RESUMEN
OBJECTIVE: Resistance at the brain receptors for leptin and insulin has been associated with increased feeding, obesity and cognitive impairments. The causal agent for central resistance is unknown but could be derived from the blood. Here we postulate whether hypertriglyceridemia, the major dyslipidemia of the metabolic syndrome, could underlie central leptin and insulin resistance. DESIGN: We used radioactively labeled triglycerides to measure blood-brain barrier (BBB) penetration, western blots to measure receptor activation, and feeding and cognitive tests to assess behavioral endpoints. RESULTS: Human CSF was determined to contain triglycerides, a finding previously unclear. The radioactive triglyceride triolein readily crossed the BBB and centrally administered triolein and peripherally administered lipids induced in vivo leptin and/or insulin resistance at hypothalamic receptors. Central triolein blocked the satiety effect of centrally administered leptin. Decreasing serum triglycerides with gemfibrozil improved both learning and memory inversely proportionate to triglyceride levels. CONCLUSIONS: Triglycerides cross the blood-brain barrier rapidly, are found in human cerebrospinal fluid, and induce central leptin and insulin receptor resistance, decreasing satiety and cognition.
Asunto(s)
Antígenos CD/metabolismo , Barrera Hematoencefálica/metabolismo , Resistencia a la Insulina/fisiología , Leptina/metabolismo , Receptor de Insulina/metabolismo , Triglicéridos/metabolismo , Anciano , Animales , Cognición/efectos de los fármacos , Femenino , Gemfibrozilo/farmacología , Humanos , Leptina/farmacología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Respuesta de Saciedad/efectos de los fármacos , Triglicéridos/sangre , Triglicéridos/líquido cefalorraquídeo , Trioleína/metabolismo , Trioleína/farmacologíaRESUMEN
SAMP8/TaJf(P8) mouse strain has an inherited age-related impairment of learning and memory with its onset relatively early in its lifespan. Previously, it was reported that cholinergic and glutamatergic drugs injected into the hippocampus after behavioral training showed considerable shifts in the dose that improved retention in mice at 12 compared to 4 months of age. Cholinergic neurons in the septum supply most of the acetylcholine released in the hippocampus. In the present study, we determined if altered functional status of neurotransmission in the septum might account for the decrease in cholinergic and glutamatergic activity in the hippocampus of older SAMP8 mice. After training on footshock avoidance, P8 mice received a drug injection into the septum. Retention was tested 1 week later. The results indicate that bicuculline, GABA-A, and saclofen, GABA-B, receptor antagonist had to be injected at a higher dose in 12- than in 4-month-old mice to improve retention. The serotonergic antagonists, ketanserin and methiothepin, both showed dose response shifts such that less drug was needed to improve retention in 12- as compared to 4-month-old mice. It required four times more L-glutamate to improve retention in 12- than in 4-month-old mice. Agonists for acetylcholine, dopamine and norepinephrine receptors or an opiate antagonist required little or no change in the dose needed to improve retention in older P8 mice. SAMP8 mice may show an age-related impairment of septohippocampal functioning.
Asunto(s)
Envejecimiento/metabolismo , Ácido Glutámico/metabolismo , Receptores de GABA-A/metabolismo , Receptores de GABA-B/metabolismo , Receptores de Serotonina/metabolismo , Animales , Antagonistas de Receptores de GABA-A , Antagonistas de Receptores de GABA-B , Ratones , Neurotransmisores/metabolismo , Antagonistas de la Serotonina/farmacologíaRESUMEN
The senescence-accelerated mouse (SAM) is a murine model of accelerated senescence that was established using phenotypic selection. The SAMP series includes nine substrains, each of which exhibits characteristic disorders. SAMP8 is known to exhibit age-dependent learning and memory deficits. In our previous study, we reported that brains from 12-month-old SAMP8 have greater protein oxidation, as well as lipid peroxidation, compared with brains from 4-month-old SAMP8 mice. In order to investigate the relation between age-associated oxidative stress on specific protein oxidation and age-related learning and memory deficits in SAMP8, we used proteomics to identify proteins that are expressed differently and/or modified oxidatively in aged SAMP8 brains. We report here that in 12 month SAMP8 mice brains the expressions of neurofilament triplet L protein, lactate dehydrogenase 2 (LDH-2), heat shock protein 86, and alpha-spectrin are significantly decreased, while the expression of triosephosphate isomerase (TPI) is increased compared with 4-month-old SAMP8 brains. We also report that the specific protein carbonyl levels of LDH-2, dihydropyrimidinase-like protein 2, alpha-spectrin and creatine kinase, are significantly increased in the brain of 12-month-old SAMP8 mice when compared with the 4-month-old SAMP8 brain. These findings are discussed in reference to the effect of specific protein oxidation and changes of expression on potential mechanisms of abnormal alterations in metabolism and neurochemicals, as well as to the learning and memory deficits in aged SAMP8 mice.
Asunto(s)
Envejecimiento/metabolismo , Encéfalo/metabolismo , Regulación de la Expresión Génica/fisiología , Estrés Oxidativo/fisiología , Proteínas/metabolismo , Envejecimiento/genética , Animales , Western Blotting/métodos , Electroforesis en Gel Bidimensional/métodos , Masculino , Espectrometría de Masas/métodos , Ratones , Ratones Endogámicos , Ratones Mutantes Neurológicos , Proteómica/métodosRESUMEN
Dehydroepiandrosterone sulfate (DHEAS) improves memory retention when administered peripherally. Estrone-3-O-sulfamate (EMATE), a steroid sulfatase inhibitor, potentiates the effect of DHEAS on memory retention such that lower doses of DHEAS improve memory retention. It is not clear if this effect is mediated by both compounds entering the central nervous system. In the current studies, mice were trained to avoid footshock in a T-maze and memory retention was tested 1 week later. DHEAS, injected into the hippocampus after training, improved memory retention in a dose-dependent manner. In previous studies, pregnenolone sulfate (PREGS) improved memory retention when injected into the hippocampus. EMATE, administered peripherally, potentiated the effect of centrally administered DHEAS on memory retention. However, EMATE did not potentiate the effect of centrally administered PREGS. It was concluded that EMATE, acting peripherally, increased plasma levels of DHEAS which entered the brain and added to the effect of centrally administered DHEAS. The failure of EMATE to potentiate PREGS is discussed.
Asunto(s)
Arilsulfatasas/antagonistas & inhibidores , Sulfato de Deshidroepiandrosterona/farmacología , Inhibidores Enzimáticos/farmacología , Estrona/análogos & derivados , Hipocampo/efectos de los fármacos , Pregnenolona/farmacología , Retención en Psicología/efectos de los fármacos , Animales , Reacción de Prevención/efectos de los fármacos , Mapeo Encefálico , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Estrona/farmacología , Inyecciones , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Esteril-SulfatasaRESUMEN
The decrease in the insulin cerebrospinal fluid/serum ratio seen in Alzheimer's disease has been suggested as a mechanism by which brain glucose utilization could be perturbed. Insulin is transported across the blood-brain barrier (BBB) by a system that is altered by pathophysiological events. We used SAMP8 mice, a strain that by 8-12 months of age develops severe deficits in learning and memory, to determine whether the insulin transporter or BBB integrity was altered with aging. BBB integrity was measured by injecting radioactive albumin intravenously, washing out the vascular space up to 17 hours later, and measuring brain/serum ratios. This very sensitive method found no increase in the permeability of the BBB to albumin in young and aged SAMP8 mice. This compares with previous studies in humans with Alzheimer's disease and in other colonies of SAMP8 mice that have found evidence for BBB disruption. For radioactively labeled insulin, we used multiple-time regression analysis to measure both the unidirectional influx rate (Ki) and the reversible binding to brain endothelium (Vi). A non-significant decrease in the transport rate for whole brain occurred in aged SAMP8 mice. Ki and Vi values significantly varied among brain regions and the Ki for the thalamus and the Vi for the cerebellum and thalamus were higher in aged mice. We conclude that alterations in BBB integrity or the activity of the BBB insulin transporter do not underlie the deficits in learning and memory seen in the aged SAMP8 mouse.
Asunto(s)
Envejecimiento/metabolismo , Barrera Hematoencefálica/fisiología , Permeabilidad Capilar , Insulina/metabolismo , Discapacidades para el Aprendizaje/metabolismo , Trastornos de la Memoria/metabolismo , Albúmina Sérica/metabolismo , Animales , Transporte Biológico/fisiología , Insulina/sangre , Discapacidades para el Aprendizaje/genética , Trastornos de la Memoria/genética , Ratones , Ratones MutantesRESUMEN
Previously, calcitonin gene-related peptide (CGRP) decreased food intake when administered ICV but not when administered peripherally to rats. Amylin, which has a close structural homology to CGRP, reduced food intake administered IP at concentrations higher than those previously tested for CGRP. We examined the effects of higher doses of IP-administered CGRP on food intake. CGRP reduced food intake from 25 to 200 micrograms/kg in mice. CGRP did not reduce water intake and was not aversive in a two-bottle test. Using a lever press, CGRP was more effective at reducing milk consumption in prefed than in nonprefed mice. The effect of CGRP on food intake was not antagonized by the cholecystokinin A receptor antagonist, L364,718. These studies suggest a role for CGRP as a satiating factor.
Asunto(s)
Péptido Relacionado con Gen de Calcitonina/farmacología , Ingestión de Líquidos/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Análisis de Varianza , Animales , Benzodiazepinonas/farmacología , Devazepida , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Privación de Alimentos , Heterocigoto , Antagonistas de Hormonas/farmacología , Masculino , Ratones , Ratones Obesos , Receptor de Colecistoquinina A , Receptores de Colecistoquinina/agonistas , Refuerzo en Psicología , Privación de AguaRESUMEN
Recent studies have suggested a role for nitric oxide in the regulation of food intake. Neuropeptide Y (NPY) is one of the most potent orexigenic agents. Chronic administration of leptin decreases food intake. This study examined the effects of NPY and leptin on nitric oxide synthase (NOS) in the hypothalamus. Previously it has been demonstrated that obese (ob/ob) mice have elevated NOS levels in the hypothalamus. In this study we demonstrated that the administration of leptin (6 microg/day) subcutaneously (SC) for 3 days decreased body weight (P < 0.001) and food intake P < 0.001) in obese (ob/ob) mice as expected. In addition, leptin decreased NOS in the hypothalamus nu 37% (P < 0.01) and in brown adipose tissue by 69% (P < 0.01) but not in white adipose tissue. NPY was administered intracerebroventricularly to CD-1 mice at doses of 0.25 and 0.50 microg. Mice were sacrificed 15 min after injection and NOS was measured in their hypothalami. NPY at the lower dose increased NOS in the hypothalamus by 147%. These results, taken together, with previously published studies support the concept that nitric oxide may play a role as a mediator of the effects of NPY and leptin on food intake. The alterations of NOS in brown adipose tissue following leptin administration could result in changes in blood flow or metabolism in the brown fat.
Asunto(s)
Ingestión de Alimentos/efectos de los fármacos , Hipotálamo/enzimología , Leptina/farmacología , Neuropéptido Y/farmacología , Óxido Nítrico Sintasa/análisis , Tejido Adiposo/enzimología , Animales , Peso Corporal/efectos de los fármacos , Inyecciones Intraventriculares , Inyecciones Subcutáneas , Masculino , Ratones , Ratones ObesosRESUMEN
Senescence accelerated (SAMP8 [P8]) mice develop age-related deficits in memory and learning. We show that increased expression of amyloid precursor protein (APP) and its mRNA in the hippocampus are also age-related. Immunocytochemical data suggest that a critical amount of APP expression may be needed to generate amyloid (Abeta) protein plaques in the hippocampus. Deficits in acquisition and retention test performance were alleviated by administration of antibody to Abeta protein into the cerebral ventricles. This reversal of cognitive deficits provides a link between increased expression of both APP and Abeta protein and learning and memory loss in these mice.
Asunto(s)
Precursor de Proteína beta-Amiloide/biosíntesis , Precursor de Proteína beta-Amiloide/química , Hipocampo/metabolismo , Aprendizaje , Memoria , Factores de Edad , Animales , Western Blotting , Electroforesis en Gel de Poliacrilamida , Inmunoglobulina G/metabolismo , Inmunohistoquímica , Masculino , Ratones , Ratones Mutantes , ARN Mensajero/metabolismo , Ribonucleasas/metabolismoRESUMEN
beta amyloid protein (Abeta) is a 40-43 amino acid peptide derived from amyloid precursor protein (APP). Abeta has been implicated as a cause of Alzheimer's disease (AD). Mice with spontaneous or transgenic overexpression of APP show the histologic hallmarks of AD and have impairments in learning and memory. We tested whether antisense phosphorothiolated oligonucleotides (AO) directed at the Abeta region of the APP gene given with or without antibody directed at Abeta could reverse the elevated protein levels of APP and the behavioral impairments seen in SAMP8 mice, a strain which spontaneously overexpresses APP. We found that intracerebroventricular (ICV) administration of antibody with either of two AOs directed at the midregion of Abeta improved acquisition and retention in a footshock avoidance paradigm, whereas two AOs directed more toward the C-terminal, a random AO, and vehicle were without effect. Three injections of the more potent AO given without antibody reduced APP protein levels by 43-68% in the amygdala, septum, and hippocampus. These results show that AO directed at the Abeta region of APP can reduce APP levels in the brain and reverse deficits in learning and memory.
Asunto(s)
Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Aprendizaje , Memoria , Oligonucleótidos Antisentido/farmacología , Factores de Edad , Enfermedad de Alzheimer/metabolismo , Amígdala del Cerebelo/metabolismo , Precursor de Proteína beta-Amiloide/biosíntesis , Animales , Western Blotting , Ensayo de Inmunoadsorción Enzimática , Hipocampo/metabolismo , Humanos , Aprendizaje por Laberinto , Ratones , Ratones Mutantes , Estructura Terciaria de Proteína , ARN Mensajero/metabolismo , Factores de TiempoRESUMEN
There is increasing evidence that estrogen is involved in CNS activity, particularly memory. Several studies have suggested that estrogen improves memory by enhancing cholinergic and glutamatergic activity. In the present studies, we examined the effects of administration into the hippocampus of 17 beta-estradiol and estrone on retention of T-maze footshock avoidance in female ovariectomized mice. Both 17 beta-estradiol and estrone improved retention on an equimolar basis in a dose-dependent fashion. We then used the T-maze footshock paradigm to test whether a dose of 17 beta-estradiol ineffective as a single injection (subthreshold) could potentiate the effects of arecoline, a cholinergic agonist, or L-glutamate, a glutamatergic agonist, on retention. The dose of either arecoline or L-glutamate needed to improve retention was reduced at least ten-fold by the low dose of 17 beta-estradiol. These findings support the concept that estrogen improves memory by potentiating the activity of the cholinergic and glutamatergic systems.
Asunto(s)
Acetilcolina/fisiología , Estradiol/farmacología , Ácido Glutámico/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Memoria/efectos de los fármacos , Animales , Arecolina/farmacología , Reacción de Prevención/efectos de los fármacos , Reacción de Prevención/fisiología , Agonistas Colinérgicos/farmacología , Sinergismo Farmacológico , Electrochoque , Femenino , Ácido Glutámico/fisiología , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Memoria/fisiología , Ratones , Ratones Endogámicos , Microinyecciones , OvariectomíaRESUMEN
To determine if serotonin and GABA regulate post-trial memory processing of the cholinergic projection from the septum to the hippocampus, mice were trained on footshock avoidance in a T-maze. Immediately after training, drugs were injected into the septum, hippocampus or both. Retention was tested 1 week after training and drug administration. Ketanserin, a serotonin type 2 receptor antagonist at a dose of 0.5 ng, had no measurable effect on retention, but it reduced the dose of bicuculline, in the septum, or arecoline in the hippocampus that was needed to improve retention. DOI, a serotonin type 2 receptor agonist at a dose of 2.5 ng, had the opposite effect of increasing the doses of bicuculline and arecoline needed to improve retention. Bicuculline, a GABA(A) receptor antagonist at a dose of 0.1 pg, did not affect retention when injected alone into the septum, but it reduced the dose of arecoline needed to improve retention in the hippocampus. Muscimol, a GABA(A) receptor agonist at a dose of 5 ng, injected into the septum, increased the dose of arecoline needed to improve retention. The results of this study are compatible with models that propose that serotonin innervation from the median raphe drives GABA interneurons in the medial septum that synapse on cholinergic neurons projecting to the hippocampus.
Asunto(s)
Colinérgicos/farmacología , GABAérgicos/farmacología , Hipocampo/efectos de los fármacos , Memoria/efectos de los fármacos , Tabique del Cerebro/efectos de los fármacos , Serotoninérgicos/farmacología , Animales , Reacción de Prevención/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Hipocampo/fisiología , Masculino , Memoria/fisiología , Ratones , Tabique del Cerebro/fisiologíaRESUMEN
The hippocampus is widely recognized as playing an important role in learning and memory. Lesions of the hippocampus can disrupt spatial navigational learning and memory and injection of drugs into the hippocampus can affect both spatial navigational and nonspatial tasks. In the current studies we tested the effects of bilateral of electrolytic lesions and reversible inactivation of the hippocampus on acquisition and retention of T-maze footshock avoidance conditioning. Electrolytic lesions, which destroyed 31+/-0.04% of the hippocampus, significantly impaired acquisition and retention for T-maze footshock avoidance. No differences were found in motivation to avoid shock, open field activity, or foot shock sensitivity between lesion and control groups. Temporary inactivation of the hippocampus with lidocaine administered immediately before training disrupted acquisition and retention for T-maze footshock avoidance. Temporary hippocampal inactivation performed just prior to retention testing and post-training inactivation in mice trained to first avoidance had no effect on retention. However, temporary post-training inactivation in 'undertrained' (enough trials to remember 1 week later if treated with saline, but not allowed to make the avoidance response) mice impaired retention. The current findings indicate that the hippocampus plays an important role in learning and memory processing in the aversive T-maze paradigm.
Asunto(s)
Reacción de Prevención/fisiología , Hipocampo/fisiología , Aprendizaje por Laberinto/fisiología , Retención en Psicología/fisiología , Animales , Conducta Animal/fisiología , Electrochoque , Hipocampo/efectos de los fármacos , Hipocampo/cirugía , Lidocaína/administración & dosificación , Masculino , Ratones , Microinyecciones , Actividad Motora/fisiología , Umbral del Dolor/fisiología , Tiempo de Reacción/fisiologíaRESUMEN
Isatin (2,3-dioxindole) is an endogenous compound which is distributed throughout the central nervous system. The studies reported here demonstrate that isatin decreased food intake in food deprived TAC (SW) male mice 12-16 weeks of age. Isatin was more effective at decreasing food intake when the mice had to work harder to obtain food. Isatin also decreased sucrose, milk and water intake. When hunger was reduced by prefeeding milk to the mice, isatin was more effective at decreasing food intake. Isatin did not alter spontaneous activity in an openfield. Behaviors observed in the home cage indicated that mice which received isatin approached the food more often without eating than the controls. Movement in the home cage was significantly reduced in mice receiving isatin. Drinking, grooming and resting were not significantly affected by administration of isatin. These studies suggest that isatin may be an endogenous modulator of food intake.
Asunto(s)
Ingestión de Alimentos/efectos de los fármacos , Isatina/farmacología , Animales , Apetito/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ingestión de Líquidos/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos , Respuesta de SaciedadRESUMEN
The septum is recognized as important in learning and memory, but relatively little is known about the role of specific neurotransmitter receptors in memory processing in the septum. We evaluated the role of the classical neurotransmitters in mice that were prepared for intraseptal microinfusion of drug solution after footshock avoidance training in T-maze. Retention for the footshock training was determined 1 week after training and drug administration. The results indicated that receptor agonists of dopamine, norepinephrine, glutamate and acetylcholine improved retention, while the antagonists impaired retention. Receptor agonists of serotonin, gamma-amino butyric acid (GABA) and opioids impaired retention, while antagonists improved retention.
Asunto(s)
Memoria/fisiología , Neurotransmisores/fisiología , Tabique Pelúcido/fisiología , Acetilcolina/farmacología , Animales , Reacción de Prevención/efectos de los fármacos , Catecolaminas/farmacología , Ácido Glutámico/farmacología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Memoria/efectos de los fármacos , Ratones , Narcóticos/farmacología , Tabique Pelúcido/efectos de los fármacos , Serotonina/farmacología , Ácido gamma-Aminobutírico/farmacologíaRESUMEN
Procarbazine has been implicated as a cause of infertility. Regionalization of drug delivery is a potential method to avoid this problem. We investigated the protective effect of testicular circulatory isolation (TCI) on gonadal toxicity during procarbazine administration in the Sprague-Dawley rat. Four groups (n = 10/group) were used. Animals in group 1 received no treatment. Rats in groups 2 and 3 were anaesthetized and received TCI of the left testis by clamping of the spermatic cord and gubernaculum immediately before a bolus of intravenous procarbazine (400 mg kg-1). The clamping was maintained for 15 min after procarbazine administration in group 2 and for 45 min in group 3. Rats in group 4 received sham surgery immediately before procarbazine administration. On day 70, all rats were killed and necropsied. Testicular toxicity was evaluated qualitatively by histology and quantitatively by measurements of testicular weight, sperm head count, repopulation index, and epididymal index. The results indicated that 15 min of TCI did not mitigate testicular toxicity; 45 min of TCI provided moderate protection against procarbazine-induced testicular toxicity.
Asunto(s)
Procarbazina/toxicidad , Testículo/efectos de los fármacos , Animales , Constricción , Inyecciones Intravenosas , Masculino , Tamaño de los Órganos , Procarbazina/administración & dosificación , Ratas , Ratas Sprague-Dawley , Flujo Sanguíneo Regional , Recuento de Espermatozoides , Testículo/irrigación sanguínea , Testículo/patología , Factores de TiempoRESUMEN
HIV-1 is associated with infection and altered functions of the CNS, especially in the elderly. Most studies indicate that HIV-1 is not evenly distributed throughout the CNS but is concentrated in deep brain nuclei. This study examined whether regional or age-related differences in the permeability of the blood-brain barrier to gp120, the viral coat of HIV-1, exist. The initial concentration of gp120 in 10 brain regions correlated with vascular content in young and old mice. Susceptibility to wheatgerm agglutinin (WGA)-induced uptake of gp120, which relates to endothelial cell internalization, varied regionally, with no induction of uptake into the striatum or hypothalamus but with large increases in the cerebellum, cortex, and midbrain. Transport across the BBB, as measured by the unidirectional influx rate (Ki), also varied regionally with the hypothalamus, hippocampus, and pons-medulla showing the highest values for Ki and the striatum the lowest. These regional variations in the permeability of the BBB to gp120 could contribute to the inhomogeneous distribution of HIV-1 within the CNS whereas the failure to see differences with aging suggests other causes underlie the susceptibility of the elderly to the CNS manifestations of AIDS.
Asunto(s)
Envejecimiento/metabolismo , Barrera Hematoencefálica , Encéfalo/metabolismo , Proteína gp120 de Envoltorio del VIH/metabolismo , Aglutininas del Germen de Trigo/farmacología , Albúminas/metabolismo , Animales , Transporte Biológico/efectos de los fármacos , Encéfalo/citología , Encéfalo/fisiología , Endocitosis/efectos de los fármacos , Endotelio/citología , Endotelio/efectos de los fármacos , Proteína gp120 de Envoltorio del VIH/sangre , Cinética , Masculino , Ratones , Ratones Endogámicos ICR , Ratones EndogámicosRESUMEN
Corticosterone increases with aging but pregnenolone, dehydroepiandrosterone, and testosterone decrease. The marked decrease in hormones that occurs with aging may contribute to the age-related deficit in learning and memory. Administration of these hormones after training was found to improve long-term memory processing in normal young mice. SAMP8 (P8) mice show an age-related loss of learning and memory for a variety of tasks whereas age-matched control mice of the closely related SAMR1 (R1) strain do not. In this study, we found an age-related decrease in serum testosterone levels of 71% between P8 mice 4 and 12 months of age, but only a 26% decrease between R1 mice of the same ages. The difference between the P8 mice was significant (p < 0.01) and the difference between the R1 mice was not. The decrease in testosterone in 12-month-old P8 mice was not accompanied by gross morphological change in the testes. A SC testosterone implant, sufficient to increase plasma testosterone levels to 414 +/- 25 ng/dl, alleviated impaired learning and memory of a foot shock avoidance task in P8 mice. Castration of 4-month-old P8 mice did not produce a deterioration in learning and memory, indicating that low levels of testosterone per se are not responsible for the impairment seen in 12-month-old P8 mice. This suggests that impaired cognitive functioning of the older P8 mice was due to an interaction of aging and reduced testosterone levels.
Asunto(s)
Envejecimiento/sangre , Envejecimiento/psicología , Aprendizaje/fisiología , Memoria/fisiología , Testosterona/sangre , Testosterona/farmacología , Animales , Reacción de Prevención/efectos de los fármacos , Implantes de Medicamentos , Aprendizaje/efectos de los fármacos , Masculino , Memoria/efectos de los fármacos , Ratones , Ratones Endogámicos , Orquiectomía , Especificidad de la Especie , Testículo/anatomía & histología , Testículo/efectos de los fármacosRESUMEN
Mice were trained to avoid footshock in a T-maze, with retention tested one week later. Adult male CD-1 mice made their first avoidance during acquisition after fewer trials than random cycling females and with less variability. Female mice in diestrus, when plasma levels of progesterone are low, learned to avoid footshock faster than females in estrus. Ovariectomized (OVX) mice learned in fewer trials than intact random cycling mice. Similar differences, though of a smaller magnitude, were found on the retention tests (i.e. males had better retention than females, mice in diestrus showed better retention 8 days later when in the same part of the estrous cycle than those in estrus, and OVX mice had better retention than cycling females). OVX mice with estrogen implants learned faster than those with progesterone implants or progesterone plus estrogen implants. Hormonal status did not affect sensitivity to acoustic or footshock stimuli as measured by a startle reflex, nor did it affect activity. Pretraining administration of amphetamine, picrotoxin and strychnine attenuated the impairing effect of progesterone on acquisition. The possibility that progesterone may impair learning and to some extent, retention by facilitating the GABAergic activity and thereby reducing arousal level is discussed.
Asunto(s)
Reacción de Prevención/fisiología , Estro/fisiología , Miedo/fisiología , Hormonas Esteroides Gonadales/fisiología , Retención en Psicología/fisiología , Animales , Nivel de Alerta/fisiología , Diestro/fisiología , Estrógenos/fisiología , Femenino , Masculino , Aprendizaje por Laberinto/fisiología , Recuerdo Mental/fisiología , Ratones , Ovario/fisiología , Progesterona/fisiología , Ácido gamma-Aminobutírico/fisiologíaRESUMEN
To evaluate the possible role of the cingulate cortex in memory processing for training using a noxious stimulus, we trained mice on foot shock avoidance in a T-maze. Cholinergic, GABAergic, serotonergic, and glutamatergic agonists and antagonists were administered into the cingulate cortex immediately after training. Retention for the foot shock avoidance training was tested 1 week later. The results indicate that muscarinic and nicotinic agonists improved retention, while antagonists impaired it. GABA and serotonin agonists impaired retention, while antagonists improved it. Drugs acting on GABA(A) and GABA(B) receptors had similar effects on retention, as did drugs acting on serotonin 1 and 2 receptor subtypes. Glutamate improved retention, and AP5, an antagonist of the excitatory amino acid site of the NMDA receptor, impaired retention. The cingulate cortex, like other parts of the limbic system, is involved in memory processing that occurs shortly after training.
Asunto(s)
Corteza Cerebral/fisiología , Memoria , Acetilcolina/farmacología , Animales , Reacción de Prevención/efectos de los fármacos , Yoduro de Dimetilfenilpiperazina/farmacología , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Receptores de GABA/fisiología , Receptores de N-Metil-D-Aspartato/fisiología , Retención en Psicología/efectos de los fármacosRESUMEN
Recent studies have demonstrated that nitric oxide may play an important role in the regulation of food intake. The studies reported here extend these findings by demonstrating that NG-nitro-arginine-methylester, N-Arg(ME), a nitric oxide synthase inhibitor, decreased intake of a highly palatable substance (i.e., milk), though at a higher dose than necessary for decreasing consumption of food pellets. N-Arg(ME) failed to inhibit lever press for milk reward in nonprefed mice, but decreased lever pressing in prefed mice. N-Arg(ME) decreased food intake in female mice, being most potent in proestrus. These studies suggest that nitric oxide synthase inhibition decreases food intake without inducing aversion or illness.