RESUMEN

The club drug ecstasy (3,4-methylenedioxymethylamphetamine or MDMA) is often taken recreationally with ethanol (EtOH). We have shown previously that EtOH potentiates the psychomotor effects of MDMA in rats. More recently, we demonstrated in striatal slices that MDMA produced preferential release of serotonin, but when combined with EtOH, the preferential release shifted to dopamine, raising the possibility that administration of EtOH may increase the reward effect of MDMA. To address this possibility, adult male Long-Evans rats were tested for conditioned place preference following treatment with saline, EtOH (0.75 g/kg), MDMA (6.6 mg/kg) or the combination. The only condition that produced a preference for the compartment associated with the drug was that of the drug combination. The current data are in line with anecdotal reports and one study in humans, indicating that EtOH alters the pharmacological effects of MDMA including self reports of enhanced or prolonged euphoria. Thus, administration of EtOH might increase the risk for compulsive use of MDMA, an issue that warrants further study.

Asunto(s)

Depresores del Sistema Nervioso Central/farmacología , Condicionamiento Psicológico/efectos de los fármacos , Etanol/farmacología , N-Metil-3,4-metilenodioxianfetamina/farmacología , Animales , Conducta Animal , Interacciones Farmacológicas , Masculino , Ratas , Ratas Long-Evans , Recompensa , Serotoninérgicos/farmacología

RESUMEN

This study aimed at investigating the effects of environmental enrichment on various aspects of contextual processing in adult female rats. In experiment 1, simple conditioning was studied using either a training procedure allowing overshadowing of the contextual cues by signalling footshock with a discrete tone or a training procedure allowing a reduction of this overshadowing by explicitly unpairing the footshock and the tone. In experiment 2, contextual discrimination and contextual occasion-setting were assessed. Rats were daily exposed to two different contexts. In one context, a footshock was delivered 30s after the offset of a tone, whereas in the other context the same tone was presented alone. Experiment 3 examined familiarization to a new context. Experiment 1 showed that environmental enrichment reduced the overshadowing of contextual cues by the tone and also reduced freezing to the more predictive cue according to the training procedure used. Experiment 2 showed that environmental enrichment increased the ability of rats to discriminate two contexts. Experiment 3 showed that enriched rats familiarized faster to a new context than standard rats. Taken together, these results suggest that environmental enrichment in adult rats enhances learning about contextual cues and reduces overall fear associated with aversive events.

Asunto(s)

Condicionamiento Clásico/fisiología , Señales (Psicología) , Ambiente , Miedo , Estimulación Acústica/efectos adversos , Análisis de Varianza , Animales , Aprendizaje por Asociación/fisiología , Conducta Animal , Aprendizaje Discriminativo/fisiología , Electrochoque/efectos adversos , Femenino , Reacción Cataléptica de Congelación/fisiología , Ratas , Ratas Long-Evans

RESUMEN

Alterations of striatal cholinergic markers may correlate with cognitive impairments in aged rats. M2 muscarinic receptors were found to be presynaptic inhibitory autoreceptors on striatal cholinergic interneurons. The effect of bilateral intrastriatal infusions of the M2 muscarinic receptor antagonist methoctramine was assessed, in cognitively impaired aged (24-26 months) Long-Evans female rats, on memory performances in a water maze. Compared with vehicle infusions, methoctramine injected bilaterally (1 microg/side) in the dorsolateral striatum, significantly improved procedural memory performance while having no effect on spatial working memory. Our results suggest that, in cognitively impaired aged rats, the blockade of M2 muscarinic receptors in the dorsolateral striatum improves procedural memory probably by enhancing the release of acetylcholine.

Asunto(s)

Trastornos del Conocimiento/tratamiento farmacológico , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/fisiología , Diaminas/farmacología , Parasimpatolíticos/farmacología , Envejecimiento/fisiología , Animales , Femenino , Aprendizaje por Laberinto/efectos de los fármacos , Memoria a Corto Plazo/efectos de los fármacos , Microinyecciones , Ratas , Ratas Long-Evans , Receptor Muscarínico M2 , Receptores Muscarínicos/fisiología , Percepción Espacial/efectos de los fármacos

RESUMEN

PURPOSE: We studied the behavioral effects of an intracavitary implantation of poly[N-(2-hydroxypropyl)-methacrylamidel (PHPMA) hydrogels combined to intraseptal grafts of fetal septal cell suspensions in adult female rats subjected to aspirative fimbria-fornix lesions. The hydrogels were used as substrates for bridging the lesion cavity between the septum and the hippocampus. METHODS: Control groups included sham-operated or lesion-only rats, as well as lesioned rats with only the hydrogel bridge in the lesion cavity, only the graft in the septum, or an intrahippocampal graft of a septal cell suspension as a control for the standardly used ectopic transplantation strategy. Up to 10 months after grafting surgery, all rats were tested for locomotor activity in their home cage, sensorimotor performances using a beam-walking test, and cognitive performances in a radial maze, a water maze and a T-maze (rewarded alternation). RESULTS: The lesions induced hyperlocomotion, sensorimotor disturbances and severe alterations of cognitive functions. We found that neither the grafts or the hydrogels, nor the combination of both, induced any significant enhancement of sensorimotor or cognitive performances. Nevertheless, in rats with both intraseptal (homotopic) grafts and a hydrogel implant, the locomotor activity did no longer differ from that found in sham-operated controls. Histological analysis showed that the hydrogels contained acetylcholinesterase(AChE)-positive fibers and that the hippocampal region in contact with the hydrogel exhibited AChE-positive reaction products over several hundreds of micrometers. CONCLUSIONS: These results are complementary to our previous report on electrophysiological evidence of septo-hippocampal reconnections (Duconseille et al., Rest. Neurol. Neurosci. 15, 1999, 305-317). They further suggest that septal neurons grafted homotopically and/or neurons from the host brain are able to elongate axonal processes through a PHPMA substrate up to the hippocampus. Although they did not affect the cognitive consequences of the lesion, the changes enabled by the homotopic grafts combined to the hydrogel have attenuated the lesion-induced hyperactivity.

Asunto(s)

Trasplante de Tejido Encefálico , Trasplante de Tejido Fetal , Fórnix/cirugía , Hidrogeles/farmacología , Ácidos Polimetacrílicos/farmacología , Tabique del Cerebro/trasplante , Animales , Conducta Animal , Femenino , Hipercinesia , Aprendizaje por Laberinto , Trastornos de la Memoria , Actividad Motora , Ratas , Ratas Long-Evans , Recuperación de la Función

RESUMEN

A model of electrically evoked release of glutamate from rat hippocampus was developed and used to detect possible changes induced by lesions of hippocampal afferences. Neuronal glutamate in hippocampal slices was labelled by preincubation with [3H]glutamine. The slices were then superfused with physiological medium in the presence of the glutamate uptake inhibitor L-transpyrrolidine-2,4-dicarboxylic acid (100 microM or 3 microM) and stimulated twice electrically (S1, S2: 240 pulses, 3 Hz, 2 ms, 26-30 mA); various drugs were added before S2. In order to determine the basal and evoked outflow of [3H]glutamate only, the mixture of 3H-labelled compounds (glutamine, glutamate and GABA) was separated by ion exchange chromatography in superfusate fractions and slices. The electrically evoked overflow of [3H]glutamate was largely Ca2+-dependent and tetrodotoxin-sensitive and hence represented action potential-induced exocytotic release of [3H]glutamate. Evoked [3H]glutamate release was significantly increased by the adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 0.1 microM), suggesting the presence of endogenous inhibitory adenosine, and reduced by the A1 receptor agonist N6-cyclopentyladenosine (1 microM, antagonized by DPCPX, 0.1 microM). There was no evidence for a cholinergic, serotonergic, or adrenergic modulation of the evoked release of [3H]glutamate: the corresponding selective agonists (or antagonists) were ineffective. After aspirative lesions of the septohippocampal pathways the hippocampal noradrenaline content was markedly increased, whereas cholinergic and serotonergic markers were reduced. The evoked release of [3H]glutamate in hippocampal slices of lesioned rats was significantly increased by a mechanism which still has to be determined, but which is not related to alterations in A1 receptor function. It is concluded that the present model was able to detect lesion-induced differences in electrically evoked release of [3H]glutamate, but the relationship of these differences to changes of noradrenergic, cholinergic or serotonergic hippocampal innervations remains to be established.

Asunto(s)

Fórnix/patología , Ácido Glutámico/metabolismo , Hipocampo/metabolismo , Receptores Purinérgicos P1/metabolismo , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Adenosina/análogos & derivados , Adenosina/farmacología , Animales , Estimulación Eléctrica/métodos , Hipocampo/efectos de los fármacos , Masculino , Agonistas del Receptor Purinérgico P1 , Antagonistas de Receptores Purinérgicos P1 , Ratas , Ratas Wistar , Xantinas/farmacología

RESUMEN

Adult female rats sustained aspirative fimbria-fornix lesions and, 2 weeks later, received intrahippocampal grafts of fetal septal or mixed septal-raphe cell suspensions. Twenty-four months later, the extracellular concentration of hippocampal acetylcholine (ACh) was determined by microdialysis. Basal ACh levels (5-65 fmol/5 microl sham-operated rats) were strongly reduced after lesioning (3-7 fmol/5 microl). In septally transplanted and septal-raphe co-transplanted rats, hippocampal ACh concentrations were restored to near-normal levels (15-25 fmol/5 microl), indicating long-term functional survival of hippocampal transplants. After administration of citalopram (100 microM by infusion) and fenfluramine (20 mg/kg i.p.), the hippocampal ACh efflux was increased by 2- to 3-fold in all groups of rats. The relative increase of ACh was highest in co-transplanted rats, an effect which was possibly due to functional interactions between grafted raphe and septal neurons.

Asunto(s)

Acetilcolina/metabolismo , Trasplante de Tejido Encefálico , Fibras Colinérgicas/metabolismo , Supervivencia de Injerto/fisiología , Hipocampo/metabolismo , Plasticidad Neuronal/fisiología , Serotonina/metabolismo , Animales , Feto , Fórnix/metabolismo , Fórnix/cirugía , Hipocampo/cirugía , Núcleos del Rafe/metabolismo , Núcleos del Rafe/cirugía , Ratas , Ratas Long-Evans , Núcleos Septales/metabolismo , Núcleos Septales/trasplante , Factores de Tiempo

RESUMEN

Intracerebral grafting techniques of fetal neural cells have been used essentially with two main types of lesion paradigms, namely damage to long projection systems, in which the source and the target are clearly separate, and damage to neurons that are involved in local circuits within a small (sub)region of the brain. With the first lesion paradigm, grafts placed homotopically (in the source) are not appropriate because their fibers grow poorly through the host parenchyma and fail to reach their normal target. To be successful, the grafts must be placed ectopically in the target region of the damaged projection systems, where generally they work as level-setting systems. Conversely, with the second paradigm, the grafts are supposed to compensate for a local loss of neurons and must be placed homotopically to induce functional effects that are based on the reconstruction of a point-to-point circuitry. By inserting a biological or artificial bridging-substrate between the source and the target of long projection systems, it might be possible to combine the positive effects of both homotopic and ectopic grafting by achieving both target reinnervation and normal control of the grafted neurons within the source area. These issues are illustrated and discussed in this review.

Asunto(s)

Trasplante de Tejido Encefálico , Trasplante de Tejido Fetal , Animales , Fibras Colinérgicas/fisiología , Trastornos del Conocimiento/fisiopatología , Humanos , Vías Nerviosas/fisiopatología , Vías Nerviosas/cirugía , Neurotransmisores/fisiología

RESUMEN

This study examined whether cholinergic and monoaminergic dysfunctions in the brain could be related to spatial learning capabilities in 26-month-old, as compared to three-month-old, Long-Evans female rats. Performances were evaluated in the water maze task and used to constitute subgroups with a cluster analysis statistical procedure. In the first experiment (histological approach), the first cluster contained young rats and aged unimpaired rats, the second one aged rats with moderate impairment and the third one aged rats with severe impairment. Aged rats showed a reduced number of choline acetyltransferase- and p75(NTR)-positive neurons in the nucleus basalis magnocellularis, and choline acetyltransferase-positive neurons in the striatum. In the second experiment (neurochemical approach), the three clusters comprised young rats, aged rats with moderate impairment and aged rats with severe impairment. Alterations related to aging consisted of reduced concentration of acetylcholine, norepinephrine and serotonin in the striatum, serotonin in the occipital cortex, dopamine and norepinephrine in the dorsal hippocampus, and norepinephrine in the ventral hippocampus. In the first experiment, there were significant correlations between water maze performance and the number of; (i) choline acetyltransferase- and p75(NTR)-positive neurons in the nucleus basalis magnocellularis; (ii) choline acetyltransferase-positive neurons in the striatum and; (iii) p75(NTR)-positive neurons in the medial septum. In the second experiment, water maze performance was correlated with the concentration of; (i) acetylcholine and serotonin in the striatum; (ii) serotonin and norepinephrine in the dorsal hippocampus; (iii) norepinephrine in the frontoparietal cortex and; (iv) with other functional markers such as the 5-hydroxyindoleacetic acid/serotonin ratio in the striatum, 3,4-dihydroxyphenylacetic acid/dopamine ratio in the dorsal hippocampus, 5-hydroxyindoleacetic acid/serotonin and homovanillic acid/dopamine ratios in the frontoparietal cortex, and 3,4-dihydroxyphenylacetic acid/dopamine ratio in the occipital cortex. The results indicate that cognitive deficits related to aging might involve concomitant alterations of various neurochemical systems in several brain regions such as the striatum, the hippocampus or the cortex. It also seems that these alterations occur in a complex way which, in addition to the loss of cholinergic neurons in the basal forebrain, affects dopaminergic, noradrenergic and serotonergic processes.

Asunto(s)

Envejecimiento/patología , Encéfalo/patología , Discapacidades para el Aprendizaje/patología , Animales , Catecolaminas/análisis , Colina O-Acetiltransferasa/análisis , Cromatografía Líquida de Alta Presión , Femenino , Humanos , Inmunohistoquímica , Discapacidades para el Aprendizaje/fisiopatología , Aprendizaje por Laberinto/fisiología , Neuronas/patología , Neurotransmisores/análisis , Ratas , Ratas Long-Evans , Receptores de Factor de Crecimiento Nervioso/análisis , Serotonina/análisis

RESUMEN

Three-month-old Long-Evans female rats sustained aspirative lesions of the dorsal septohippocampal pathways and, 2 weeks later, received intrahippocampal suspension grafts containing fetal cells from the mesencephalic raphe (rich in serotonergic neurons; RAPHE), the medial septum and the diagonal band of Broca (rich in cholinergic neurons; SEPT), or a mixture of both (COTR). Lesion-only (LES) and sham-operated rats (SHAM) were used as controls. Hippocampal slices of these rats (5-9 month after surgery) were preincubated with [3H]choline or [3H]5-HT, superfused continuously (in the presence of hemicholinium-3 or fluvoxamine) and stimulated electrically (360 pulses, 2 ms, 3 Hz, 26-28 mA) in order to study the presynaptic modulation of acetylcholine (ACh) and serotonin (5-HT) release. The accumulation of [3H]choline and the evoked overflow of [3H]ACh were significantly reduced in slices from LES and RAPHE rats, but reached a close-to-normal level in SEPT and COTR rats. As to accumulation and overflow of [3H]5-HT, the lesion-induced reduction was compensated for only in RAPHE and COTR rats. The relative amount of evoked [3H]5-HT release (in % of tissue-3H) was significantly increased in LES and SEPT rats. Only slight differences (group LES) were found in the sensitivity of muscarinic and serotonergic autoreceptors towards oxotremorine and CP 93,129, respectively. Moreover, CP 93,129 induced a significantly weaker inhibition of ACh release in slices of COTR rats than in all other groups. Using the 5-HT1A receptor agonist 8-OH-DPAT and antagonist Way 100,635, no evidence for a modulatory influence of 5-HT1A receptors was found in RAPHE and COTR rats. It is concluded that despite substantial lesion- and graft-induced changes in the amount of ACh and 5-HT released by hippocampal slices of lesion-only or grafted rats, the presynaptic modulation of these transmitters is only slightly affected by changes in the neuronal environment.

Asunto(s)

Acetilcolina/metabolismo , Trasplante de Tejido Encefálico , Fórnix/metabolismo , Hipocampo/metabolismo , Neuronas/trasplante , Serotonina/metabolismo , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Acetilcolina/fisiología , Animales , Transporte Biológico/efectos de los fármacos , Colina/farmacocinética , Colina O-Acetiltransferasa/análisis , Banda Diagonal de Broca/metabolismo , Estimulación Eléctrica , Femenino , Agonistas Muscarínicos/farmacología , Neuronas/química , Neuronas/enzimología , Técnicas de Cultivo de Órganos , Oxotremorina/farmacología , Piridinas/farmacología , Pirroles/farmacología , Núcleos del Rafe/metabolismo , Ratas , Ratas Long-Evans , Receptor de Serotonina 5-HT1B , Receptores Muscarínicos/análisis , Receptores de Serotonina/análisis , Receptores de Serotonina 5-HT1 , Núcleos Septales/metabolismo , Serotonina/farmacocinética , Serotonina/fisiología , Agonistas de Receptores de Serotonina/farmacología , Tritio

RESUMEN

Three-month-old Long-Evans female rats sustained aspirative lesions of the dorsal septohippocampal pathways and, 2 weeks later, received intrahippocampal suspension grafts containing cells from the mesencephalic raphe, cells from the medial septum and the diagonal band of Broca, or a mixture of both. Lesion-only and sham-operated rats were used as controls. All rats were tested for locomotor activity 1 week, 3 and 5 months after lesion surgery, for spatial working memory in a radial maze from 5 to 9 months, and for reference and working memory in a water tank during the 9th month after lesioning. Determination of hippocampal concentration of acetylcholine, noradrenaline, and serotonin was made after completion of behavioral testing. Compared to sham-operated rats, all rats with lesions, whether grafted or not, exhibited increased levels of locomotor activity and made more errors in the radial maze. The lesioned rats were also impaired in the probe trial (30 first seconds) of the water-tank test made according to a protocol requiring intact reference memory capabilities. While rats with septal or raphe grafts were also impaired, the rats with co-grafts showed performances not significantly different from those of sham-operated rats. With a protocol requiring intact working memory capabilities, all lesioned rats, whether grafted or not, were impaired in the water-tank test. In the dorsal hippocampus of lesion-only rats, the concentration of acetylcholine and serotonin was significantly reduced. In rats with septal grafts or co-grafts, the concentration of acetylcholine was close to normal, as was that of serotonin in rats with raphe grafts or co-grafts. These results confirm previous findings showing that co-grafts enabled the neurochemical properties of single grafts to be combined. Data from the water-tank test suggest that cholinergic and serotonergic hippocampal reinnervations by fetal cell grafts may induce partial recovery of spatial reference, but not working memory capabilities in rats.

Asunto(s)

Trasplante de Tejido Encefálico , Trasplante de Tejido Fetal , Hipocampo/cirugía , Memoria/fisiología , Fibras Nerviosas/trasplante , Acetilcolina/análisis , Vías Aferentes/cirugía , Análisis de Varianza , Animales , Fibras Colinérgicas/trasplante , Inhibidores de la Colinesterasa/farmacología , Femenino , Hipocampo/química , Hipocampo/lesiones , Aprendizaje , Mesencéfalo/trasplante , Actividad Motora/efectos de los fármacos , Norepinefrina/análisis , Ratas , Ratas Long-Evans , Serotonina/análisis , Serotoninérgicos/farmacología

RESUMEN

Three-month old Long-Evans female rats were submitted to aspirative lesions of the fimbria-fornix and intrahippocampal grafts of a cell suspension prepared from a region of the fetal brain including the septum and the diagonal band of Broca (rich in cholinergic neurons) or the raphe (rich in serotonergic neurons). A group of lesioned rats was grafted with both suspensions mixed. Lesion-only and sham-operated rats served as controls. Four months after the lesions, all rats were tested daily for locomotor activity in their home cage, 1 day without being injected, 2 days with an injection of NaCl and 5 days with an injection of 1 mg/kg (i.p.) d-amphetamine. The effects of the lesions and grafts were assessed by measuring the accumulation of [3H]-choline or [3H]-5-hydroxytryptamine (5-HT) by hippocampal slices, and the electrically-evoked release of tritium. Amphetamine injections produced hyperlocomotion which was potentiated by the lesion. This lesion-induced potentiation was also found in rats with septal grafts, but not in those with raphe or co-grafts. The uptake and electrically-evoked release of [3H]-acetylcholine or [3H]-5-HT were reduced in hippocampal slices from lesion-only rats. In rats which received grafts of septal cells or co-grafts, but not in those with raphe grafts, uptake and release of [3H]-acetylcholine were close to normal. Uptake and release of [3H]-5-HT were close to normal in rats with raphe grafts or with co-grafts, but not in those with septal grafts. Altogether, these data suggest that damage to the serotonergic afferents of the hippocampus might play some role in the potentiation of amphetamine-induced hyperlocomotion associated with fimbria-fornix lesions.

Asunto(s)

Anfetamina/farmacología , Encefalopatías/fisiopatología , Hipocampo/cirugía , Actividad Motora/efectos de los fármacos , Neuronas/metabolismo , Neuronas/trasplante , Serotonina/metabolismo , Animales , Encefalopatías/patología , Encefalopatías/cirugía , Colina/metabolismo , Sinergismo Farmacológico , Estimulación Eléctrica , Femenino , Lóbulo Frontal/citología , Lóbulo Frontal/embriología , Hipocampo/metabolismo , Ratas , Ratas Long-Evans , Tabique Pelúcido/citología , Tabique Pelúcido/embriología

RESUMEN

Fimbria-fornix lesions disrupt important parts of serotonergic and noradrenergic hippocampal afferents and elicit sprouting of sympathetic fibers from the superior cervical ganglion. Since 5-hydroxytryptamine (5-HT) release in the hippocampus is modulated by 5-HT1B auto- and alpha2-heteroreceptors, we investigated whether such lesions may alter these presynaptic mechanisms. Hippocampal slices of sham-operated (SHAM) and fimbria-fornix-lesioned (LES) rats (14 months after surgery) were preincubated with [3H]5-HT, superfused continuously, and stimulated electrically using two stimulation conditions: either (a) 360 pulses 3 Hz, or (b) 20 pulses 100 Hz (2 ms, 28 mA, 4 V/chamber). The amount of [3H]5-HT taken up by slices from LES rats was significantly reduced, whereas the evoked 5-HT release (in percent of tissue-3H) was unchanged compared to that of SHAM rats. The 5-HT1B agonist CP 93,129 or the alpha2-agonist UK 14,304 reduced the evoked 5-HT release more potently in slices from LES rats, but only using stimulation condition (a), which permits inhibition by endogenously released transmitters. In LES rats, the facilitatory effect of the 5-HT antagonist metitepine was weaker, whereas that of the alpha2-antagonist idazoxane was more pronounced than in SHAM rats. In LES rats, hippocampal 5-HT content was reduced to about 45% of SHAM levels, whereas that of noradrenaline was increased by about 30% (high-performance liquid chromatography). We conclude: (1) despite LES-induced changes in tissue levels of endogenous ligands, there is no down- or upregulation of 5-HT1B-autoreceptors or alpha2-heteroreceptors on serotonergic neurons in the denervated rat hippocampus. (2) The reduced endogenous autoinhibition (by 5-HT) seems to be compensated for by an increased heteroinhibition (by noradrenaline).

Asunto(s)

Encefalopatías/metabolismo , Hipocampo/metabolismo , Receptores de Serotonina/metabolismo , Serotonina/metabolismo , Agonistas alfa-Adrenérgicos/farmacología , Antagonistas Adrenérgicos alfa/farmacología , Animales , Estimulación Eléctrica , Femenino , Hipocampo/efectos de los fármacos , Técnicas In Vitro , Ratas , Ratas Long-Evans , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología

RESUMEN

As a first step, the present experiment aimed at characterizing learning and memory capabilities, as well as some motor and sensorimotor faculties, in aged (24-26.5 months) Long-Evans female rats. As a second step, a psychopharmacological approach was undertaken in order to examine the sensitivity of aged rats to muscarinic blockade and to cholinomimetic treatments. Young adult (3-5.5 months) and aged rats were tested for beam-walking performance, locomotor activity in the home cage and an open field, and spatial learning/memory performance in a water maze and a radial maze. Spontaneous alternation rates were assessed in a T-maze. Statistical analysis discriminated between aged rats showing moderate impairment (AMI) and those showing severe impairment (ASI) in the water maze test. Beside their different degrees of impairment in the water maze, AMI and ASI rats were similarly (no significant difference) impaired in beam-walking capabilities, home cage activity and radial maze performance. In the spontaneous alternation task aged rats were not impaired and, in the open-field test, AMI rats were hypoactive, but not as much as ASI rats. Neither of the cognitive deficits was correlated with a locomotor or a sensorimotor variable, or with the body weight. When tested in the radial maze, a low dose of scopolamine (0.1 mg/kg i.p.) produced memory impairments which were significant in AMI and ASI rats, but not in young rats. Combined injections of scopolamine and physostigmine (0.05 and 0.1 mg/kg) or tacrine (THA, 3 mg/kg) showed physostigmine (0.1 mg/kg) to compensate for the scopolamine-induced impairments only in AMI rats. whereas THA was efficient in both AMI and ASI rats. The results indicate: (i) that rats with different degrees of spatial memory impairment in the water maze are similarly hypersensitive to muscarinic blockade when tested in a radial maze test; and (ii) that under the influence of a dose of scopolamine which is subamnesic in young rats, aged rats respond to anticholinesterase treatments according to the level of performance achieved in the water maze: moderately impaired rats are sensitive to both physostigmine and THA, whereas more severely impaired rats are sensitive only to THA.

Asunto(s)

Envejecimiento/efectos de los fármacos , Colinérgicos/farmacología , Recuerdo Mental/efectos de los fármacos , Orientación/efectos de los fármacos , Percepción Espacial/efectos de los fármacos , Animales , Encéfalo/efectos de los fármacos , Reacción de Fuga/efectos de los fármacos , Femenino , Aprendizaje por Laberinto/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Fisostigmina/farmacología , Equilibrio Postural/efectos de los fármacos , Desempeño Psicomotor/efectos de los fármacos , Ratas , Ratas Long-Evans , Retención en Psicología/efectos de los fármacos , Escopolamina/farmacología , Tacrina/farmacología

RESUMEN

Lesions of the septohippocampal pathways elicit sprouting of sympathetic fibers from the superior cervical ganglion, a phenomenon which, within a few months, raises the hippocampal noradrenaline (NA) content above normal. In peripheral sympathetic fibers, the release of NA is modulated via presynaptic muscarinic receptors. Such receptors have not been detected so far on terminals of noradrenergic neurons originating in the locus coeruleus. Whether the release of NA could become sensitive to muscarinic modulation in the hippocampus following sympathetic fiber ingrowth was the major question in this experiment. The contribution of presynaptic nicotinic receptors was also studied. Slices from the ventral hippocampus (only dentate gyrus+CA3 region) of sham-operated (SHAM) and fimbria-fornix lesioned (LES) Long-Evans rats (8-10 months after surgery) were preincubated with [3H]NA and stimulated either once (S1) with 100 microM nicotine or (in parallel experiments) twice electrically (S1, S2), using conditions (six pulses 100 Hz, 2 ms, 28 mA, 4 V/chamber) that precluded autoinhibition. In experiments using electrical stimulation, the superfusion medium contained desipramine (1 microM). In LES rats, the tissue NA content had almost doubled (171% of SHAM levels), but the amount of [3H]NA taken up by the slices was unchanged, and the overflow evoked at S1 by both nicotinic and electrical stimulation was significantly reduced in comparison with SHAM rats. In both groups, the addition of oxotremorine or oxotremorine+atropine (1 microM, each) before S2 failed to affect the electrically evoked overflow of 3H. Nicotine-induced NA release was inhibited by hexamethonium (100 microM) in both groups, although significantly less potently in LES rats. Tissue activity of choline acetyltransferase was reduced in LES rats to 15% of SHAM levels and the 5-hydroxytryptamine content was also strongly diminished (38% of SHAM values). It is concluded that lesion-induced sprouting of sympathetic fibers into the hippocampus is not accompanied by the emergence of a muscarinic modulation of NA release in this tissue, and that the sensitivity of the presynaptic stimulatory effect of nicotine was modified by the lesion.

Asunto(s)

Hipocampo/citología , Neuronas/química , Norepinefrina/farmacocinética , Receptores Muscarínicos/fisiología , Sistema Nervioso Simpático/citología , Animales , Colina O-Acetiltransferasa/análisis , Estimulación Eléctrica , Femenino , Hexametonio/farmacología , Ácido Hidroxiindolacético/análisis , Neuronas/efectos de los fármacos , Neuronas/enzimología , Nicotina/farmacología , Antagonistas Nicotínicos/farmacología , Ratas , Ratas Long-Evans , Receptores Nicotínicos/fisiología , Serotonina/análisis , Tritio

RESUMEN

Various spatial memory deficits have been described in rats with damage to the hippocampal formation (including the subiculum and the entorhinal cortex) and particularly in rats with selective lesions of the hippocampus proper. So far, the involvement of the entorhinal cortex in spatial memory is still controversial and the role of the subiculum is poorly documented. The aim of the present study was to compare the behavioural effects of selective lesions of the hippocampus, the entorhinal cortex or the subiculum in (a) a water-maze task using testing procedures sensitive to the disruption of reference or working memory and (b) in an object exploration task designed to evaluate habituation and subsequently reactions to changes of the spatial layout of objects (spatial change) or to the substitution of a familiar object by a new one (nonspatial change). Our results showed several similarities between the behavioural consequences of damage to each of the three structures. A few differences were also noted. Hippocampal rats were impaired in all spatial tasks, but they reacted like controls to a nonspatial change. The rats sustaining lesions of the entorhinal cortex or the subiculum were not impaired in the reference-memory procedure of the water-maze task and showed a deficit in reacting to a nonspatial change. Overall, our results confirm the central role of the hippocampus in spatial memory and also suggest a role for the entorhinal cortex and the subiculum in processing spatial informations. In addition, they indicate that the entorhinal cortex and the subiculum may have a hippocampal-independent role in memory.

Asunto(s)

Corteza Entorrinal/fisiología , Habituación Psicofisiológica/fisiología , Hipocampo/fisiología , Memoria/fisiología , Percepción Espacial/fisiología , Animales , Agonistas de Aminoácidos Excitadores/toxicidad , Conducta Exploratoria/fisiología , Ácido Iboténico/toxicidad , Masculino , Aprendizaje por Laberinto/fisiología , Actividad Motora/fisiología , Ratas

RESUMEN

The behavioral effects of interrupting the axons that pass in the fimbria and dorsal fornix were compared with the effects of selective removal of the cells that comprise the hippocampus with ibotenic acid. Starting 4.5 months after surgery, lesioned and control rats were (i) trained in both the Morris water maze and the eight-arm radial maze using protocols that placed an emphasis on either working memory (WM) or reference memory (RM) and (ii) tested for locomotor activity in the home cage. In comparison to sham-operated rats, the rats from both lesion groups were impaired in most learning/memory tasks, but there were some interesting differences between the two lesioned groups. When compared to rats with fimbria-fornix lesions (FIFX rats), hippocampal rats (HIPP rats) were slower in learning to swim to a visible platform and showed a greater impairment than FIFX rats in the radial-maze task when the testing procedure required the utilization of RM and WM in a more demanding WM task. In the test of locomotor activity, FIFX and control rats did not differ, but HIPP rats were more active than the rats in both other groups. The pattern of results obtained after a 4.5-month recovery period support the following general conclusions. (1) While there are some similarities in the effects on behavior of interrupting the axons in the fimbria-fornix compared to removing the hippocampus, there are some important differences. (2) From the findings that are available, a possible explanation to account for the difference between FIFX and HIPP rats is that the 4.5-month survival time permitted some recovery in the group of rats with FIFX lesions. (3) While it is well known that the Morris water maze and the radial-arm maze tasks provide useful measures of spatial learning and memory processes, our results suggest that the information provided by the two spatial learning tasks may differ in important respects.

Asunto(s)

Agonistas de Aminoácidos Excitadores/efectos adversos , Hipocampo/efectos de los fármacos , Hipocampo/patología , Ácido Iboténico/efectos adversos , Locomoción/efectos de los fármacos , Aprendizaje por Laberinto/efectos de los fármacos , Trastornos de la Memoria/inducido químicamente , Conducta Espacial/efectos de los fármacos , Análisis de Varianza , Animales , Conducta Animal/fisiología , Electrodos Implantados , Hipocampo/cirugía , Masculino , Trastornos de la Memoria/diagnóstico , Trastornos de la Memoria/patología , Ratas , Técnicas Estereotáxicas , Sobrevida , Factores de Tiempo

RESUMEN

Long-Evans male, adult rats received selective and bilateral lesions of either the hippocampus, subiculum or lateral entorhinal cortex, and were then housed for 30 days in either enriched or standard conditions. Rats were then tested in the eight-arm radial maze to assess spatial working memory and the strategies that were employed (i.e. pattern of arms visited). Lesions of the hippocampus induced both a working-memory impairment and a loss in the use of allocentric strategies to perform the task. Rats with lesions of the subiculum were also impaired but less than hippocampectomized rats and showed a similar pattern of arm visits as control rats. In contrast with other lesioned rats, rats with lateral entorhinal cortex lesions performed the task like control rats. Postoperative enriched housing conditions (EHC) globally enhanced performance of rats, but did not affect the strategies selected by the rats to solve the task. The beneficial effect of EHC was particularly obvious in rats with lesions of the subiculum. In enriched rats with such lesions, performance was not significantly different from that of control rats housed in standard conditions. The present results indicate that 1) the structures within the hippocampal formation are not similarly involved in spatial learning and memory processes and in the management of navigational demands of the radial maze, and 2) enriched conditions may enhance the spared spatial abilities of some lesioned rats thus promoting functional recovery.

RESUMEN

To examine the regeneration capacity of dorsal septohippocampal neurons in the presence of an artificial growth-promoting substrate, biocompatible polymeric hydrogels were implanted between the septum and the hippocampus in a fimbria-fornix lesion cavity. Unmodified (control) or aminosugar-containing (glucosamines or N-acetyl-glucosamines) hydrogels were implanted immediately or ten days after the lesions. Six months later, brain sections were processed for cresyl-violet, acetylcholinesterase, and immunocytochemical (glial fibrillary acidic protein, protein S100, neurofilaments, laminin, fibronectin) staining. All hydrogels were well integrated in the brain, constituting a stable bridge between the septum and the hippocampus. Weak gliosis occasionally surrounded the hydrogel in rats from the immediate-implantation group, whereas a more pronounced gliosis was observed in those from the delayed-implantation group. The hydrogels contained blood vessels and were invaded by host cells including astrocytes. Astrocytes formed a loose tissue network filling the porous structure of the hydrogels. Within the hydrogels, laminin-, fibronectin- or neurofilaments-immunopositive networks were also observed. Moreover, numerous acetylcholinesterase-positive fibers penetrated into the hydrogels from the septal, cortical and striatal areas. Fibre penetration was most important in the N-acetylglucosamines-containing hydrogels. Despite these features, the hippocampus failed to show any increase of acetylcholinesterase-staining as compared to that seen in lesion-only rats. These results confirm the regeneration capacity of severed septohippocampal neurons into polymeric substrates used as a bridge inserted in a fimbria-fornix lesion cavity. As such, biomaterials might be of clinical interest not only in the case of spinal cord sections, but also in cases of brain trauma.

RESUMEN

The monosialoganglioside GM1 is a compound with neurotrophic properties found to foster functional recovery in various paradigms of brain damage. The present experiment examined whether systemic treatment with GM1 may facilitate behavioral recovery in rats with fimbria-fornix lesions and intrahippocampal grafts rich in cholinergic neurons. Among 68 Long-Evans female rats, 46 sustained a bilateral electrolytic lesion of the fimbria and the dorsal fornix and 22 were sham-operated. Fourteen days later, half the lesioned rats were subjected to intrahippocampal grafts of a fetal septal cell suspension. Starting a few hours after lesion surgery and over a 2-month period, half the rats of each surgical treatment group received a daily injection of GM1 (30 mg/kg i.p.), the other half being injected with saline as a control. All rats were subsequently tested for locomotor activity and radial maze learning. The lesions induced locomotor hyperactivity and impaired learning performances in both an uninterrupted and an interrupted radial maze testing procedure. In all rats with surviving grafts, the grafts had provided the hippocampus with a new and dense organotypic acetylcholinesterase-positive innervation pattern which did not differ between saline- and GM1-treated subjects. The scores/performances of the rats that had received only the grafts or only the GM1 treatment did not differ significantly from those of their respective lesion-only counterparts. However, in the radial-arm maze task, the grafted rats given GM1 showed improved learning performances as compared with their saline-treated counterparts: they used more efficient visit patterns under the uninterrupted testing conditions and made fewer errors under the interrupted ones. The results suggest that GM1 treatment or intrahippocampal grafts used separately do not attenuate the lesion-induced behavioral deficits measured in this experiment. However, when GM1 treatment and grafts are used conjointly, both may interact in a manner allowing part of these deficits to be attenuated.

Asunto(s)

Conducta Animal/efectos de los fármacos , Gangliósido G(M1)/farmacología , Hipocampo/fisiología , Tabique Pelúcido/trasplante , Acetilcolinesterasa/metabolismo , Animales , Ritmo Circadiano/fisiología , Conducta Exploratoria/fisiología , Femenino , Habituación Psicofisiológica/fisiología , Hipocampo/cirugía , Aprendizaje por Laberinto/fisiología , Actividad Motora/fisiología , Ratas

RESUMEN

In order to study the effects of differential housing conditions on recovery from damage to different components of the hippocampal formation, 85 rats received bilateral lesions of the hippocampus, entorhinal cortex, or subiculum or sham surgery and then were housed for 30 days in either an enriched environment or an impoverished environment. Rats were subsequently tested on a battery of tasks for assessing locomotor activity in their home cage, reactivity to novelty, spatial working and reference memory in the Morris water maze, and learning in the Hebb-Williams maze. Rats with the hippocampus removed showed impairments in most of the tasks we used (home-cage and novelty-induced locomotor activity, water maze, and Hebb-Williams maze). Most of the deficits induced by lesions to the entorhinal cortex were similar to those induced by the removal of the hippocampus. Some differences appear to be among the deficits induced by the lesions of these structures when assessing the home-cage locomotor activity, the reactions to novelty, and one aspect of the Hebb-Williams maze learning. Lesions to the subiculum induced only an impairment in the probe trial of the water-maze task. Confirming and extending previous findings in rats with various (but nonexcitotoxic) lesions of the hippocampus, an enriched environment had a beneficial effect on several of the deficits observed in the tasks we used. Further, only the rats with hippocampal lesions benefitted from having been housed in the enriched environment. However, their facilitated recovery was not observed in all tasks. After damage to different components of the hippocampal formation, the beneficial effects induced by the enriched housing conditions were shown to be both lesion-locus- and task-dependent.

Asunto(s)

Corteza Entorrinal/fisiopatología , Ambiente , Hipocampo/fisiopatología , Animales , Conducta Animal , Aprendizaje , Locomoción , Masculino , Ratas , Factores de Tiempo