RESUMEN
BACKGROUND: α2-Adrenoceptor agonists are used frequently in human and veterinary anesthesia as sedative/analgesic drugs. However, they can impair cognition. Little is known about the concentration-dependent effects of α2-adrenoceptor agonists on synaptic plasticity, the neurophysiological basis of learning and memory. Therefore, we investigated the effects of different concentrations of medetomidine, an α2-adrenoceptor agonist, on basal excitatory synaptic transmission and on 2 forms of synaptic plasticity: paired-pulse facilitation (PPF) and long-term potentiation (LTP). METHODS: Evoked field excitatory postsynaptic potentials were recorded in Schaffer fibers-CA1 pyramidal cell synapses of mouse hippocampal slices, and the initial field excitatory postsynaptic potentials slope was measured. For basal synaptic transmission and PPF, increasing concentrations of medetomidine (1-200 µM) were applied to each slice. For LTP experiments, individual slices were used for each tested concentration of medetomidine (0.1-0.4 µM), where LTP induction and LTP maintenance were measured. RESULTS: The lower tested concentrations of medetomidine decreased LTP in a concentration-dependent manner, whereas greater concentrations were required to decrease fiber volley amplitude and basal excitatory synaptic transmission. PPF was only affected by the greatest concentration (200 µM). CONCLUSIONS: Medetomidine decreased LTP in the mouse hippocampus, in accordance with the ability of medetomidine to induce memory deficits.
Asunto(s)
Agonistas de Receptores Adrenérgicos alfa 2/farmacología , Región CA1 Hipocampal/efectos de los fármacos , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Medetomidina/farmacología , Plasticidad Neuronal/efectos de los fármacos , Células Piramidales/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Agonistas de Receptores Adrenérgicos alfa 2/toxicidad , Factores de Edad , Animales , Región CA1 Hipocampal/citología , Región CA1 Hipocampal/fisiología , Relación Dosis-Respuesta a Droga , Potenciales Evocados/efectos de los fármacos , Femenino , Técnicas In Vitro , Depresión Sináptica a Largo Plazo/efectos de los fármacos , Medetomidina/toxicidad , Memoria/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Células Piramidales/fisiología , Factores de TiempoRESUMEN
Ketamine is frequently used to induce analgesia or anesthesia in laboratory animals, but its effects on learning and memory are poorly characterized. Long-term potentiation (LTP) is considered a cellular mechanism for learning and memory. Ketamine administration immediately abolishes hippocampal LTP in vivo, but whether this effect persists is not known. The authors administered one of two doses of ketamine to adult male C57BL/6 mice and measured LTP in hippocampal slices from the mice 24 h later. Neither LTP induction nor LTP maintenance differed significantly in mice that were administered ketamine compared with mice that were administered saline. The findings suggest that a single intraperitoneal dose of ketamine does not persistently alter LTP in adult male mice.
Asunto(s)
Anestesia/veterinaria , Hipocampo/efectos de los fármacos , Ketamina/farmacología , Potenciación a Largo Plazo/efectos de los fármacos , Animales , Estimulación Eléctrica , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Ketamine, an analgesic/anesthetic drug, is increasingly popular in clinical practice due to its analgesic properties and importance for emergency procedures. The impact of ketamine on basal excitatory synaptic transmission and synaptic plasticity are not yet fully understood. Therefore we investigated the effects of different concentrations of ketamine on basal excitatory synaptic transmission and on two forms of synaptic plasticity: paired-pulse facilitation (PPF) and long-term potentiation (LTP). Evoked field excitatory postsynaptic potentials (fEPSP) were recorded in Schaffer fiber - CA1 pyramid synapses of mouse hippocampal slices and the initial slope of the fEPSP was measured to estimate the percentage of inhibition of the basal synaptic transmission. Presynaptic volley amplitude, PPF and LTP induction and maintenance were also calculated. For basal synaptic transmission and PPF increasing concentrations of ketamine (1, 3, 10, 30, 100, 200, 300 and 600µM) were applied to each slice and for LTP individual slices were used for each concentration (3, 10, 30 or 100µM). Clinically relevant concentrations of ketamine decreased LTP in a concentration-dependent manner without changing PPF, whereas basal excitatory synaptic transmission and presynaptic volley amplitude was affected only with high concentrations of ketamine (300 and 600µM). These results allow dissociating the blockade of LTP from a reduced synaptic input in the action of clinically relevant concentrations of ketamine in the CA1 region of the mouse hippocampus. Moreover, this work shows that the effects of ketamine on LTP and on basal synaptic transmission are dependent of the concentration used.
Asunto(s)
Anestésicos/farmacología , Hipocampo/efectos de los fármacos , Ketamina/farmacología , Potenciación a Largo Plazo/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Vías Aferentes/efectos de los fármacos , Vías Aferentes/fisiología , Animales , Región CA1 Hipocampal/efectos de los fármacos , Región CA1 Hipocampal/fisiología , Región CA3 Hipocampal/efectos de los fármacos , Región CA3 Hipocampal/fisiología , Relación Dosis-Respuesta a Droga , Estimulación Eléctrica , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Femenino , Hipocampo/fisiología , Ratones Endogámicos BALB C , Microelectrodos , Plasticidad Neuronal/fisiología , Terminales Presinápticos/efectos de los fármacos , Terminales Presinápticos/fisiología , Células Piramidales/efectos de los fármacos , Células Piramidales/fisiología , Técnicas de Cultivo de TejidosRESUMEN
BACKGROUND: Ketamine is an anaesthetic and analgesic drug used in research and clinical practice. Little is known about the effects of different doses of this drug on memory and brain cellular death. OBJECTIVE: To study the effects of different doses of ketamine on working and reference memory, and neurodegeneration in adult mice. DESIGN: A randomised study. SETTINGS: The study was carried out in a basic science laboratory, between March 2011 and August 2012. ANIMALS: Forty-eight 7-month-old, male C57BL/6 mice were used. INTERVENTION: Animals received a single intraperitoneal injection of physiological saline solution or one of three doses of ketamine (25, 75 or 150 mg kg(-1)). Each group consisted of 12 animals (seven animals for behavioural tests and five animals for histopathological and immunohistochemical studies). The animals used for histopathology studies were sacrificed 3 h after anaesthesia. MAIN OUTCOME MEASURES: Working and reference memories were assessed using the radial-maze test over 12 consecutive days. The equilibrium was tested using the vertical pole (4 and 24 h after injection), whereas locomotion was assessed using the open field (24, 48 and 72 h after injection). Histopathological (haematoxylin-eosin staining) and immunohistochemical analyses (procaspase-3 and activated caspase-3 detections) were performed 3 h after injection to assess neurodegeneration in the retrosplenial and visual cortices, pyramidal cell layer of the cornu Ammonis 1 and cornu Ammonis 3 areas of the hippocampus, in the granular layer of the dentate gyrus, in the laterodorsal thalamic nucleus, striatum and accumbens nucleus. RESULTS: No significant differences were observed between the groups regarding the number of dead cells and cells showing positive immune-reactivity in the different regions of the brain studied. The performance in the vertical pole test and the number of reference and working memory errors in the radial-maze were similar in all groups. Nevertheless, the animals treated with ketamine 75 mg kg(-1) were transiently more active, walking a greater total distance at a greater speed in the open field than other groups (power of 0.96). CONCLUSION: These data indicate that a single intraperitoneal injection of ketamine at subanaesthetic and anaesthetic doses does not impair working memory, reference memory or neurodegeneration in adult mice, but an intermediate dose of ketamine produces transitory hyperlocomotion.
Asunto(s)
Anestésicos Disociativos/administración & dosificación , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Ketamina/administración & dosificación , Memoria a Corto Plazo/efectos de los fármacos , Degeneración Nerviosa , Memoria Espacial/efectos de los fármacos , Animales , Encéfalo/patología , Encéfalo/fisiopatología , Inyecciones Intraperitoneales , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Factores de TiempoRESUMEN
Anesthetics, such as the ketamine/midazolam combination, are used in research with animals and in human clinical practice; thus, it is essential to clarify the potential effects of these anesthetics on memory. This study aimed to evaluate how a low dose of the ketamine/midazolam combination affects the acquisition, consolidation, or recall of a spatial memory task. Thirty-three adult male C57BL/6 mice were divided into four treatment groups: unanesthetized control animals and three groups of animals treated with 40 mg/kg of ketamine and 10mg/kg of midazolam administered in a single intraperitoneal injection. The different treatment groups received the same anesthetic dose at different time points, to study the acquisition, consolidation, and recall of spatial memory in the Y-maze task. The percentage of correct choices was measured. Six mice were killed 4 days and 12 days after anesthesia for histopathological analyses. There were no differences between treatment and control groups regarding the acquisition of spatial memory, measured as the slope of the learning curve, or in the percentage of correct choices in the consolidation or recall periods of the task. Similarly, no differences were detected between groups regarding the number of cells per square millimeter in the visual and retrosplenial cortex, in the dentate gyrus, and in the CA1 and CA3 regions of the hippocampus. Hence, a low dose of the ketamine/midazolam combination did not impair memory processes or brain integrity in adult mice, suggesting that this combination is unlikely to cause cognitive complications.
Asunto(s)
Anestésicos/farmacología , Ketamina/farmacología , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Memoria/efectos de los fármacos , Midazolam/farmacología , Conducta Espacial/fisiología , Animales , Encéfalo/citología , Encéfalo/efectos de los fármacos , Encéfalo/fisiología , Conducta de Elección/efectos de los fármacos , Conducta de Elección/fisiología , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Ratones Endogámicos C57BL , Conducta Espacial/efectos de los fármacosRESUMEN
BACKGROUND: Volatile anesthetics such as isoflurane are widely used in clinical and research contexts. Concerns have been raised that the effects of these drugs on the central nervous system may result in long-term impairment after surgery or general anesthesia. Hence, this study aimed to detect how different isoflurane concentrations influence spatial learning and cell death in adult mice. METHODS: Fifty-two C57BL/6 mice were randomly divided in four groups. Mice in three groups were exposed to different concentrations of isoflurane (1, 1.5, and 2%) for 1 h; the control group was not exposed to anesthesia. Five mice per group were killed 3 h after anesthesia to perform histopathologic and immunohistochemical analyses (hematoxylin-eosin staining; caspase-3 activation). Eight mice per group were used for behavioral tests (open field, T-maze spontaneous alternation, and water maze) on subsequent days. RESULTS: There were no differences between groups in the T-maze spontaneous alternation test or in the open field (no confounding effects of stress or locomotion). The group anesthetized with 1% isoflurane performed worse in the water maze task on day 1 (550.4 ±162.78 cm) compared with the control group (400.1 ± 112.88 cm), 1.5% isoflurane (351.9 ± 150.67 cm), and 2% isoflurane (364.5 ± 113.70 cm; P ≤ 0.05) and on day 3 (305.0 ± 81.75 cm) compared with control group (175.13 ± 77.00 cm) and 2% isoflurane (204.11 ± 85.75 cm; P ≤ 0.038). In the pyramidal cell layer of the region cornu ammonis 1 of the hippocampus, 1% isoflurane showed a tendency to cause more neurodegeneration (apoptosis) (61.4 ± 26.40, profiles/mm) than the group with 2% of isoflurane (20.6 ± 17.77, profiles/mm; P = 0.051). CONCLUSION: Low isoflurane concentration (1%) caused spatial learning impairment and more neurodegeneration compared with higher isoflurane concentrations. Results for mice receiving the latter concentrations were similar to those of control mice.