Receptores NMDA: fundamentos e implicaciones terapéuticas en el manejo del dolor / NMDA receptors: foundations and therapeutic implications in the management of pain

The NMDA receptors has been described in the development of acute pain and maintenance of chronic pain; the knowledge of physiological processes has led to the growing interest in NMDA receptors antagonists, demonstrating optimal analgesic results. Inhibition of NMDA receptors is an effective therapeutic alternative in the management of pain; with beneficial results in the management of acute postoperative pain, chronic and neuropathic pain. The current scientific challenge is to identify antagonists that perform a selective inhibition of receptor subunits, achieving optimal analgesic results. For this non-systemic review, a search of the available scientific evidence was made in databases (Pubmed/Medline, Science Direct, OVID, SciELO) through the use of keywords (Pain, NMDA receptors, antagonists, ketamine).

Los receptores NMDA han sido descritos en el desarrollo del dolor agudo y mantenimiento del dolor crónico; el conocimiento de los procesos fisiológicos ha llevado al creciente interés en los antagonistas de los receptores NMDA, demostrando resultados analgésicos óptimos. La inhibición de los receptores NMDA es una alternativa terapéutica eficaz en el manejo del dolor; con resultados benéficos en el manejo del dolor agudo postoperatorio, dolor crónico y neuropático. El reto científico actual es identificar antagonistas que realicen una inhibición selectiva de las subunidades del receptor, logrando óptimos resultados analgésicos. Para esta revisión no sistemática se realizó una búsqueda de la evidencia científica disponible en bases de datos (Pubmed/Medline, Science Direct, OVID, SciELO) mediante el uso de palabras clave (dolor, receptores NMDA, antagonistas, ketamina).

The role of NMDA receptor antagonists, amantadine and memantine, in schizophrenia treatment: a systematic review

Abstract Objective Schizophrenia is a complex and chronic psychiatric disorder. In recent years, studies have found glutamatergic system participation in its etiopathogenesis, especially through aberrant NMDA receptors functioning. Thus, drugs that modulate this activity, as amantadine and memantine, could theoretically be used in its treatment. To perform a systematic literature review about memantine and amantadine use as adjunct in schizophrenia treatment. Methods A systematic review of papers published in English indexed in the electronic database PubMed ® using the terms "memantine", "amantadine" and "schizophrenia" published until October 2016. Results We found 144 studies, 8 selected for analysis due to meet the objectives of this review. Some of these have shown benefits from such drug use, especially in symptoms measured by PANSS and its subdivisions, while others do not. Discussion: The data in the literature about these drugs use for schizophrenia treatment is still limited and have great heterogeneity. Thus, assay with greater robustness are needed to assess real benefits of these drugs as adjuvant therapy.

Subarachnoid injection of ifenprodil and ketamine association improves the anti-hyperalgesic action of ketamine in dogs / Injeção subaracnoidea da associação ifenprodil e cetamina melhora a ação anti-hiperalgésica da cetamina em cães

To test clinically whether a small dose of ifenprodil can enhance the anti-hyperalgesic effect of ketamine in dogs, a prospective randomized cross-over study was done with eight mongrel dogs (weighing 16.9 ± 3.7kg). Animals received two distinct treatments: ketamine (0.3mg kg-1; KT) and an ifenprodil plus ketamine combination (0.03mg kg-1 and 0.3mg kg-1, respectively; IKT). Dogs were anesthetized with propofol (5mg kg-1 intravenously) and a subarachnoid needle was placed between the 5th and 6th lumbar vertebrae. Five minutes after subarachnoid injection of KT or IKT, an incision including cutaneous and subcutaneous tissues was made on the common pad of one hind limb and was immediately closed with a simple interrupted suture pattern. The dogs were treated again 20 days later, using the contralateral pad and the opposite treatment. Sedation score (SS), lameness score (LS), heart rate (HR), respiratory rate (fR), and mechanical nociceptive threshold using von Frey filaments, were evaluated before anesthesia and at 1, 1.5, 2, 3, 4, 8, 12, and 24 hours after subarachnoid injection. There were no differences in SS, LS, HR or fR between treatments. The intensity of hyperalgesia was higher in KT than in IKT for 24 hours. The anti-hyperalgesic effect of IKT remained without statistical significant difference between 1 and 24 h. Prior subarachnoid administration of ifenprodil enhances the anti-hyperalgesic effect of subarachnoid ketamine in dogs. Ifenprodil can be co-administrated with ketamine to enhance its anti-hyperalgesic effect and to reduce acute post-incisional hyperalgesia without motor impairment and sedation.

Com a finalidade de testar se uma dose baixa de ifenprodil pode melhorar a ação anti-hiperalgésica da cetamina em cães, um estudo randomizado prospectivo no formato cross-over foi realizado em oito cães sem raça definida (pesando 16,9±3.7kg). Os animais receberam dois tratamentos distintos: cetamina (0,3mg kg-1; KT) e a associação de ifenprodil com cetamina (0,03mg kg-1 e 0,3mg kg-1, respectivamente; IKT). Os cães foram anestesiados com propofol (5mg kg-1, via intravenosa), e uma agulha subaracnoidea foi introduzida entre a quinta e sexta vértebras lombares. Após cinco minutos da injeção subaracnoidea de KT ou IKT, uma incisão abrangendo os tecidos cutâneo e subcutâneo foi realizada no coxim plantar comum de um dos membros pélvicos e imediatamente fechada com um padrão de sutura simples e interrompido. Os cães foram novamente tratados após 20 dias, usando-se o coxim plantar contralateral e o outro tratamento. Os escores de sedação (SS) e claudicação (LS); as frequências cardíacas (HR) e respiratória (fR) e o limiar nociceptivo ao estímulo mecânico, utilizando os filamentos de von Frey, foram avaliados antes da anestesia e uma, uma e meia; duas; três; quatro; oito; 12 e 24 horas após a injeção subaracnoidea. Não foram observadas diferenças significativas em SS, LS, HR ou na fR entre os tratamentos. A intensidade da hiperalgesia foi maior em KT que em IKT nas 24 horas. O efeito anti-hiperalgésico de IKT se manteve sem diferença significativa entre os tempos uma hora e 24 horas. A administração prévia de ifenprodil aumentou a ação anti-hiperalgésica da cetamina subaracnoidea em cães. O ifenprodil pode ser coadministrado com cetamina para aumentar seu efeito anti-hiperalgésico e reduzir a hiperlagesia aguda pós-incisional, sem alterações motoras e sedação.

Nuevos blancos terapéuticos en el tratamiento de las depresiones resistentes: Moduladores glutamatérgicos / New Therapeutic Targets in the Treatment of Resistant Depression: glutamatergic modulators

Dentro de los trastornos del estado de ánimo, los trastornos depresivos son padecimientos generalmente recurrentes que tienen, según las estadísticas, una prevalencia anual de un 3 % a un 6 % en la población. Desde la década de los 60' la hipótesis aminérgica de Schildkraut y posteriores, establecieron que las depresiones estaban vinculadas a alteraciones en la neurotransmisión catecolaminérgica y serotoninérgica. Los fármacos antidepresivos apuntaron a esas disfunciones pero las dificultades terapéuticas, retraso en el inicio de la acción y limitaciones en la eficacia, llevaron a la búsqueda de otras posibilidades, que surgieron de las investigaciones sobre la neurotransmisión glutamatérgica. En modelos animales se descubrió en los comienzos de los 90' la acción antidepresiva de los fármacos que antagonizaban la neurotransmisión de los receptores N-metil-D-aspartato (NMDA). El objetivo de este trabajo se orienta a establecer los fundamentos de la teoría glutamatérgica de las depresiones y a describir los fármacos que potencialmente podrían utilizarse en la clínica...

Depressive disorders are usually recurrent diseases that, according to statistics, afects from 3 % to 6 % of the population. Since the early '60s the Schildkraut aminergic hypothesis and subsequent, established that depressions were associated with alterations in cahtecolaminegic and serotonergic neurotransmission. Antidepressant drugs aimed at these dysfunctions but the therapeutic difficulties, delayed onset of action and efficacy limitations, led to the search of other possibilities that emerged from the research on glutamatergic neurotransmission. In animal models it was discovered in the early 90's the antidepressant action of drugs antagonized the NMDA receptor neurotransmission. The objective of this work is aimed at establishing the foundations of the glutamatergic theory of depressions and describe drugs that potentially could be used in the clinic...

Inibição do receptor de glutamato do tipo NMDA em um modelo de hipóxia-isquemia prenatal: avaliação morfofuncional do cerebelo / Inhibition of glutamate NMDA receptor in a prenatal hipoxia-ischemia model: morphofunctional analises of cerebellum

Lesões sistêmicas peri e pré-natais alteram o desenvolvimento do SNC, levando a problemas cognitivos e motores em crianças que podem perdurar por toda a vida. Um tipo particular de lesão é a hipóxia-isquemia (HI), caracterizada pela interrupção momentânea ou permanente do fluxo sanguíneo. Um dos mecanismos propostos para as lesões decorrentes da HI é a excitotoxicidade glutamatérgica. O uso de inibidores da neurotransmissão glutamatérgica tem sido estudados em diversos modelos de HI. Neste trabalho, avaliamos os efeitos morfofuncionais da administração de um antagonista não-competitivo do receptor de glutamato NMDA sobre o desenvolvimento do cerebelo. Ratas no 18º dia de gestação foram anestesiadas, os cornos uterinos expostos e as 4 artérias uterinas obstruídas por 45 minutos (Grupo H). Animais controle tiveram os úteros expostos, sem a obstrução (Grupo S). Após a cirurgia a gestação prosseguiu. Somente animais nascidos a termo foram utilizados. Um dia após o nascimento, metade de cada ninhada foi designada para receber MK801, 0,3mg/kg/dia, (grupos SM e HM) e a outra metade recebeu solução salina (grupos SS e HS), por 5 dias. Após anestesia e perfusão-fixação com paraformaldeído 4% aos 9, 23, 30 e 60 dias pós-natais, cortes parassagitais do cerebelo foram obtidos em criótomo e submetidos à imunohistoquímica para calbindina, GFAP, GLAST, PDGFRα e MBP. A partir de 45 dias de vida, os animais foram testados em vários de testes comportamentais: labirinto em cruz elevado (LCE), campo vazado (CV), ROTAROD, teste de caminhada sobre barras (ladder test) e teste do comprimento da passada (stride length). Aos 9 dias, a espessura da árvore dendrítica era menor nos animais SM, HS/HM, demonstrando efeitos deletérios tanto do MK801 quanto da HI. Menor número de células PDGFRα+ foi observado nos animais HS/HM, sem efeitos da administração de MK801. Aos 23 dias, maior número de células PDGFRα+ foi observado nos animais HM comparado aos outros 3 grupos, indicando efeito ...

Peri and prenatal systemic lesions alter CNS development leading to motor and cognitive problems in children that might persist throughout life. A particular kind of injury, the hypoxic ischemic (HI), is characterized by a permanent or temporary blockage of blood flow. One of the proposed mechanisms downstream from a HI event is called glutamatergic excitotoxicity. The administration of glutamate inhibitors has been studied in HI models for several years. In this work, we evaluated the effects of administration of a non-competitive antagonist of glutamate receptor, NMDA, on cerebellar development and behavioral tests of HI animals. Pregnant rats in the 18th gestational day were anesthetized, the uterine horns were exposed and the four uterine arteries were clamped for 45 minutes (group H). Sham controls had the uterine horns exposed, but no arteries were clamped (group S). Gestation proceeded after surgery. Only full term animals were used. One day after birth half the animals was assigned to receive either SALINE (groups SS and HS) or MK801 (groups SM and HM). Animals were anesthetized and perfused with 4% paraformaldehyde at 9, 23, 30 and 60 days of age. Parasagittal cerebellar sections were submitted to Calbindin, GFAP, GLAST, PDGFRα and MBP immunohistochemistry. Beginning at P45 animals were subjected to a battery of behavioral tests: elevated plus maze (EPM), hole board (HB), ROTAROD, ladder test and stride length. At P9 the dendritic tree of Purkinje cells were thinner in SM, HS/HM animals, indicating that both HI and MK801 are deleterious regarding this Purkinje cell differentiation. A lower number of PDGFRα+ cells was observed in HS/HM animals, with no effects of MK801 administration. At P23 a greater number of PDGFRα+ cells was found in HM animals when compared to the other 3 groups, demonstrating a neuroprotector effect of MK801. A lower number of myelinated fibers (MBP+) was observed in HS animals at P9, and MK801 administration reverse this ...

Ketamina, una antigua droga que renace ante el dolor: Parte II / Ketamine, an old drug coming back for pain management: Part II

Esta segunda parte trata el tema de la hiperalgesia, siguiendo el modelo de la hiperalgesia postoperatoria. Se sabe que a pesar del conocimiento de la neurofisiología del dolor, sigue teniendo una alta incidencia de dolor postoperatorio, dolor crónico postoperatorio y dolor crónico postraumático. En todas estas situaciones, la nocicepción del dolor está aumentada, dada principalmente por la presencia de hiperalgesia. Se sabe que su diagnóstico es difícil, pero es necesario sospecharla para tratarla precozmente y evitar las repercusiones negativas en el individuo. En la hiperalgesia existe activación de los receptores NMDA,se postula que al ser bloqueado por la ketamina, principal antagonista de estos receptores, se tendría menor hiperalgesia y, por ende, menor dolor.

This second part addresses hyperalgesia following the postoperative hyperalgesia model. It is well known that in spite of the wide knowledge regarding pain neurophysiology, it still has a great impact on postoperative pain, postoperative chronic pain and post traumatic chronic pain. In all those situations, pain nociception is increased mainly due to the presence of hyperalgesia. Diagnosing it is difficult, however, one should suspect it so to start treatment at an early stage and avoid negative consequences for patients. Hyperalgesia is present in NMDA receivers which, as some think, if blocked by Ketamine, the main antagonist of these receivers, hyperalgesia will be lessened, hence pain reduced.

NMDA receptor blockade alters the intracellular distribution of neuronal nitric oxide synthase in the superficial layers of the rat superior colliculus

Nitric oxide (NO) is a molecular messenger involved in several events of synaptic plasticity in the central nervous system. Ca2+ influx through the N-methyl-D-aspartate receptor (NMDAR) triggers the synthesis of NO by activating the enzyme neuronal nitric oxide synthase (nNOS) in postsynaptic densities. Therefore, NMDAR and nNOS are part of the intricate scenario of postsynaptic densities. In the present study, we hypothesized that the intracellular distribution of nNOS in the neurons of superior colliculus (SC) superficial layers is an NMDAR activity-dependent process. We used osmotic minipumps to promote chronic blockade of the receptors with the pharmacological agent MK-801 in the SC of 7 adult rats. The effective blockade of NMDAR was assessed by changes in the protein level of the immediate early gene NGFI-A, which is a well-known NMDAR activity-dependent expressing transcription factor. Upon chronic infusion of MK-801, a decrease of 47 percent in the number of cells expressing NGFI-A was observed in the SC of treated animals. Additionally, the filled dendritic extent by the histochemical product of nicotinamide adenine di-nucleotide phosphate diaphorase was reduced by 45 percent when compared to the contralateral SC of the same animals and by 64 percent when compared to the SC of control animals. We conclude that the proper intracellular localization of nNOS in the retinorecipient layers of SC depends on NMDAR activation. These results are consistent with the view that the participation of NO in the physiological and plastic events of the central nervous system might be closely related to an NMDAR activity-dependent function.

Receptor antagonist of NMDA and animal models of schizophrenia / 法医学杂志

Schizophrenia is one of the common mental diseases. Because the mechanism of the schizophrenia is significantly complicated, the cause is still unknown. N-methyl-D-aspartate receptor antagonist can simulate the positive and negative symptoms, as well as the cognitive disorder of schizophrenia. Thus it has been widely used to establish the animal models of schizophrenia. The relationship of the three blocking agents of ion channels (phencyclidine, MK-801, ketamine) and the establishment of schizophrenia animal models is reviewed in this article.

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

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

Topography and axon arbor architecture in the visual callosal pathway: effects of deafferentation and blockade of TV-methyl-D-aspartate receptors

Visual callosal fibers link cortical loci in opposite hemispheres that represent the same visual field but whose locations are not mirror-symmetric with respect to the brain midline. Presence of the eyes from postnatal day 4 (P4) to P6 is required for this map to be specified. We tested the hypothesis that specification of the callosal map requires the activation of A'-methyl-D-aspartate receptors (NMDARs). Our results show that blockade of NMDARs with MK-801 during this critical period did not induce obvious abnormalities in callosal connectivity patterns, suggesting that retinal influences do not operate through NMDAR-mediated processes to specify normal callosal topography. In contrast, we found that interfering with NMDAR function either through MK801-induced blockade of NMDARs starting at P6 or neonatal enucleation significantly increases the length of axon branches and total length of arbors, without major effects on the number of branch tips. Our results further suggest that NMDARs act by altering the initial elaboration of arbors rather than by inhibiting a later-occurring remodeling process. Since the callosal map is present by P6, just as axonal branches of simple architecture grow into gray matter, we suggest that regulation of arbor development by NMDAR-mediated processes is important for maintaining the precision of this map.

Influence of NMDA and non-NMDA antagonists on acute and inflammatory pain in the trigeminal territory: a placebo control study / Influência dos antagonistas dos receptores NMDA e não-NMDA sobre a dor aguda e inflamatória ao nível do território do trigêmeo: um estudo placebo controlado

NMDA and non-NMDA receptors are involved in spinal transmission of nociceptive information in physiological and pathological conditions. Our objective was to study the influence of NMDA and non-NMDA receptor antagonists on pain control in the trigeminal system using a formalin-induced orofacial pain model. Motor performance was also evaluated. Male Rattus norvegicus were pre-treated with topiramate (T) (n=8), memantine (M) (n=8), divalproex (D) (n=8) or isotonic saline solution (ISS) (n=10) intraperitoneally 30 minutes before the formalin test. Formalin 2.5 percent was injected into the right upper lip (V2 branch) and induced two phases: phase I (early or neurogenic) (0-3 min) and phase II (late or inflammatory) (12-30 min). For motor behavior performance we used the open-field test and measured latency to movement onset, locomotion and rearing frequencies, and immobility time. Pre-treatment of animals with M and D only attenuated nociceptive formalin behavior for phase II. T increased locomotion and rearing frequencies and reduced immobility time. Treatment with M increased immobility time and with D reduced locomotion frequency. Our results showed that the NMDA antagonist (M) is more potent than the non-NMDA antagonists (D and T) in the control of pain in the inflammatory phase. The non-NMDA topiramate improved motor performance more than did D and M, probably because T has more anxiolytic properties.

Receptores NMDA e não-NMDA estão envolvidos na transmissão das informações nociceptivas em condições fisiológicas e patológicas. Com o objetivo de estudar a influência dos antagonistas dos receptores NMDA e não-NMDA sobre o controle de dor no sistema trigeminal utilizamos modelo de dor orofacial induzida pela formalina. Testes de desempenho motor foram também avaliados. Ratos machos da espécie Rattus norvegicus foram tratados com topiramato (T) (n=8), memantina (M) (n=8), divalproato de sódio (D) (n=8) ou solução salina isotônica (SSI) (n=10), por via intraperitoneal, 30 minutos antes dos testes com a formalina. Formalina 2.5 por cento foram injetadas na região do lábio superior dos animais (segundo ramo do trigêmeo) induzindo comportamento em duas fases distintas: fase I (precoce ou neurogênica) (0-3 min ) e fase II (tardia ou inflamatória) (12-30 min). Para avaliação da atividade motora utilizou-se o teste do campo aberto mensurando-se a latência para o início dos movimentos, número de casas andadas, freqüência de levantamentos e tempo de imobilidade. Animais pré-tratados com M e D atenuaram a fase inflamatória do teste da formalina. O T aumenta o número de casas andadas, freqüência de levantamentos e reduz o tempo de imobilidade. Nossos resultados mostram que o antagonista NMDA é mais potente do que os antagonistas não-NMDA para o controle da fase inflamatória da dor. O topiramato entretanto aumenta a atividade motora provavelmente porque apresente propriedades ansiolíticas.

Possible involvement of nitric oxide (NO) signaling pathway in the antidepressant-like effect of MK-801(dizocilpine), a NMDA receptor antagonist in mouse forced swim test.

L-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) is an important signaling pathway involved in depression. With this information, the present study aimed to study the involvement of this signaling pathway in the antidepressant-like action of MK-801 (dizocilpine; N-methyl-d-aspartate receptor antagonist) in the mouse forced-swim test. Total immobility period was recorded in mouse forced swim test for 6 min. MK-801 (5-25 microg/kg., ip) produced a U-shaped curve in reducing the immobility period. The antidepressant-like effect of MK-801 (10 microg/kg, ip) was prevented by pretreatment with L-arginine (750 mg/kg, ip) [substrate for nitric oxide synthase (NOS)]. Pretreatment of mice with 7-nitroindazole (7-NI) (25 mg/kg, ip) [a specific neuronal nitric oxide synthase inhibitor] produced potentiation of the action of subeffective dose of MK-801 (5 microg/kg, ip). In addition, treatment of mice with methylene blue (10 mg/kg, ip) [direct inhibitor of both nitric oxide synthase and soluble guanylate cyclase] potentiated the effect of MK-801 (5 microg/kg, ip) in the forced-swim test. Further, the reduction in the immobility period elicited by MK-801 (10 microg/kg, ip) was also inhibited by pretreatment with sildenafil (5 mg/kg, ip) [phosphodiesterase 5 inhibitor]. The various modulators used in the study and their combination did not produce any changes in locomotor activity per se and in combination with MK-801. MK-801 however, at higher doses (25 microg/kg, ip) produced hyperlocomotion. The results demonstrated the involvement of nitric oxide signaling pathway in the antidepressant-like effect of MK-801 in mouse forced-swim test.

Efficacy of memantine in acute non-arteritic ischemic optic neuropathy

Evaluation of efficacy of Memantine [N-Methyl-D-Aspartate Receptor Antagonist] on visual function of patients with acute non-arteritic ischemic optic neuropathy [NAION]. The study was conducted as interventional case series from November 2005 through November 2006 in Farabi Eye Hospital. Twenty-two patients with acute NAION of less than 8 weeks duration entered the study. Memantine was prescribed with a dose of 5 mg per day for the first week and 10 mg per day for the following two weeks. Baseline best corrected visual acuity [BCVA]; visual evoked potential [VEP] and visual field was done for all patients. BCVA recording repeated 3 weeks, 3 and 6 months later. VEP and perimetry repeated 3 months after treatment. After 3 weeks, 3 and 6 months, BCVA improved -0.32 +/- 0.40 LogMAR, -0.51 +/- 0.49 and -0.51 +/- 0.49, respectively [P=0.005, P=0.001 and P=0.001, respectively]. VEP recordings after 3 months, demonstrated -8.61 +/- 14.51 db mean decrease in implicit time [P=0.019]. Amplitude of voltage did not show significant difference with baseline [P=0.10]. Perimetry results after 3 months showed that mean deviation [MD] improved 2.77 +/- 3.94 db [P=0.016]. Memantine resulted in significant improvement of BCVA 3 weeks, 3 and 6 months after treatment of acute NAION. Memantine also resulted in significant decrease of implicit time and significant improvement of mean deviation in VEP and perimetry after 3 months

The Role of NMDA Receptor Antagonists in Nicotine Tolerance, Sensitization, and Physical Dependence: A Preclinical Review

Nicotine, the primary psychoactive component of tobacco products, produces diverse neurophysiological, motivational, and behavioral effects through several brain regions and neurochemical pathways. Various neurotransmitter systems have been explored to understand the mechanisms behind nicotine tolerance, dependence, and withdrawal. Recent evidence suggests that glutamate neurotransmission has an important role in this phenomenon. The aim of the present review is to discuss preclinical findings concerning the role of N-methyl-D-aspartate (NMDA) receptor neurotransmission in mediating the behavioral effects of nicotine, tolerance, sensitization, dependence, and withdrawal. Based on preclinical findings, it is hypothesized that NMDA receptors mediate the common adaptive processes that are involved in the development, maintenance, and expression of nicotine addiction. Modulation of glutamatergic neurotransmission with NMDA receptor antagonists may prove to be useful in alleviating the symptoms of nicotine abstinence and facilitate tobacco-smoking cessation.

Effects of dextromethorphan on dopamine dependent behaviours in rats.

Dextromethorphan, a noncompetitive blocker of N-methyl-D- aspartate (NMDA) type of glutamate receptor, at 7.5-75 mg/kg, ip did not induce oral stereotypies or catalepsy and did not antagonize apomorphine stereotypy in rats. These results indicate that dextromethorphan at 7.5-75 mg/kg does not stimulate or block postsynaptic striatal D2 and D1 dopamine (DA) receptors. Pretreatment with 15 and 30 mg/kg dextromethorphan potentiated dexamphetamine stereotypy and antagonised haloperidol catalepsy. Pretreatment with 45, 60 and 75 mg/kg dextromethorphan, which release 5-hydroxytryptamine (5-HT), however, antagonised dexamphetamine stereotypy and potentiated haloperidol catalepsy. Apomorphine stereotypy was not potentiated or antagonised by pretreatment with 7.5-75 mg/kg dextromethorphan. This respectively indicates that at 7.5-75 mg/kg dextromethorphan does not exert facilitatory or inhibitory effect at or beyond the postsynaptic striatal D2 and D1 DA receptors. The results are explained on the basis of dextromethorphan (15-75 mg/kg)-induced blockade of NMDA receptors in striatum and substantia nigra pars compacta. Dextromethorphan at 15 and 30 mg/kg, by blocking NMDA receptors, activates nigrostriatal dopaminergic neurons and thereby potentiates dexampetamine stereotypy and antagonizes haloperidol catalepsy. Dextromethorphan at 45, 60 and 75 mg/kg, by blocking NMDA receptors, releases 5-HT and through the released 5-HT exerts an inhibitory influence on the nigrostriatal dopaminergic neurons with resultant antagonism of dexampetamine stereotypy and potentiation of haloperidol catalepsy.

Modelos fisiopatológicos de la esquizofrenia; de dopamina a glutamato, de glutamato a GABA / Pathophysiologycal models of schizophrenia; from dopamine to glutamate, and glutamate to GABA

A pesar de los avances en el conocimiento de las bases biológicas de la conducta, los mecanismos neurobiológicos precisos involucrados en la esquizofrenia permanecen desconocidos. Como consecuencia de esto las terapias farmacológicas actuales descansan más sobre bases empíricas que sobre explicaciones fisiopatológicas. En el presente trabajo se propone un modelo de la esquizofrenia que podría ser de utilidad en el diseño de nuevas estrategias terapéuticas. Este modelo intenta integrar recientes hallazgos neuropsicológicos y de neuroimagen con lo que hoy sabemos respecto a la biología del desarrollo y plasticidad cerebral normal. Se propone que la esquizofrenia es una enfermedad del neurodesarrollo caracterizada por una neurotransmisión glutamatérgica inadecuadamente modulada a consecuencia de la disfunción de interneuronas GABAérgicas en múltiples regiones del cerebro. Anormalidades sutiles en el balance entre GABA y Glutamato explicarían los defectos en la cognición, la conducta social y la coordinación motora reportados en las etapas pre-psicóticas de la esquizofrenia. Más tarde en la historia natural de la enfermedad, estados hiperglutamatérgicos desencadenados por la incrementada neurotransmisión dopaminérgica propia de la peri-adolescencia y adultez temprana llevarían a la psicosis. Esta excesiva actividad glutamatérgica conduciría a su vez a las reducciones progresivas en sustancia gris y blanca observadas en recientes estudios prospectivos. En apoyo a esta hipótesis, se describen estudios propios y de otros laboratorios con pacientes esquizofrénicos, así como en un modelo animal de exposición intermitente a fenciclidina. Como corolario, drogas moduladoras de la neurotransmisión glutamatérgica, tales como acamprosato y lamotrigina, son propuestas como estrategias terapéuticas potencialmente utilizables en las etapas tempranas de la esquizofrenia.

Neuroprotective agents in acute ischemic stroke.

The concept of neuroprotection relies on the principle that delayed neuronal injury occurs after ischemia. The phenomenon of the "ischemic cascade" has been described, and each step along this cascade provides a target for therapeutic intervention. A wide variety of drugs have been studied in humans. Ten classes of neuroprotective agents have reached phase III efficacy trials but have shown mixed results. They included calcium channel antagonists, NMDA receptor antagonists, lubeluzole, CDP-choline, the free radical scavenger tirilazad and ebselen, enlimomab, GABA agonist clomethiazole, the sodium channel antagonist fosphenytoin, magnesium, glycine site antagonist GV150526 and piracetam. Furthermore, the mechanisms that underlie the development of focal ischemic injury continue to be discovered, opening new therapeutic perspective for neuroprotection that might clinically be applicable in the future.

Effect of fluvoxamine and N-methyl-D-aspartate receptor antagonists on shock-induced depression in mice.

We have earlier demonstrated that NMDA receptor antagonists possess antidepressant effect and also they show a synergism with imipramine. The present study attempts to investigate whether NMDA receptor antagonists also interact with selective serotonin reuptake inhibitors. The study was conducted in albino mice using shock-induced depression model. The mice were placed on a grid floor and shock delivered were of 2 sec duration with a 9 sec interval for 1 h. Twenty four hours later depression was measured by an open field test followed by a forced swimming test. Presentation of inescapable foot shock significantly reduced ambulation (from 159.50 +/- 5.42 to 80.50 +/- 4.61) and rearing (from 22.10 +/- 2.15 to 11.30 +/- 1.32) in the open field arena and increased immobility duration in the forced swimming test (from 82.20 +/- 3.51 to 158.90 +/- 4.61). Pretreatment with fluvoxamine, MK-801, ketamine and the combination of fluvoxamine with either of the NMDA antagonists antagonised shock-induced depression. Haloperidol and ketanserin pretreatment modified the effect of these agents. These findings suggest an interaction of NMDA receptor antagonists with fluvoxamine, and an involvement of brain dopaminergic and tryptaminergic mechanisms in the behavioural suppression observed after inescapable foot shock.