Modulation of EEG rhythmicity and spike activity in the rat hippocampus by systemically administered tetrahydroaminoacridine, scopolamine and atipamezole.

The hippocampal EEG recording electrodes were implanted bilaterally in the hilus of the dentate gyrus (DG) and the stratum radiatum layer of the CA1 area in young (2-3-month-old) and aged (17-20-month-old) rats. In the subgroups of rats, brain noradrenaline (NA) was depleted by DSP-4 neurotoxin (50 mg/kg, IP). The aged animals were included in DSP-4-lesioned group in order to diminish the plastic regeneration of the noradrenergic system which may be more effective in young subjects. All the EEG recordings, after the administration of different agents or vehicle, were made while rats were awake and immobile. Approximately 40% decrease of brain NA had no noticeable effects on the nonrhythmical hippocampal EEG in either age group. In all the rats, compared to the baseline recordings, scopolamine hydrobromide (2 mg/kg, IP, a muscarinic antagonist) increased the incidence of spontaneous EEG spikes, while tetrahydroaminoacridine (THA, 12.5 mg/kg, IP, an acetylcholine esterase inhibitor) decreased the spike activity and induced theta rhythm. Atipamezole (3 mg/kg, SC), a noradrenergic alpha 2-antagonist, increased the baseline amplitude of the nonrhythmical EEG in the DG and increased slightly the spike activity in the CA1 area. The combined blockade of muscarinic receptors by scopolamine (2 mg/kg) and noradrenergic alpha 2-receptors by atipamezole (3 mg/kg) resulted in irregular EEG pattern and corresponding power spectra differed from the scopolamine spectra. The last combination treatment suggests that the effect of atipamezole was not mediated by the secondary cholinergic activation. In the DG, the spectral power increase caused by atipamezole may be related to the increased excitability/bursting liability of granular cells because NA turnover is increased by this agent and NA increases the excitability of granular cells.(ABSTRACT TRUNCATED AT 250 WORDS)     

Reductions in spontaneous locomotor activity in aged male, but not female, rats in a model of early Parkinson's disease

The excessive loss of dopamine (DA) neurons that occurs with Parkinson's disease is usually confined to older individuals. While 6-hydroxydopamine (6-OHDA) is often used in animal models of DA neuron degeneration, there have been relatively few studies that have examined the effects of 6-OHDA in older animals. In the present study, we compared the effects of a bilateral, partial lesion with 6-OHDA in young (4 months), middle-aged (14 months), and aged (24 months) Fischer-344 rats of both sexes. Animals were given a single injection of vehicle or 100 mug 6-OHDA into the right lateral ventricle. Four weeks later, spontaneous locomotor activity was monitored. Microdialysis experiments were carried out 1 to 3 days later. The 6-OHDA treatments had no effect on horizontal activity or total distance traveled in young adults. However, with aged rats, there was a decrease in both measures in the vehicle-treated control rats compared to young adult controls, and a further decrease in the lesioned aged male rats. The 6-OHDA treatments led to significant decreases in both potassium- and amphetamine-evoked overflow of DA from the striatum in all groups. Thus, partial bilateral lesions of the nigrostriatal DA system led to decreases in evoked release of DA in the striatum of male and female rats of all three ages, but to changes in spontaneous activity only in the aged males. These results indicate that there are both age and sex differences in the brain's response to 6-OHDA, and imply that compensatory or neuroprotective mechanisms in the young brain and aged female brain are more efficient than in the aged male brain.     

Specificity and efficacy of noradrenaline, serotonin depletion in discrete brain areas of Swiss mice by neurotoxins

The aim of this work is to define neurotoxins doses to have efficient and specific depletion of noradrenaline (NA), serotonin (5-HT) neurotransmission in cortex, striatum, hippocampus and hypothalamus of Swiss mice after intraperitoneal administration of, respectively, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4) and para-chlorophenylalanine methyl ester hydrochloride (PCPA). The neurotransmitters concentrations were determined by high performance liquid chromatography with amperometric detection. The minimal single dose necessary to produce a highly significant decrease of NA levels (p<0.01 in comparison with control group) in hypothalamus (-44%), hippocampus (-91%), striatum (-40%) and cortex (-68%) was 50mg/kg but DA and 5-HT levels were modified, respectively, in hypothalamus and striatum. Three doses of PCPA 300 mg/kg over 3 consecutive days involve a profound depletion of 5-HT transmission in all discrete brain areas but NA and DA levels were also significantly reduced. In conclusion, DSP-4 has a different efficacy in discrete brain areas with a noradrenergic specificity which is not absolute, PCPA has a similar efficacy in all brain areas but is unspecific of 5-HT transmission.     

Partial protection by desmethylimipramine of the mesocortical dopamine neurones from the neurotoxic effect of 6-hydroxydopamine injected in ventral mesencephalic tegmentum. The role of noradrenergic innervation

As shown in the rat by estimation of dopamine (DA) and noradrenaline (NA) levels, bilateral 6-hydroxydopamine (6-OHDA, 4 micrograms/microliter) lesions made in the ventral mesencephalic tegmentum (VMT) destroy both ascending DA and NA neurones. Pretreatment of rats with desmethylimipramine (DMI, 30 mg/kg, i.p.), 30 min before microinjection of 6-OHDA into the VMT partially prevented the destruction of the DA neurones innervating the prefrontal and cingulate cortices but not those innervating subcortical structures (nucleus accumbens, olfactory tubercles, septum). Results obtained from the prefrontal cortex of rats with extensive lesions of the ascending NA neurones performed 15 days prior to the 6-OHDA lesions of the VMT in the presence of DMI, imply that NA innervation of the VMT seems to be required for DMI to protect the cortical DA neurons from the neurotoxic effect of 6-OHDA.     

Lesions of noradrenergic neurons in rats with spontaneous generalized non-convulsive epilepsy.

The role of noradrenergic neurons in the control of a spontaneous generalized non-convulsive epilepsy (GNCE) was investigated. In rats with genetic spontaneous absence seizures, we produced lesions using 2 neurotoxins: 6-hydroxydopamine (6-OHDA) and N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4). Lesions of noradrenergic neurons were made either in pups by neonatal 6-OHDA intraperitoneal (i.p.) injection (2 x 100 mg/kg) or in adult rats by i.p. administration of DSP4 (60 mg/kg) or bilateral microinjection of 6-OHDA in the locus coeruleus (LC) (4 micrograms/microliters, 2 microliters/side). Effectiveness of the lesions was controlled by measuring dopamine (DA) and noradrenaline (NA) contents in the brains. Neonatal 6-OHDA administration did not lead to any difference in seizures in adult animals, compared with control rats. DSP4 injections and LC lesions with local injections of 6-OHDA produced a transient increase of the seizures. Within one to two weeks, the seizure duration went back to prelesion levels. No seizure occurred when the same lesions were performed in non epileptic rats. These results suggest that NA is not involved in the genesis of this generalized non-convulsive epilepsy; they confirm that NA participates in the control of seizures in this model, but the rapid development of compensatory mechanisms shows that this control is not critical.     

Amygdalar noradrenergic and dopaminergic mechanisms in the regulation of hunger and thirst-motivated behavior

The feeding behavior of rats was studied after neurochemical damage of the amygdalar terminal fields of mesolimbic dopaminergic (DA) and coerular noradrenergic (NA) pathways. 6-Hydroxydopamine (6-OHDA) or 6-hydroxydopa (6-OHDOPA) were injected bilaterally into the central part of amygdala. 6-OHDA was also injected after desmethylimipramine (DMI) pretreatment in order to study the selective destruction of DA terminals. The body weight increased after 6-OHDA injection and a mild hyperphagia and hyperdipsia developed. The 6-OHDA plus DMI treatment resulted in body weight decrease, hypophagia and hypodipsia. These effects were dose-dependent. While a high dose of 6-OHDOPA (15 mug/mul) decreased the body weight, an increase of weight was observed after a low dose (4 mug/0.5 mul). After 6-OHDA, 6-OHDA plus DMI or the high dose of 6-OHDOPA the DA concentration dropped significantly in the amygdala while low-dose 6-OHDOPA resulted in DA increase. In every case there was a parallel change in striatal DA content. The amygdalar NA concentration decreased after both 6-OHDA and the high dose of 6-OHDOPA. There was no change in NA levels after 6-OHDA plus DMI treatment and the NA concentration increased after the injection of a low dose of 6-OHDOPA. When DA/NA ratio was calculated the results showed that body weight increases were accompanied by a relative deficit in NA while a relative deficit of DA was present if body weight decreased. Our results suggest that the amygdalar balance of these transmitters may play an important role in the regulation of body weight and the contradictions of results with electrolytic lesions in the amygdala can be resolved at transmitter level.     

Suppression of noradrenergic innervation compensates for behavioral deficits induced by lesion of dopaminergic terminals in the lateral septum

Spontaneous alternation which is disrupted by lesion of septal dopaminergic (DA) afferents was chosen as a behavioral marker for the study of functional interactions between DA and noradrenergic (NA) innervation of the lateral septum. Three groups of rats were studied: a solvent group which received only vehicle injection, and two lesioned groups, one with DA lesion and the second with simultaneous DA + NA lesion of the septal innervation. DA lesion was produced by infusing 6-hydroxydopamine (6-OHDA) into the lateral septum after pretreatment with desmethylimipramine (DMI) injected intraperitoneally. The DA + NA lesion was produced by infusing 6-OHDA without DMI pretreatment. The lesion of DA innervation alone led to a disturbance of alternation behavior in a Y-maze, but performance was not affected by the combined DA + NA lesion. The group with septal DA lesion was then injected with 6-OHDA into the pedunculus cerebellaris superior (PCS) in order to destroy NA efferents from the locus coeruleus. The two other groups were sham-operated. After post-operative recovery, the rats were retested for spontaneous alternation. The rats with the PCS NA lesion subsequent to the DA septal lesion displayed normal alternation behavior. Their performance was not different from that of animals with both NA and DA lesions in the septum. Thus the NA lesion appears to prevent the alternation deficits induced by the DA septal lesion, and also abolishes the deficits induced by the prior DA lesions. These results may have therapeutic implications.     

Chemical lesions of the nucleus accumbens septi in rats: effects on muricide and apomorphine-induced aggression

To assess the influence of monoaminergic neurones in the nucleus accumbens septi (NAS) on muricidal and apomorphine-induced aggression, bilateral intraaccumbens injections of relevant neurotoxins were performed. Neurochemical effects in the mesolimbic area (NAS and tuberculi olfactorii) and striatal tissue were investigated using high performance liquid chromatography. 6-Hydroxydopamine (6-OHDA) with desipramine pretreatment significantly decreased mesolimbic dopamine (DA) metabolism, 5,7-dihydroxytryptamine (5,7-DHT) plus desipramine diminished serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA), while DSP-4 depleted noradrenaline (NA), 5-HT, 5-HIAA and tryptophan in the mesolimbic area. No significant biochemical changes were observed in the striatum. Behaviourally, 6-OHDA-treated rats were markedly more aggressive in the apomorphine-induced fighting test. Similarly, DSP-4 injections into the NAS (10 micrograms/1 microliter) enhanced this type of aggression. The 5,7-DHT lesion did not alter apomorphine-induced fighting. None of the neurotoxins induced muricidal behaviour. It is concluded that dopaminergic postsynaptic receptors in the NAS may be involved in the pro-aggressive effect of apomorphine. The results support the hypothesis that NA-containing neurones play an inhibitory role in apomorphine-induced aggression and suggest that such a DA-NA interaction might occur in the NAS.     

Effects of norepinephrine depletion in rats during cerebral post-ischemic reperfusion

The present paper reports the effects of norepinephrine depletion in rats, after treatment with N-(2-chloroethyl)-N-ethyl 2-bromobenzylamine (DSP-4) neurotoxin, on partial cerebral ischemia and reperfusion. Histological observations made under experimental conditions of noradrenergic (NA)-depletion demonstrated that neuronal lesions were not exacerbated; in fact, in DSP-4-treated ischemic animals, a minor number of neurons appeared damaged. Our results suggest that neuronal recovery after post-ischemic reperfusion is not affected by NA-depletion. DSP-4 neurotoxin does not induce 5-hydroxy-triptamine (5-HT) depletion.     

Clonidine-induced sedation in rats: Evidence for mediation by postsynapticα 2-adrenoreceptors

Summary The effect of low doses of clonidine on exploration and motility was investigated in rats after destruction of central noradrenergic systems by 6-hydroxydopamine (6-OHDA) or DSP-4. In accordance with previous results, clonidine decreased exploration and motility in control animals. This sedative effect of clonidine was potentiated in animals that suffered selective and extensive depletions of brain NA as a result of neonatal treatment with 6-OHDA. Depletion of NA by administration of DSP-4 to adult animals did not influence clonidine's sedative effects. Yohimbine, but not phentolamine, antagonized clonidine-induced hypomotility both in control and in neonatal 6-OHDA treated groups. The results suggest that clonidineinduced sedation is mediated by postsynaptic ₂-adrenoreceptors.     

Body weight changes after neurochemical manipulations of lateral amygdala: Noradrenergic and dopaminergic mechanisms

The feeding behavior of rats was studied after neurochemical lesions of lateral amygdalar terminal fields of mesolimbic dopaminergic (DA) and coerular noradrenergic (NA) systems. 6-Hydroxydopamine (6-OHDA) with or without desmethylimipramine (DMI) premedication was bilaterally injected into the lateral amygdala or periamygdaloid-piriform area. Lateral amygdalar injections of 6-OHDA resulted in hyperdipsia, hyperphagia and body weight increase with a relative decrease in amygdalar NA concentration, while 6-OHDA plus DMI treatments were followed by weight decrease and a mild decrease in DA level. When the cannulas were placed into the periamygdaloid-piriform cortex nothing but body weight increase developed. The importance of the actual balance of the two amygdalar catecholaminergic (CA) systems in feeding is discussed.     

Spatial Learning and Noradrenaline Content in the Brain and Periphery of Young and Aged Rats

The present experiment studied whether a dysfunction of the noradrenergic neurons is related to spatial learning impairment by investigating the levels of noradrenaline in the brain and periphery as well as the acquisition of water maze task in saline-pretreated young rats, in noradrenergic neurotoxin (DSP-4)-pretreated young rats and in saline-pretreated aged rats. Aged rats, which had an increased escape latency onto the hidden platform, revealed a decreased noradrenaline content in the heart, but not in the hippocampus, striatum, or hypothalamus, whereas DSP-4-pretreated rats had decreased noradrenaline content in the brain; the acquisition of water maze task was not impaired. These results suggest that the peripheral noradrenergic system can show age-related changes different from those in the central noradrenergic system, and they failed to provide support for the hypothesis that decreased activity of the central noradrenergic nerves is related to impairment in the acquisition of the water maze task.     

DSP-4: A novel compound with neurotoxic effects on noradrenergic neurons of adult and developing rats

The pharmacological actions of the compound N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4) are compatible with a specific neurotoxic effect on both peripheral and central noradrenergic neurons. The systemic injection of DSP-4 to adult rats transiently alters sympathetic neurons in the periphery but in the central nervous system the compound determines a marked and prolonged reduction of noradrenaline (NA) levels in all brain regions studied. When DSP-4 was injected systemically to rats at birth in doses ranging from 6.25 to 100 μg/g, no changes were found in peripheral sympathetic neurons 40 days later. On the contrary, in the same conditions and in relation to the dose injected, there were marked and persistent changes in the levels of NA in different regions of the brain. In the cerebral cortex and the spinal cord, the neonatal injection of DSP-4 produced a marked and long-lasting depletion of NA levels, similar to that observed after injection of the compound to adult rats. These changes were accompanied by a moderate increase in brain stem NA and a marked elevation of the amine in the cerebellum. These changes, different from the depletion observed in both regions when the compound was given to adult rats, are however similar to those observed after the neonatal injection of the neurotoxic compounds 6-hydroxydopamine or its precursor amino acid, 6-hydroxydopa. This indicates that probably central noradrenergic neurons respond in the same manner after different chemical injuries. DSP-4 crosses the placental barrier because when it was given to pregnant rats at the end of gestation, long-term changes were found in brain NA levels in their offspring, similar to those produced by the neonatal administration of the compound. This new neurotoxic compound provides a very useful tool for the study of noradrenergic neurons both in adult animals and during ontogenesis.     

Selective lesion of central dopamine or noradrenaline neuron systems in the neonatal rat: motor behavior and monoamine alterations at adult stage

Different parameters of motor behavior (locomotion, rearing and total activity counts) were studied in the adult rat following neonatal intracisternal 6-hydroxydopamine (6-OHDA, 50 micrograms) treatment combined with noradrenaline (NA) uptake blocker (desipramine) or dopamine (DA) uptake blockers (amfolenic acid or GBR 12909) to obtain selective DA or NA lesions respectively. At 61-65 days of age, selective DA-lesioned animals showed an initial decrease in spontaneous motor behavior at test days 1 and/or 2, while at test days 4 and 5 hyperactivity was observed. However, following amfolenic acid or GBR 12909 pretreatment leading to a selective NA lesion, no difference in spontaneous motor behavior was seen on any of the 5 test days. Determination of regional brain levels of NA and DA confirmed the type of lesion predicted from the various pretreatments with selective uptake blockers. These data suggest that changes in motor behavior in the adult rats, following neonatal 6-OHDA treatment, are specifically related to a DA-denervation, whereas an NA lesion does not seem to influence the spontaneous motor behavior. However, following the selective DA lesion, significant increases of serotonin levels in striatum and cerebellum were observed, while following selective NA lesions an increase of cerebellar NA levels was found concomitant with drastic reductions of NA levels in frontal cortex and spinal cord.     

Behavioral and neurochemical effects of noradrenergic depletions with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine in 6-hydroxydopamine-induced rat model of Parkinson's disease

In Parkinson's disease, besides the dopaminergic neurodegeneration, locus coeruleus noradrenergic neurons degenerate as well. Noradrenergic neurons have potential anti-parkinsonian, neuromodulatory and neuroprotective properties. Presently, an animal model with dopaminergic lesion has been used as a standard model of Parkinson's disease. The behavioral effects of dopaminergic agents in a Parkinson's animal model with additional noradrenergic lesions has not been studied so far. Here, the behavioral effects of dopaminergic agents L-DOPA (15 mg/kg) and D-amphetamine (4 mg/kg) in two different pathophysiological conditions have been explored; One group involving only dopaminergic deficiency with 6-hydroxydopamine (6-OHDA) and the other group with both dopaminergic and noradrenergic deficiency with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4). DSP-4 specifically depleted noradrenaline from locus coeruleus terminal fields. 6-OHDA lesion depleted dopamine and its metabolites DOPAC, HVA and 3-MT in the regions of basal ganglia and it was potentiated by additional locus coeruleus denervation. Dopaminergic lesion produced catalepsy and hypoactivity. Hypoactivity in openfield was potentiated by additional noradrenergic denervation of locus coeruleus neurons. L-DOPA produced effective anticataleptic activity in group with both dopaminergic and noradrenergic lesions and D-amphetamine was found to be more effective in group only with dopaminergic lesions, indicating increased dopaminergic neurodegeneration after noradrenergic lesions. L-DOPA produced hyperactivity in dual neurodegenerated group indicating its differential activity in an animal model with noradrenergic and dopaminergic lesions. These findings indicate the neuroprotective and symptomatic role of noradrenergic neurons. It implicates the importance of noradrenergic pathophysiology in Parkinson's disease and its treatment and need for a more relevant animal model.     

Behavioural and biochemical effects of dopamine and noradrenaline depletion within the medial prefrontal cortex of the rat

The effects of 6-hydroxydopamine (6-OHDA) lesions of catecholamine terminals within the medial prefrontal cortex on spontaneous motor activity, dopamine (DA)-dependent stereotyped behaviour and subcortical dopamine turnover were investigated in the rat. Two types of lesions were examined, bilateral injection of 6-OHDA into the medial prefrontal cortex of untreated rats (6-OHDA alone), and bilateral injection of 6-OHDA into the medial prefrontal cortex of animals pretreated with the noradrenaline (NA) uptake blocking agent desmethylimipramine (6-OHDA/-DMI). Ten days after surgery the 6-OHDA lesions produced no significant change in spontaneous motor activity and had no overall effects on stereotyped behaviour induced by apomorphine or (+)-amphetamine. This lesion caused gross depletion of NA within the medial prefrontal cortex and curiously, elevated DA concentrations within this site. No changes in DA concentration were recorded within subcortical sites, although concentrations of DA metabolites within striatum and nucleus accumbens were reduced. In contrast, the 6-OHDA/DMI lesion of the medial prefrontal cortex significantly enhanced spontaneous motor activity and amphetamine-induced stereotyped behaviour. Apomorphine-induced stereotypy, on the other hand, was significantly reduced. Biochemically the lesion caused a large depletion of DA with relatively little loss of NA within the medial prefrontal cortex. In addition, from this and another study (ref. 33), increases in DA and its metabolite concentrations were measured in striatum and nucleus accumbens, together with an apparent increased in DA turnover within these subcortical sites. It is thus apparent that in the absence of a substantial portion of the DA innervation of the medial prefrontal cortex, with a largely intact NA innvervation, there is an increase in motor activity and amphetamine-induced stereotypy which may be related to functional changes in DA activity within subcortical telecephalic structures. Such a finding might suggest that DA within the frontal cortex has a behaviourally inhibitory role in the rat, although further work is required to substantiate this.     

Monoamine and metabolite levels in the prefrontal cortex and the mesolimbic forebrain following neonatal lesions of the ventral tegmental area

Monoamine metabolism was determined in the medial prefrontal cortex (mPFC) and the limbic forebrain (LFB) of adult rats following neonatal lesions of the ventral tegmental area. The dopamine (DA) and serotonin (5-HT) levels were decreased down to 30% in both the mPFC and the LFB. The noradrenaline (NA) level was also significantly decreased, but only in the mPFC of the right hemisphere. The metabolite/transmitter ratios of DA and 5-HT, but not of NA, were greatly increased in the depleted mPFC, but not in the LFB, which suggests an increased activity of the remaining cortical DA and 5-HT fibres in the mPFC.     

5-HT agonist induced analgesia modulated by central but not peripheral noradrenaline depletion in rats

Summary The antinociceptive effect elicited by the 5-hydroxytryptamine (5-HT) agonist 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) was reversed or blocked in animals which had previously sustained severe spinal noradrenaline (NA) depletion via either systemic N-2-chlorethyl-N-ethyl-2-bromobenzylamine hydrochloride (DSP 4), neonatal 6-hydroxydopamine (neon. 6-OHDA), or intrathecal 6-OHDA treatment. Biochemical analysis of the lumbar spinal cord samples confirmed severe central NA depletions. Animals were tested with nondamaging heat pain (tail-flick test, hot-plate test) and electric footshock titration to determine the amount of antinociception or nociception. Peripheral NA depletion following intravenous (i.v.) 6-OHDA injection to adult rats had no effect on the antinociception induced by 5-MeODMT, but did cause severe NA depletions in the left heart atrium. These results suggest a modulatory effect of central and not peripheral noradrenergic system upon 5-HT agonist induced analgesia, and also give evidence that this effect is spinally mediated.     

Noradrenergic denervation facilitates the release of acetylcholine and serotonin in the hippocampus: towards a mechanism underlying upregulations described in MCI patients?

Patients with mild cognitive impairment (MCI), who are at risk for Alzheimer's disease (AD), or those with early AD, exhibit noradrenergic degeneration in the locus coeruleus. In MCI patients, upregulations of cholinergic and serotonergic functions were described in the hippocampus. To investigate the effects of selective noradrenergic denervation on hippocampal neurotransmitter functions, rats were treated with 50mg/kg (i.p.) of N-2-chlorethyl-N-ethyl-2-bromobenzylamin (DSP-4). DSP-4 treatment reduced hippocampal noradrenaline (NA) by more than 90% (vs. controls), whereas dopamine and 5-HT levels were unaffected. The accumulation and electrically-evoked release (in nCi) of [³H]-NA in hippocampal slices were strongly reduced. Accumulation of [³H]-5-HT was reduced in DSP-4 rats, whereas spontaneous and electrically-evoked release of [³H]-5-HT was significantly enhanced, probably due to a weaker effect of endogenous NA via α₂-adrenoceptors on serotonergic terminals. Accordingly, the α₂-agonist UK-14,304 [5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline] more potently inhibited the evoked 5-HT release in DSP-4 rats, whereas the α₂-antagonist idazoxan failed to exert facilitatory effects. Most surprisingly, the accumulation of [³H]-choline, and both the basal and electrically-evoked overflow of [³H] from hippocampal slices preincubated with [³H]-choline, were also significantly increased in DSP-4 rats. These observations suggest that noradrenergic damage in the locus coeruleus may facilitate cholinergic and serotonergic functions in the hippocampus. Although the current lesion model does not mimic the protracted evolution of neurodegenerative processes in MCI and AD, our data could point to an explanation for the upregulations of cholinergic and serotonergic functions described in the hippocampus of MCI patients.     

铁对大鼠黑质神经递质影响的初步研究

目的:探讨Fe3+/Fe2+对大鼠黑质神经递质影响。方法:黑质内分别注射:FeCl3、FeCl2和6-羟多巴胺(6-OHDA),四周后应用阿朴吗啡诱发旋转行为、高压液相色谱分析检测黑质内多巴胺、去甲肾上腺素、肾上腺素和5-羟色胺水平。结果:注射FeCl3的大鼠出现向损毁同侧的旋转行为;注射FeCl3和FeCl2侧黑质内多巴胺水平显著降低,去甲肾上腺素、肾上腺素和5-羟色胺水平不受影响。结论:Fe3+/Fe2+对大鼠黑质多巴胺能神经元具有特异性的毒性作用。