. Based on this information, we have designed and conducted a simulation experiment to compare Principal Component analysis (PCA) and zero-inflated PCA (ZI PCA) by their ability to reveal true symptom associations. Results: Exploratory analysis of the ADAMS database revealed overlapping multivariate distributions of NPI symptom scores. Simulation experiments have indicated that PCA and ZI PCA cannot handle data with multiple overlapping patterns. Although the principal component analysis approach is commonly applied to NPI scores, it is at risk to reveal BPSD clusters that are a statistical phenomenon rather than symptom associations occurring in clinical practice. Conclusions: We recommend the thorough characterization of multivariate distributions before subjecting any dataset to Principal Component Analysis.
Asunto(s)
Enfermedad de Alzheimer , Humanos , Análisis de Componente Principal , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/psicología , Síntomas Conductuales/diagnóstico , Síntomas Conductuales/etiología , Envejecimiento , Pruebas NeuropsicológicasRESUMEN
Oligomers of the beta-amyloid (Abeta) peptide have been indicated in early neuropathologic changes in Alzheimer's disease. Here, we present a synthetic Abeta(20-42) oligomer (named globulomer) with a different conformation to monomeric and fibrillar Abeta peptide, enabling the generation of highly Abeta oligomer-specific monoclonal antibodies. The globulomer-derived antibodies specifically detect oligomeric but not monomeric or fibrillar Abeta in various Abeta preparations. The globulomer-specific antibody A-887755 was able to prevent Abeta oligomer binding and dynamin cleavage in primary hippocampal neurons and to reverse globulomer-induced reduced synaptic transmission. In amyloid precursor protein (APP) transgenic mice, vaccination with Abeta globulomer and treatment with A-887755 improved novel object recognition. The cognitive improvement is likely attributable to reversing a deficit in hippocampal synaptic spine density in APP transgenic mice as observed after treatment with A-887755. Our findings demonstrate that selective reduction of Abeta oligomers by immunotherapy is sufficient to normalize cognitive behavior and synaptic deficits in APP transgenic mice.
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Péptidos beta-Amiloides/inmunología , Precursor de Proteína beta-Amiloide/genética , Anticuerpos Monoclonales/uso terapéutico , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/inmunología , Análisis de Varianza , Animales , Anticuerpos Monoclonales/inmunología , Células Cultivadas , Modelos Animales de Enfermedad , Femenino , Hipocampo/citología , Hipocampo/inmunología , Inmunoprecipitación , Masculino , Ratones , Ratones Transgénicos , Neuronas/citología , Neuronas/inmunología , Ratas , Ratas Wistar , Reconocimiento en PsicologíaRESUMEN
Dopamine D2 receptor blockade has been an obligate mechanism of action present in all medications that effectively treat positive symptoms of schizophrenia (e.g., delusions and hallucinations) and have been approved by regulatory agencies since the 1950s. Blockade of 5-hydroxytryptamine(2A) receptors plays a contributory role in the actions of the second generation of antipsychotic drugs, the so-called atypical antipsychotics. Nevertheless, substantial unmet medical needs remain for the treatment of negative symptoms and cognitive dysfunction. Recognition that dissociative anesthetics block the N-methyl-D-aspartate (NMDA) receptor channel has inspired a search for glutamatergic therapeutic mechanisms because ketamine and phencyclidine are known to induce psychotic-like symptoms in healthy volunteers and exacerbate the symptoms of patients with schizophrenia. Current pathophysiological theories of schizophrenia emphasize that hypofunction of NMDA receptors at critical sites in local circuits modulate the function of a given brain region or control projections from one region to another (e.g., hippocampal-cortical or thalamocortical projections). The demonstration that a metabotropic glutamate 2/3 (mGlu2/3) receptor agonist prodrug decreased both positive and negative symptoms of schizophrenia raised hopes that glutamatergic mechanisms may provide therapeutic advantages. In addition to discussing the activation of mGlu2 receptors with mGlu2/3 receptor agonists or mGlu2 receptor positive allosteric modulators (PAMs), we discuss other methods that may potentially modulate circuits with hypofunctional NMDA receptors such as glycine transporter inhibitors and mGlu5 receptor PAMs. The hope is that by modulating glutamatergic neurotransmission, the dysfunctional circuitry of the schizophrenic brain (both local circuits and long-loop pathways) will be improved.
Asunto(s)
Lóbulo Frontal/fisiología , Red Nerviosa/fisiología , Receptores de N-Metil-D-Aspartato/fisiología , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatología , Animales , Lóbulo Frontal/efectos de los fármacos , Humanos , Interneuronas/metabolismo , Interneuronas/patología , Red Nerviosa/efectos de los fármacos , Receptores AMPA/agonistas , Receptores AMPA/antagonistas & inhibidores , Receptores AMPA/fisiología , Receptores de N-Metil-D-Aspartato/agonistas , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Esquizofrenia/tratamiento farmacológico , Potenciales Sinápticos/fisiologíaRESUMEN
RATIONALE: Metabotropic glutamate 1 (mGlu1) receptor antagonists were reported to induce cognitive deficits in several animal models using aversive learning procedures. OBJECTIVE: The present study aimed to further characterize behavioral effects of mGlu1 receptor antagonists using appetitively motivated tasks that evaluate working memory, timing, and impulsivity functions. MATERIALS AND METHODS: Separate groups of adult male Wistar rats were trained to perform four food-reinforced operant tasks: delayed non-matching to position (DNMTP), differential reinforcement of low rates of responding 18 s (DRL 18-s), signal duration discrimination (2-s vs 8-s bisection), and tolerance to delay of reward. Before the tests, rats were pretreated with (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate (EMQMCM; 2.5-10 mg/kg, i.p.; JNJ16567083). RESULTS: In DNMTP task, EMQMCM produced delay-dependent increases in performance accuracy so that, at 10 mg/kg dose level, percentage of correct lever choices was enhanced at 8- and 16-s delays. In DRL task, at all three tested doses, response rates were higher, and reinforcement rates were lower than under control conditions. In signal duration discrimination tasks, EMQMCM did not have any specific effects on temporal control. In tolerance to delay of reward, EMQMCM (5 and 10 mg/kg) facilitated choice of the lever associated with large reward at longer delay levels. CONCLUSIONS: Blockade of mGlu1 receptors improves working memory and reduces impulsive choice at the doses that have no effects on time perception but appear to facilitate impulsive action.
Asunto(s)
Conducta Impulsiva/prevención & control , Memoria/efectos de los fármacos , Quinolinas/farmacología , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Percepción del Tiempo/efectos de los fármacos , Análisis de Varianza , Animales , Conducta Animal/efectos de los fármacos , Condicionamiento Operante/efectos de los fármacos , Discriminación en Psicología , Relación Dosis-Respuesta a Droga , Conducta Impulsiva/fisiopatología , Inhibición Psicológica , Inyecciones Intraperitoneales , Masculino , Quinolinas/administración & dosificación , Ratas , Ratas Wistar , Esquema de Refuerzo , RecompensaRESUMEN
There is a growing body of evidence indicating that stimulation of metabotropic glutamate type II receptors (mGlu2/3) reduces anxiety in laboratory animals and humans. Surprisingly, it was reported that mGlu2/3 receptor antagonists have antidepressant- and anxiolytic-like activities in laboratory animal studies as well. The present study aimed to resolve this controversy by characterizing behavioral effects of a selective mGlu2/3 receptor antagonist, LY-341495, in a variety of animal models sensitive to clinically used anxiolytic and antidepressant agents. In agreement with previous reports, LY-341495 (0.3-3 mg/kg, i.p.) reduced immobility in the mouse forced swim test. LY-341495 was also effective in the marble burying test in mice, although similar effects were observed after administration of various drugs including methamphetamine. Further, LY-341495 had no effects in the elevated plus maze and stress-induced hyperthermia tests in mice, as well as on punished drinking (Geller-Seifter's test) and differential reinforcement of low rates of responding (DRL) in rats. It is concluded that behavioral profile of mGlu2/3 receptor antagonists as represented by LY-341495 is different from that of conventional anxiolytic and antidepressant drugs.
Asunto(s)
Aminoácidos/farmacología , Ansiedad/tratamiento farmacológico , Ansiedad/psicología , Conducta Animal/efectos de los fármacos , Depresión/tratamiento farmacológico , Depresión/psicología , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Xantenos/farmacología , Anfetamina/farmacología , Animales , Ansiolíticos/farmacología , Antidepresivos de Segunda Generación/farmacología , Estimulantes del Sistema Nervioso Central/farmacología , Condicionamiento Operante/efectos de los fármacos , Oscuridad , Diazepam/farmacología , Fiebre/fisiopatología , Fiebre/psicología , Fluoxetina/farmacología , Luz , Masculino , Ratones , Paroxetina/farmacología , Esquema de Refuerzo , Estrés Psicológico/fisiopatología , Estrés Psicológico/psicologíaRESUMEN
RATIONALE: Preclinical studies suggest that the GABAB receptor is a potential target for treatment of substance use disorders. However, recent clinical trials report adverse effects in patients treated with the GABAB receptor agonist baclofen and even question efficacy. How can the discrepancy between preclinical and clinical findings be explained? OBJECTIVE: To test efficacy and adverse effects of baclofen and the novel GABAB positive allosteric modulator (PAM) CMPPE in rat addiction models, which were developed in accordance with DSM. METHODS: We used a well-characterized rat model of long-term alcohol consumption with repeated deprivation phases that result in compulsive alcohol drinking in a relapse situation, and a rat model of long-term intravenous cocaine self-administration resulting in key symptoms of addictive behavior. We tested repeated baclofen (0, 1, and 3 mg/kg; i.p.) and CMPPE doses (0, 10, and 30 mg/kg; i.p.) in relapse-like situations, in either alcohol or cocaine addicted-like rats. RESULTS: Baclofen produced a weak anti-relapse effect at the highest dose in alcohol addicted-like rats, and this effect was mainly due to the treatment-induced sedation. CMPPE had a better profile, with a dose-dependent reduction of relapse-like alcohol drinking and without any signs of sedation. The cue-induced cocaine-seeking response was completely abolished by both compounds. CONCLUSION: Positive allosteric modulation of the GABAB receptor provides efficacy, and no observable side effects in relapse behavior whereas baclofen may cause, not only sedation, but also considerable impairment of food intake or metabolism. However, targeting GABAB receptors may be effective in reducing certain aspects of addictive-like behavior, such as cue-reactivity.
Asunto(s)
Alcoholismo/tratamiento farmacológico , Baclofeno/uso terapéutico , Trastornos Relacionados con Cocaína/tratamiento farmacológico , Agonistas de Receptores GABA-B/uso terapéutico , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Receptores de GABA-B/fisiología , Alcoholismo/psicología , Regulación Alostérica/efectos de los fármacos , Regulación Alostérica/fisiología , Animales , Baclofeno/efectos adversos , Conducta Adictiva/tratamiento farmacológico , Conducta Adictiva/psicología , Cocaína/administración & dosificación , Trastornos Relacionados con Cocaína/psicología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Etanol/administración & dosificación , Agonistas de Receptores GABA-B/efectos adversos , Masculino , Pirazoles/efectos adversos , Pirimidinas/efectos adversos , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Autoadministración , Resultado del TratamientoRESUMEN
Glutamatergic neurotransmission is believed to be critically involved in the acquisition and maintenance of drug addiction. The present study evaluated the role of metabotropic glutamate (mGlu) 1 receptors in the reinstatement of nicotine-seeking behavior. Rats were trained to nose-poke to receive response-contingent intravenous infusions of nicotine (0.01 mg/kg/infusion, free base). Following the subsequent extinction phase, reinstatement tests were conducted in animals that were exposed either to response-contingent presentations of the nicotine-associated discrete light cues or to non-contingent nicotine priming injection (0.3mg/kg, s.c., salt) just prior to the test session. In a separate experiment, rats were subjected to the nearly identical response-reinstatement procedure but operant responding was established using food pellets instead of nicotine infusions. Pretreatment with the mGlu1 receptor antagonist EMQMCM (JNJ16567083, (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate) significantly inhibited cue-induced reinstatement of nicotine-seeking behavior (5 and 10, but not 2.5 mg/kg). EMQMCM (5 mg/kg) also prevented nicotine priming-induced reinstatement of nicotine-seeking behavior. At the highest tested dose only (10 mg/kg), EMQMCM attenuated cue-induced reinstatement of food-seeking behavior. Taken together with the previous reports, the present findings further suggest that blockade of mGlu1 receptors may be beneficial for preventing relapse to tobacco smoking in nicotine-dependent individuals.
Asunto(s)
Señales (Psicología) , Extinción Psicológica/efectos de los fármacos , Nicotina/administración & dosificación , Agonistas Nicotínicos/administración & dosificación , Receptores de Glutamato Metabotrópico/fisiología , Refuerzo en Psicología , Animales , Conducta Animal , Condicionamiento Operante/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Conducta Alimentaria/efectos de los fármacos , Alimentos , Masculino , Quinolinas/farmacología , Ratas , Ratas Wistar , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Autoadministración/métodosRESUMEN
Modulation of the mGlu1 receptor was repeatedly shown to inhibit various phenomena associated with exposure to abused drugs. Efficacy in preclinical models was observed with both positive and negative allosteric modulators (PAMs and NAMs, respectively) using essentially non-overlapping sets of experimental methods. Taken together, these data indicate that the mGlu1 receptor certainly plays a significant role in the plasticity triggered by the exposure to abused drugs and is involved in the maintenance of drug-seeking and drug-taking behaviors. Understanding whether modulation of the mGlu1 receptor activity can also affect drug-seeking and drug-taking in humans could have a significant impact on the future development of medications in this field. We argue that the mGlu1 receptor NAMs have a significant value as potential tools for human experimental pharmacology that could help to validate methods used in preclinical research. Compared with the PAMs, the mGlu1 receptor NAMs appear to be better candidates for this role due to the following: (1) a number of highly potent, selective, and chemically diverse mGlu1 receptor NAMs to choose from; (2) availability of high-quality PET ligands to monitor target exposure; and (3) a rich pharmacological profile with a number of effects that can complement anti-addictive action (e.g., anxiolytic/antidepressant) and may also serve as additional pharmacodynamic readouts during the preclinical-to-clinical translation. We believe that the mGlu1 receptor NAMs have a significant value as potential tools for human experimental pharmacology that could help to validate methods used in preclinical research.
Asunto(s)
Sistemas de Liberación de Medicamentos/métodos , Receptores de Glutamato Metabotrópico/metabolismo , Trastornos Relacionados con Sustancias/tratamiento farmacológico , Trastornos Relacionados con Sustancias/metabolismo , Regulación Alostérica/efectos de los fármacos , Regulación Alostérica/fisiología , Animales , Ansiolíticos/administración & dosificación , Antidepresivos/administración & dosificación , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Comportamiento de Búsqueda de Drogas/fisiología , Agonistas de Aminoácidos Excitadores/administración & dosificación , Antagonistas de Aminoácidos Excitadores/administración & dosificación , Humanos , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/antagonistas & inhibidoresRESUMEN
RATIONALE: Metabotropic glutamate receptors (mGluRs) were reported to regulate various behavioral effects of addictive drugs. OBJECTIVE: The present study evaluated the role of group I mGluRs in the progressive augmentation ("sensitization") of the behavioral effects observed after repeated, intermittent cocaine exposure. MATERIALS AND METHODS: After habituation to handling and baseline activity measurement (days 1-2), rats received eight injections of cocaine (10 mg/kg) or saline on days 3-6, 8-11, and then, were tested twice with acute saline and cocaine given in a counterbalanced manner on days 13 and 15. Before the test sessions, subjects were pretreated with mGluR1 antagonist EMQMCM (JNJ16567083, (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate) and mGluR5 antagonist MTEP ([(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine). RESULTS: Pretreatment with EMQMCM (2.5-10 mg/kg) but not MTEP (2.5-10 mg/kg) significantly reduced expression of the sensitized ambulatory motor activity of the cocaine-experienced animals acutely challenged with cocaine. Both EMQMCM and MTEP significantly reduced vertical motor activity across all cocaine/saline treatment conditions. CONCLUSIONS: These findings indicate that the expression of behavioral sensitization to cocaine-induced stimulation of locomotor activity may be modulated by group I mGluR antagonists (mGluR1 rather than mGluR5), but these effects occur at the dose levels that attenuate vertical activity.
Asunto(s)
Conducta Animal/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/farmacología , Cocaína/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Actividad Motora/efectos de los fármacos , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Análisis de Varianza , Animales , Trastornos Relacionados con Cocaína/metabolismo , Relación Dosis-Respuesta a Droga , Masculino , Piridinas/farmacología , Quinolinas/farmacología , Ratas , Ratas Wistar , Receptor del Glutamato Metabotropico 5 , Receptores de Glutamato Metabotrópico/metabolismo , Tiazoles/farmacología , Factores de TiempoRESUMEN
Both human and animal studies suggest that there are sex differences in responding to noxious stimulation as well as in effects of opiate analgesic drugs. Development and/or expression of tolerance to opiate analgesia are also affected by the hormonal status of the experimental subjects. The present study aimed to compare acute tolerance to morphine in cycling and ovariectomized female rats and to evaluate the effects of N-methyl-D-aspartate (NMDA) receptor channel blocker memantine as well as 17-beta-estradiol on tolerance development using the tail-flick test. Acute tolerance to morphine analgesia was observed as a substantial reduction in the response to a test dose of morphine (10 mg/kg) given 6 h after the tolerance-inducing dose (10 mg/kg). Significant acute tolerance was observed in proestrous female rats and was prevented by memantine (3 or 10 mg/kg) treatment. Ovariectomized rats did not demonstrate tolerance to morphine analgesic effects but chronic estradiol administration (5 microg/day, 5 days) reinstated induction of tolerance. Both estrogen receptor modulator tamoxifen (5 mg/kg/day, 5 days) and memantine (3 mg/kg/day, 5 days) prevented estradiol-induced tolerance in ovariectomized rats. Thus, estrogens were found to play a key role in induction of acute tolerance to morphine antinociception. Estradiol-induced acute morphine tolerance may have NMDA receptor-dependent mechanisms.
Asunto(s)
Estrógenos/farmacología , Memantina/farmacología , Morfina/farmacología , Analgésicos Opioides/farmacología , Análisis de Varianza , Animales , Relación Dosis-Respuesta a Droga , Tolerancia a Medicamentos , Estradiol/farmacología , Antagonistas de Estrógenos/farmacología , Ciclo Estral , Antagonistas de Aminoácidos Excitadores/farmacología , Femenino , Ovariectomía , Ratas , Ratas Wistar , Tamoxifeno/farmacologíaRESUMEN
This randomized placebo-controlled trial tested the efficacy of oral naltrexone with or without fluoxetine for preventing relapse to heroin addiction and for reducing HIV risk, psychiatric symptoms, and outcome. All patients received drug counseling with parental or significant-other involvement to encourage adherence. Patients totaling 414 were approached, 343 gave informed consent, and 280 were randomized (mean age, 23.6 +/- 0.4 years). At 6 months, two to three times as many naltrexone patients as naltrexone placebo patients remained in treatment and had not relapsed, odds ratio (OR) = 3.5 (1.96-6.12), p < .0001. Overall, adding fluoxetine did not improve outcomes, OR = 1.35 (0.68-2.66), p = .49; however, women receiving naltrexone and fluoxetine showed a trend toward a statistically significant advantage when compared to women receiving naltrexone and fluoxetine placebo, OR = 2.4 (0.88-6.59), p = .08. HIV risk, psychiatric symptoms, and overall adjustment were markedly improved among all patients who remained on treatment and did not relapse, regardless of group assignment. More widespread use of naltrexone could be an important addition to addiction treatment and HIV prevention in Russia.
Asunto(s)
Antidepresivos de Segunda Generación/uso terapéutico , Fluoxetina/uso terapéutico , Dependencia de Heroína/rehabilitación , Heroína/efectos adversos , Naltrexona/uso terapéutico , Antagonistas de Narcóticos/uso terapéutico , Abuso de Sustancias por Vía Intravenosa/rehabilitación , Síndrome de Abstinencia a Sustancias/rehabilitación , Adulto , Antidepresivos de Segunda Generación/efectos adversos , Terapia Combinada , Método Doble Ciego , Quimioterapia Combinada , Femenino , Fluoxetina/efectos adversos , Infecciones por VIH/prevención & control , Humanos , Masculino , Naltrexona/efectos adversos , Antagonistas de Narcóticos/efectos adversos , Psicoterapia , Federación de Rusia , Prevención Secundaria , Síndrome de Abstinencia a Sustancias/diagnósticoRESUMEN
Previous studies suggested that metabotropic glutamate 5 (mGlu5) receptors play an important role in the reinforcing effects of abused drugs. The present experiments evaluated the effects of the mGlu5 receptor antagonist, MPEP (2-methyl-6-(phenylethynyl)-pyridine hydrochloride; 1-10 mg/kg, salt, i.p.), in rat models of nicotine-seeking behavior that may have relevance to relapse to drug-taking. Male Wistar rats (with restricted access to food) were trained to nose-poke to receive intravenous infusions of nicotine (0.03 mg/kg per infusion, base) under a fixed ratio 5 time out 60 s schedule of reinforcement. After stable nicotine self-administration was acquired, nose-poking behavior was extinguished in the absence of nicotine-associated cues. During the reinstatement test phase, independent groups of animals were exposed to: (a) response-contingent nicotine-associated cues (cue-induced reinstatement); or (b) response-noncontingent presentations of 45-mg food pellets under fixed time 2 min schedule (schedule-induced reinstatement). Additional control experiments were conducted to demonstrate that in nicotine-naïve animals MPEP does not affect cue-induced reinstatement of food-seeking behavior and has no effects on operant behavior maintained by a simple fixed interval 2 min schedule of food reinforcement. Pretreatment with MPEP (10 mg/kg) significantly attenuated the reinstatement of nicotine-seeking in both experiments. Further, MPEP (10 mg/kg) significantly attenuated polydipsia induced by a fixed time 2 min food schedule. In conclusion, the present findings indicate that the blockade of mGlu5 receptors attenuates cue-induced reinstatement of nicotine self-administration behavior (but not food-seeking) and may produce a general inhibition of schedule-induced behaviors, including schedule-induced nicotine-seeking.
Asunto(s)
Condicionamiento Operante/efectos de los fármacos , Señales (Psicología) , Nicotina/administración & dosificación , Agonistas Nicotínicos/administración & dosificación , Piridinas/farmacología , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Esquema de Refuerzo , Análisis de Varianza , Animales , Conducta Animal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Conducta Exploratoria/efectos de los fármacos , Alimentos , Masculino , Ratas , Ratas Wistar , Receptor del Glutamato Metabotropico 5 , AutoadministraciónRESUMEN
To reveal peripheral components of opiate analgesia, effects of loperamide, opioid agonist which does not penetrate the blood-brain barrier, were examined in formalin and acute thermal pain tests in comparison with morphine. Formalin administration induces pain behaviour such licking/biting of injected paw expressed as two phases. The first phase is caused by C-fibre activation due to peripheral stimulation, the second phase attributed to ongoing input from peripheral site, leading to spinal hyperexcitability, which is dependent on N-methyl-D-aspartate (NMDA) receptor activation. Loperamide (3-10 mg/kg) and morphine (6 mg/kg) reduced formalin-induced nociceptive behaviours and these effects were reversed by naloxone methiodide (0.03-10 mg/kg), opioid receptor antagonist which poorly penetrates the blood-brain barrier. Loperamide action was enhanced only by centrally active NMDA receptor antagonists memantine (3 mg/kg) and CGP 37849 (3 mg/kg), but not by NMDA/glycineB receptor antagonists showing weak or no central nervous system (CNS) activity. Present results suggest that central NMDA receptor blockade may be necessary to enhance analgesia induced through peripheral opioid mechanisms in formalin-evoked nociception.
Asunto(s)
Analgésicos Opioides/farmacología , Loperamida/farmacología , Morfina/farmacología , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores Opioides/metabolismo , Animales , Antagonistas de Aminoácidos Excitadores/farmacología , Formaldehído , Calor , Masculino , Destreza Motora/efectos de los fármacos , Antagonistas de Narcóticos , Dolor/inducido químicamente , Dimensión del Dolor , Equilibrio Postural/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores Opioides/agonistasRESUMEN
Previous studies suggested that combining N-methyl-d-aspartate (NMDA) receptor antagonists with either mu-opioid agonist morphine or alpha2-adrenoreceptor agonist clonidine results in the significant synergistic enhancement of analgesic activity in the animal models of acute and neuropathic pain. When given alone, NMDA receptor antagonists, morphine and clonidine are capable of attenuating tactile allodynia associated with chronic nerve injury. The present study aimed to assess anti-allodynic effects of these compounds and to test additivity of these interactions using isobolographic analysis. Adult male Wistar rats with unilateral loose ligation of sciatic nerve developed significant tactile allodynia (between-paw difference of about 18-20 g). In separate groups of animals, dose-dependent anti-allodynic activity was confirmed for memantine (1.8-17.8 mg/kg), neramexane (1.8-17.8 mg/kg), morphine (1-10 mg/kg) and clonidine (0.01-0.1 mg/kg). In a subsequent series of experiments, memantine (or neramexane) and morphine (or clonidine) were co-administered at the fixed equi-effective dose ratios (six dose levels per drug combination). None of the tested combinations produced supra-additive, synergistic effects. In fact, memantine+clonidine, neramexane+clonidine and morphine+neramexane were producing simple additive effects, while morphine+memantine was characterized as the infra-additive combination. Thus, despite expectations based on previous studies, NMDA receptor channel blockers, memantine and neramexane, produce no synergistic interactions with either morphine or clonidine when administered acutely to rats with nerve injury-induced tactile allodynia.
Asunto(s)
Clonidina/farmacología , Morfina/farmacología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Neuropatía Ciática/tratamiento farmacológico , Agonistas de Receptores Adrenérgicos alfa 2 , Analgésicos/farmacología , Analgésicos Opioides/farmacología , Animales , Ciclopentanos/farmacología , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Masculino , Memantina/farmacología , Dimensión del Dolor/métodos , Ratas , Ratas Wistar , Receptores Opioides mu/agonistas , Neuropatía Ciática/fisiopatologíaRESUMEN
The purpose of the present study was to compare anxiolytic activity of the metabotropic glutamate receptor 1 (mGlu) antagonist, EMQMCM ((3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate) and the mGlu5 receptor antagonist MTEP ([(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine) and MPEP (2-methyl-6-(phenylethynyl)pyridine) in animal models of anxiety. In the elevated plus maze, diazepam (1 mg/kg), but not the mGlu1 or mGlu5 receptor antagonists induced anxiolytic-like effects. Meanwhile, MTEP (2.5 and 5 mg/kg), EMQMCM (5 mg/kg), and diazepam (2 mg/kg) all significantly inhibited fear potentiated startle. In the contextual fear conditioning test, MTEP (1.25 and 2.5 but not 5 mg/kg) and EMQMCM (0.6 to 5 mg/kg) attenuated freezing responding. In the Geller-Seifter conflict test, MPEP (1 and 3 mg/kg), MTEP (3 mg/kg), chlordiazepoxide (10 and 20 mg/kg) and midazolam (1 mg/kg) all facilitated punished responding, while ECMQCM failed to produce any significant effects up to 3 mg/kg dose. To summarise, the present data further support a significant anxiolytic potential of group I mGlu receptor antagonists, while suggesting the effects of mGlu1 receptor antagonists may depend on the experimental procedure and may be qualitatively different from those of mGlu5 receptor antagonists.
Asunto(s)
Ansiolíticos/farmacología , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Análisis de Varianza , Animales , Ansiedad/prevención & control , Ansiedad/psicología , Conducta Animal/efectos de los fármacos , Clordiazepóxido/farmacología , Condicionamiento Operante/efectos de los fármacos , Diazepam/farmacología , Relación Dosis-Respuesta a Droga , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Midazolam/farmacología , Castigo/psicología , Piridinas/farmacología , Quinolinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptor del Glutamato Metabotropico 5 , Receptores de Glutamato Metabotrópico/metabolismo , Reflejo de Sobresalto/efectos de los fármacos , Tiazoles/farmacologíaRESUMEN
Previous studies have indicated that blockade of N-methyl-D-aspartate (NMDA) subtype of glutamate receptors prevents acquisition of instrumental behaviors reinforced by food and drugs such as morphine and cocaine. The present study aimed to extend this evidence by testing whether NMDA receptor channel blocker, memantine, would exert similar effects on acquisition of cocaine and nicotine self-administration in mice. Inasmuch as memantine also acts as nicotinic receptor channel blocker, this study assessed the effects of mecamylamine and MRZ 2/621 that are more selective nicotinic blockers. Adult male Swiss mice were allowed to self-administer cocaine (0.8-2.4 microg/infusion) or nicotine (0.08-0.32 microg/infusion) during the 30-min test. Pretreatment with memantine (0.1-10 mg/kg) prevented acquisition of nicotine but not cocaine self-administration. Pretreatment with mecamylamine (0.3-3 mg/kg) and MRZ 2/621 (0.3-10 mg/kg) produced dose-dependent suppression of both cocaine and nicotine self-administration. Taken together with the previous reports, these results indicate that nicotinic receptor blockers antagonize acute reinforcing effects of cocaine while NMDA receptor blockade may have limited effectiveness.
Asunto(s)
Conducta Adictiva/tratamiento farmacológico , Cocaína/administración & dosificación , Nicotina/administración & dosificación , Receptores de N-Metil-D-Aspartato/fisiología , Receptores Nicotínicos/fisiología , Animales , Relación Dosis-Respuesta a Droga , Antagonistas de Aminoácidos Excitadores/uso terapéutico , Infusiones Intravenosas , Masculino , Ratones , Antagonistas Nicotínicos/uso terapéutico , AutoadministraciónRESUMEN
Varenicline, the most successful smoking cessation aid, is a selective partial agonists at α4ß2* nicotinic receptors. Its efficacy is likely to be shared by other drugs with similar receptor action, including cytisine. The present study aimed to characterize behavioral effects of cytisine compared with nicotine using locomotor activity tests, intracranial self-stimulation of ventral tegmental area (discrete-trial threshold current intensity titration procedure), drug discrimination (0.6 mg/kg nicotine from vehicle), physical dependence (osmotic minipumps delivering 6 mg/kg/day of nicotine) and intravenous nicotine self-administration (0.01 mg/kg per infusion) in adult Wistar rats. Cytisine (1-3 mg/kg) partially substituted for nicotine and at the highest dose tended to antagonize nicotine's discriminative stimulus effects. Nicotine (0.05-0.4 mg/kg), but not cytisine (0.3-3 mg/kg), lowered ICSS thresholds and cytisine dose-dependently reversed effects of nicotine. Nicotine (0.15-0.6 mg/kg), but not cytisine (0.3-3 mg/kg), stimulated locomotor activity and cytisine (3 mg/kg) fully reversed these effects of nicotine. Acute pretreatment with nicotine (0.15-0.6 mg/kg), but not cytisine (0.3-3 mg/kg), reinstated extinguished nicotine self-administration. Continuous infusion of nicotine induced physical dependence, as indicated by reduced rates of food-reinforced responding induced by a challenge dose of mecamylamine. At the highest tested dose (3 mg/kg), cytisine tended to reduce response rates irrespective of whether the rats were continuously exposed to nicotine or saline. Cytisine behaves like a weak partial agonist, mimicking effects of nicotine to a limited degree. Although cytisine reversed several effects of nicotine, it seemed to have a reduced potential to produce withdrawal signs in nicotine-dependent subjects.
Asunto(s)
Alcaloides/farmacología , Agonistas Nicotínicos/farmacología , Antagonistas Nicotínicos/farmacología , Animales , Azocinas/farmacología , Discriminación en Psicología/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Estimulación Eléctrica , Electrodos Implantados , Masculino , Actividad Motora/efectos de los fármacos , Nicotina/administración & dosificación , Agonistas Nicotínicos/administración & dosificación , Quinolizinas/farmacología , Ratas Wistar , Memoria Implícita/efectos de los fármacos , Autoadministración , Tabaquismo/tratamiento farmacológico , Área Tegmental Ventral/efectos de los fármacos , Área Tegmental Ventral/fisiologíaRESUMEN
In contrast to conventional opioid analgesics, antagonists acting at the N-methyl-d-aspartate (NMDA) subtype of glutamate receptors are capable of suppressing pain-related phenomena in chronic pain models while having little or no effect on acute nociception. One of the few clinically used NMDA receptor antagonists, memantine, differs from prototypic antagonists with psychotomimetic activity such as phencyclidine and (+)MK-801, in showing lower receptor affinity, faster unblocking kinetics and stronger voltage-dependency. Recently, a series of novel amino-alkyl-cyclohexanes was reported to interact with NMDA receptors in a manner similar to that of memantine. The present study aimed to evaluate the effects of these compounds as well as (+)MK-801 and memantine in two rat models of chronic pain and the rotarod test. Unlike (+)MK-801 and memantine, most of the tested compounds were inactive against tactile allodynia induced by sciatic nerve ligation. On the other hand, all tested drugs were found to inhibit formalin-induced grooming behavior-a model of chronic pain induction. In agreement with previous reports on the effects of NMDA receptor antagonists in similar assays, the late phase seemed to be inhibited to a greater extent than the early phase. For all tested compounds, inhibition of formalin-induced behaviors occurred at dose levels that were also producing significant motor deficits (rotarod test). These results confirm low efficacy of acute administration of NMDA receptor antagonists in the models of established pain states. Thus, studies on the prevention and management of chronic pain should focus on preemptive or long-term administration of NMDA receptor antagonists.
Asunto(s)
Antagonistas de Aminoácidos Excitadores/uso terapéutico , Dolor/tratamiento farmacológico , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Animales , Enfermedad Crónica , Maleato de Dizocilpina/farmacología , Electrofisiología , Formaldehído , Aseo Animal/efectos de los fármacos , Ligadura , Masculino , Memantina/farmacología , Oocitos/efectos de los fármacos , Oocitos/metabolismo , Dimensión del Dolor/efectos de los fármacos , Equilibrio Postural/efectos de los fármacos , ARN Complementario/biosíntesis , Ratas , Ratas Wistar , Receptores de N-Metil-D-Aspartato/biosíntesis , Receptores de N-Metil-D-Aspartato/genética , Nervio Ciático/fisiología , Neuropatía Ciática/tratamiento farmacológico , Neuropatía Ciática/psicología , XenopusRESUMEN
The deprivation effect (DE)--an increase in the level of free-choice consumption of alcohol after a period of forced abstinence--may reflect relapselike drinking and be relevant for modeling alcohol abuse. However, the behavioral mechanisms of the DE are unclear. In these experiments, rats had unlimited free-choice access to water and saccharin-containing solutions and underwent repeated episodes of saccharin deprivation. It was found that DE magnitude correlates positively with the deprivation phase duration, expression of the DE is highly context dependent, and the DE can be prevented by extinguishing response to the saccharin-associated stimuli. Thus, DE procedures may be useful for studying the effects of continued exposure to stimuli associated with various primary reinforcers such as drugs of abuse.
Asunto(s)
Conducta Animal/efectos de los fármacos , Privación de Alimentos , Sacarina/farmacología , Análisis de Varianza , Animales , Asociación , Conducta Animal/fisiología , Conducta de Elección/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ambiente , Masculino , Ratas , Ratas Wistar , Edulcorantes/farmacología , Factores de TiempoRESUMEN
In humans and laboratory animals, drug withdrawal often is associated with depression-like behaviors. In the present study, rats had unlimited free-choice access to water and a saccharin-containing solution before being subjected to repeated episodes of saccharin deprivation. Saccharin deprivation (1) reduced immobility time in the forced swim test, (2) increased reinforcement rate in rats trained to lever-press under the differential reinforcement of a low-rate (72-sec) schedule of food reinforcement, and (3) lowered intracranial self-stimulation thresholds in a discrete-trial current titration procedure. Taken together, these findings suggest that deprivation from a nondrug reinforcer, saccharin, is not associated with depression-like behaviors. In contrast, saccharin-deprived rats demonstrated improved performance in the behavioral paradigms used here.