Biomedical subjects

J C Cassel

Publications and source records attributed to J C Cassel.

At least 19 recordsLinked to original sources

PubMed2006

Reversible inactivation of the dorsal hippocampus by tetrodotoxin or lidocaine: a comparative study on cerebral functional activity and motor coordination in the rat.

Reversible inactivation of the hippocampus by lidocaine or tetrodotoxin is used to investigate implications of this structure in memory processes. Crucial points related to such inactivation are the temporal and spatial extents of the blockade. We compared effects of intrahippocampal infusions of commonly-used doses of lidocaine (5 or 10 mug) or tetrodotoxin (5 or 10 ng) in rats at two post-infusion delays (5 or 30 min), using 2-deoxyglucose autoradiography to visualize local cerebral glucose metabolism, and beam-walking performance to assess motor coordination. In addition, memory retrieval was evaluated in a water maze after bilateral infusions of 10 mug lidocaine. A unilateral tetrodotoxin infusion induced dose- and time-dependent reductions of 2-deoxyglucose uptake in the vicinity of the infusion site (dorsal hippocampus: -29% to -67%) and in other ipsi- and contralateral brain regions (ventral hippocampus, lateral thalamus, cortical regions). The maximal effect was at 10 ng, at the delay of 30 min between the tetrodotoxin infusion and the 2-deoxyglucose injection. Uni- and bilateral infusions of tetrodotoxin induced dramatic motor coordination deficits. Conversely, lidocaine reduced 2-deoxyglucose uptake (-19%) in the dorsal hippocampus only at 10 mug, with weak extrahippocampal effects. Whether infused uni- or bilaterally and regardless of the dose, lidocaine did not alter motor coordination. When infused bilaterally, however, 10 microg of lidocaine impaired short-term retrieval of spatial information in a water maze. Because lidocaine i) induced a weak though significant functional blockade mainly restricted to the infusion site, ii) had no consequences on motor coordination and, nevertheless iii) altered short-term spatial memory retrieval, we conclude that acute intrahippocampal infusions of lidocaine may offer some advantages over tetrodotoxin at the doses used herein.

Analysis of Variance↗

PubMed2001

Cognitive performances and locomotor activity following dentate granule cell damage in rats: role of lesion extent and type of memory tested.

Intradentate injection of colchicine is one of the techniques used to destroy granule cells. This study compared the behavioral effects of various amounts of colchicine (1.0, 3.0, and 6.0 microg; Col 1, Col 3, and Col 6, respectively) injected into the dentate gyrus of adult Long-Evans male rats. Starting 10 days after lesion surgery, behavioral testing assessed home-cage and open-field locomotion, alternation in a T-maze, water-maze, and radial-maze learning according to protocols placing emphasis on reference, and working memory. All of these tasks are sensitive to hippocampal disruption. Histological verifications showed that the extent of the lesions depends on the dose of colchicine (index of dentate gyrus shrinkage: -33% in Col 1, -54% in Col 3, and -67% in Col 6 rats). Colchicine dose-dependently increased nocturnal home cage activity (an effect found 10 days but not 5 months after surgery), but had no significant effect on open-field locomotion or T-maze alternation. A dose-dependent reference memory impairment was found during the acquisition of spatial navigation in the water maze; Col 3 and Col 6 rats were more impaired than Col 1 rats. During the probe trial (platform removed), control rats spent a longer distance swimming over the platform area than all rats with colchicine lesions. In the working memory version of the test, all rats with colchicine lesions showed significant deficits. The deficits were larger in Col 3 and Col 6 rats compared to Col 1 rats. The lesions had no effect on swimming speed. In the radial-maze test, there was also a dose-dependent working memory impairment. However, reference memory was disrupted in a manner that did not differ among the three groups of lesioned rats. Our data are in line with the view that the dentate gyrus plays an important role in the acquisition of new information and is an integral neural substrate for spatial reference and spatial working memory. They also suggest that damage to granule cells might have more pronounced effects on reference than on working memory in the radial maze. Finally, they demonstrate that part of the variability in the conclusions from previous experiments concerning the role of granule cells in cognitive processes, particularly in spatial learning and memory, may be due to the type of tests used and/or the extent of the damage produced.

Animals↗

PubMed2001

Electrically evoked release of glutamate in rat hippocampal slices: effects of various drugs and fimbria-fornix lesions.

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.

Action Potentials↗

PubMed2001

Effects of MDL 73005 on water-maze performances and locomotor activity in scopolamine-treated rats.

The stimulation of 5-HT1A receptors in the raphe or their blockade in the hippocampus can reduce cognitive deficits induced by blockade of muscarinic receptors in the hippocampus. We investigated the effects of MDL 73005 (8-[2-(2,3-dihydro-1,4-benzodioxin-2-ylmethylamino) ethyl]-8-azaspiro[4,5] decane-7,9-dione methyl sulphonate), an agonist at 5-HT1A somatodendritic autoreceptors and an antagonist at postsynaptic 5-HT1A receptors in rats treated systemically with scopolamine. Spatial memory was assessed in a water maze using protocols testing reference and working memory. Home cage locomotor activity was also determined. Working memory and locomotor activity were evaluated before and after para-chlorophenylalanine (pCPA) treatment. Scopolamine produced a weak impairment of reference memory at 0.5 mg/kg, and a more pronounced impairment of working memory at 0.25 and 0.5 mg/kg. MDL 73005 alone (2 mg/kg, i.p.) had no effect, but prevented the memory impairments induced by 0.25 mg/kg of scopolamine. Scopolamine induced hyperlocomotion. MDL 73005 alone did not affect locomotor activity, but exacerbated the hyperlocomotion induced by 0.5 mg/kg of scopolamine. pCPA did not abolish the effects of MDL 73005, suggesting that these effects were not due to an action at presynaptic receptors, or even that they involved receptors other than serotonergic ones (e.g., D2). In conclusion, MDL 73005 is able to antagonise moderate spatial memory dysfunctions induced by systemic muscarinic blockade.

Animals↗

PubMed2001

Homotopic grafts of septal neurons combined to polymeric hydrogels placed into a fimbria-fornix lesion cavity attenuate locomotor hyperactivity but not mnemonic dysfunctions in rats.

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.

Animals↗

PubMed2000

Serotonergic modulation of hippocampal acetylcholine release after long-term neuronal grafting.

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.

Acetylcholine↗

PubMed2000

Preserved olfactory short-term memory after combined cholinergic and serotonergic lesions using 192 IgG-saporin and 5,7-dihydroxytryptamine in rats.

Young adult Long-Evans female rats were subjected to intracerebroventricular injections of 150 microg 5,7-dihydroxytryptamine (5,7-DHT), 2 microg 192 IgG-saporin, or a combination of both neurotoxins. All rats were tested for olfactory recognition (short-term memory) using a task based on spontaneous exploration of odor sources. Compared with animals undergoing sham operations, 5,7-DHT reduced the concentration of serotonin by 60-80% in the frontoparietal cortex, hippocampus, striatum and the olfactory bulbs. After 192 IgG-saporin treatment, acetylcholine concentrations were reduced by approximately 40% in all these structures, except the striatum. Neither lesion induced a significant deficit in olfactory recognition. These data suggest that combined lesions of cholinergic and serotonergic neurons in the rat brain do not alter olfactory perception or olfactory short-term memory.

5,7-Dihydroxytryptamine↗

PubMed2000

Intraseptal infusions of 8-OH-DPAT in the rat impairs water-maze performances: effects on memory or anxiety?

In the rat, 5-HT1A receptors are found on medial septal cholinergic neurons. The effects of intraseptal infusions of the 5-HT1A receptor agonist 8-OH-DPAT (8-hydroxy-2-(di-n-propyl-amino)-tertralin) were assessed on reference memory performances in a water maze. Compared with vehicle infusions, 0.5 and 4 microg of 8-OH-DPAT significantly impaired (but did not prevent) acquisition of the task and probe-trial performances. The results suggest that activation of 5-TH1A receptors in the (medial) septal area impairs spatial learning, perhaps directly by reducing the hippocampal cholinergic tonus, or indirectly by an effect on anxiety.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed2000

Selective lesions of the entorhinal cortex, the hippocampus, or the fimbria-fornix in rats: a comparison of effects on spontaneous and amphetamine-induced locomotion.

Using adult Long-Evans male rats, this experiment compared spontaneous (assessed 15 days and 4.5 months after surgery) and amphetamine-induced (assessed from 4.5 months after surgery onwards; 1 mg/kg, i.p., ten injections, 48 h apart) locomotor activity following N-methyl-D-aspartate lesions of the entorhinal cortex, electrolytic lesions of the fimbria-fornix, or ibotenate lesions of the hippocampus. Sham-operated rats were used as controls. Hippocampal and fimbria-fornix lesions, but not entorhinal-cortex lesions induced diurnal and nocturnal hyperactivity, which was attenuated over time, but only in rats with fimbria-fornix lesions. Amphetamine-induced hyperlocomotion was assessed in a familiar environment. Lesions of the entorhinal cortex potentiated the locomotor effects of amphetamine, but not lesions of the hippocampus or interruption of the axons in the fimbria-fornix pathway. Sensitization appeared to be decreased by fimbria-fornix lesions and to be prevented by hippocampal lesions. Rats with entorhinal-cortex lesions behaved as if they had already been sensitized by the lesion. These results clearly show that lesions of the fimbria-fornix, the hippocampus, and of the entorhinal cortex have different effects on spontaneous and amphetamine-induced hyperactivity, as they also have on learning and memory tasks.

Amphetamine↗

PubMed2000

Immunohistochemical and neurochemical correlates of learning deficits in aged rats.

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.

Aging↗

PubMed2000

Combined lesions of cholinergic and serotonergic neurons in the rat brain using 192 IgG-saporin and 5,7-dihydroxytryptamine: neurochemical and behavioural characterization.

This study assessed behavioural and neurochemical effects of i.c.v. injections of both the cholinergic toxin 192 IgG-saporin (2 microgram) and the serotonergic toxin 5,7-dihydroxytryptamine (5,7-DHT; 150 microgram) in Long-Evans female rats. Dependent behavioural variables were locomotor activity, forced T-maze alternation, beam walking, Morris water-maze (working and reference memory) and radial-maze performances. After killing by microwave irradiation, the concentrations of acetylcholine, monoamines and 5-hydroxyindoleacetic acid (5-HIAA) were measured in the hippocampus, frontoparietal cortex and striatum. 192 IgG-saporin reduced the concentration of acetylcholine by approximately 40% in the frontoparietal cortex and hippocampus, but had no effect in the striatum. 5,7-DHT lesions reduced the concentration of serotonin by 60% in the frontoparietal cortex and 80% in the hippocampus and striatum. Noradrenaline was unchanged in all structures except the ventral hippocampus where it was slightly increased in rats given 192 IgG-saporin. Cholinergic lesions induced severe motor deficits but had no other effect. Serotonergic lesions produced diurnal and nocturnal hyperactivity but had no other effect. Rats with combined lesions were more active than those with only serotonergic lesions, showed motor dysfunctions similar to those found in rats with cholinergic lesions alone, and exhibited impaired performances in the T-maze alternation test, the water-maze working memory test and the radial-maze. Taken together and although cholinergic lesions were not maximal, these data show that 192 IgG-saporin and 5,7-DHT lesions can be combined to selectively damage cholinergic and serotonergic neurons, and confirm that cholinergic-serotonergic interactions play an important role in some aspects of memory, particularly in spatial working memory.

5,7-Dihydroxytryptamine↗

PubMed2000

Central cholinergic depletion induced by 192 IgG-saporin alleviates the sedative effects of propofol in rats.

We examined the effect of central cholinergic depletion on the sedative potency of propofol in rats. Depletion was produced by intracerebroventricular administration of an immunotoxin specific to cholinergic neurones (192 IgG-Saporin; 2 microg). As a result of this lesion, acetylcholine concentration was reduced by about 40% in the frontoparietal cortex and in the hippocampus but was essentially normal in the striatum and cerebellum. Sedation in rats was assessed as the decrease in locomotor activity. Sedative potency of propofol (30 mg kg(-1) i.p.) was reduced by about 50% in rats who received the injection of 192 IgG-Saporin as compared to controls. These results show that a central cholinergic depletion alleviates the sedative effect of propofol, and indicates that basal forebrain cholinergic neurones might mediate part of the sedative/hypnotic effects of propofol.

Acetylcholine↗

PubMed2000

Intracerebral transplants and memory dysfunction: circuitry repair or functional level setting?

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.

Animals↗

PubMed1999

Modulation of acetylcholine and 5-hydroxytryptamine release in hippocampal slices of rats with fimbria-fornix lesions and intrahippocampal grafts containing cholinergic and/or serotonergic neurons.

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.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1999

Intrahippocampal grafts containing cholinergic and serotonergic fetal neurons ameliorate spatial reference but not working memory in rats with fimbria-fornix/cingular bundle lesions.

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.

Acetylcholine↗

PubMed1999

The potentiation of amphetamine-induced hyperlocomotion by fimbria-fornix lesions in rats is abolished by intrahippocampal grafts rich in serotonergic neurons.

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.

Amphetamine↗

PubMed1999

Modulation of 5-hydroxytryptamine release in hippocampal slices of rats: effects of fimbria-fornix lesions on 5-HT1B-autoreceptor and alpha2-heteroreceptor function.

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).

Adrenergic alpha-Agonists↗

PubMed1999

Sympathetic sprouting: no evidence for muscarinic modulation of noradrenaline release in hippocampal slices of rats with fimbria-fornix lesions.

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.

Animals↗