Brain norepinephrine and convulsions in the genetically epilepsy-prone rat: sex-dependent responses to Ro 4-1284 treatment

Seizure predisposition in the Genetically Epilepsy-Prone Rat (GEPR) is at least partially dependent on central nervous system noradrenergic deficits. We have previously shown that moderate seizure GEPRs (GEPR-3) experience an increase in seizure severity after receiving Ro 4-1284, a monoamine vesicle inactivating drug. We are now reporting the effect of this drug on severe seizure GEPRs (GEPR-9). Motives for this study were: (a) to determine the effects of further depletion of innately deficient monoaminergic stores on seizure latencies and (b) to investigate whether a previously documented seizure severity difference between the sexes is related to the defective monoaminergic system in these subjects. GEPR-9s with known seizure history were tested for latency to onset of running phase and convulsion 45 minutes after Ro 4-1284 or saline administration. Brain norepinephrine levels were also determined. Ro 4-1284 caused severe depletion of monoamines in all brain areas assayed in both sexes of GEPR-9s and also caused a reduction in the latencies for onset of running and convulsion. The drug-induced norepinephrine depletion across the brain areas surveyed was significantly greater in females than in their male littermates. These observations prompt us to postulate that noradrenergic neurons in female GEPR-9s are functionally different from those in males and that this difference is detected in the differential effectiveness of Ro 4-1284 between the two sexes. Also, the influence of gonadal hormones on seizure predisposition and on the neurochemical actions of Ro 4-1284 may be different in GEPR-9 males and females.     

Effect of Ro 4-1284 on audiogenic seizure susceptibility and intensity in epilepsy-prone rats

The effects of CNS monoamine depletion on audiogenic seizure (AGS) susceptibility and intensity were studied in two types of Sprague-Dawley derived rats: (1) the progeny of a nonsusceptible strain (controls); and (2) the nonsusceptible progeny of epilepsy-prone (audiogenic seizure susceptible) parents (NSPSP). Forty-five minutes after injection of the benzoquinolizine Ro 4-1284, a significant fraction of the NSPSP developed AGS susceptibility, whereas the incidence in controls was not significant. AGS intensity was also significantly elevated 45 minutes and 19 days following Ro 4-1284 in NSPSP. In controls, there was a smaller, but significant, elevation of seizure intensity only at the earlier time period. Both types of rats exhibited a marked depletion of norepinephrine (NE) and 5-hydroxytryptamine (5-HT) in all of the six different areas of the CNS which were examined. In the NSPSP, a significant incidence of seizure susceptibility was retained as long as 19 days after Ro 4-1284 administration, despite the complete repletion of monoamine stores. These observations suggest that CNS monoaminergic neurons function as determinants of AGS susceptibility and intensity in animals which also carry some other genetically determined susceptibility factor(s). A deficiency in monoaminergic transmission is insufficient to cause susceptibility in animals not carrying the other trait(s). Also, although a monoaminergic deficit may initially cause the appearance of susceptibility, the presence of the deficit may not be necessary for the continuation of susceptibility once an animal has actually sustained an AGS in the presence of the monoaminergic deficit.     

The genetically epilepsy-prone rat: an overview of seizure-prone characteristics and responsiveness to anticonvulsant drugs

The Genetically Epilepsy-Prone Rat (GEPR) is rapidly gaining support as a model of epilepsy. In addition to a marked sensitivity to both sound-induced and hyperthermic seizures, GEPRs exhibit unusual sensitivity to a number of seizure-provoking modalities, including various forms of electrical and chemical stimulation. The existence of a moderate seizure colony (GEPR-3) and a severe seizure colony (GEPR-9) allows pathophysiological studies of seizure susceptibility and severity. The consistency of seizures within each colony allows for comparisons in seizure naive GEPRs and seizure experienced GEPRs. The consistent seizure responses of the GEPR are also ideal for the testing of anticonvulsant drugs. Further, the relative potencies of anticonvulsant drugs between the two colonies of GEPRs predict the clinical efficacies of traditional antiepileptic drugs and may be able to predict novel anticonvulsants.     

Cataplexy-active neurons in the hypothalamus: implications for the role of histamine in sleep and waking behavior

Noradrenergic, serotonergic, and histaminergic neurons are continuously active during waking, reduce discharge during NREM sleep, and cease discharge during REM sleep. Cataplexy, a symptom associated with narcolepsy, is a waking state in which muscle tone is lost, as it is in REM sleep, while environmental awareness continues, as in alert waking. In prior work, we reported that, during cataplexy, noradrenergic neurons cease discharge, and serotonergic neurons greatly reduce activity. We now report that, in contrast to these other monoaminergic "REM-off" cell groups, histamine neurons are active in cataplexy at a level similar to or greater than that in quiet waking. We hypothesize that the activity of histamine cells is linked to the maintenance of waking, in contrast to activity in noradrenergic and serotonergic neurons, which is more tightly coupled to the maintenance of muscle tone in waking and its loss in REM sleep and cataplexy.     

Testosterone alters genomic responses to song and monoaminergic innervation of auditory areas in a seasonally breeding songbird

Behavioral responses to social stimuli often vary according to endocrine state. Our previous work has suggested that such changes in behavior may be due in part to hormone‐dependent sensory processing. In the auditory forebrain of female white‐throated sparrows, expression of the immediate early gene ZENK (egr‐1) is higher in response to conspecific song than to a control sound only when plasma estradiol reaches breeding‐typical levels. Estradiol also increases the number of detectable noradrenergic neurons in the locus coeruleus and the density of noradrenergic and serotonergic fibers innervating auditory areas. We hypothesize, therefore, that reproductive hormones alter auditory responses by acting on monoaminergic systems. This possibility has not been examined in males. Here, we treated non‐breeding male white‐throated sparrows with testosterone to mimic breeding‐typical levels and then exposed them to conspecific male song or frequency‐matched tones. We observed selective ZENK responses in the caudomedial nidopallium only in the testosterone‐treated males. Responses in another auditory area, the caudomedial mesopallium, were selective regardless of hormone treatment. Testosterone treatment reduced serotonergic fiber density in the auditory forebrain, thalamus, and midbrain, and although it increased the number of noradrenergic neurons detected in the locus coeruleus, it reduced noradrenergic fiber density in the auditory midbrain. Thus, whereas we previously reported that estradiol enhances monoaminergic innervation of the auditory pathway in females, we show here that testosterone decreases it in males. Mechanisms underlying testosterone‐dependent selectivity of the ZENK response may differ from estradiol‐dependent ones.© 2013 Wiley Periodicals, Inc. Develop Neurobiol 73: 455–468, 2013     

Preferential transmission of paternal alleles at risk genes in attention-deficit/hyperactivity disorder

Family, twin, and adoption studies have demonstrated a significant genetic contribution to the etiology of attention-deficit/hyperactivity disorder (ADHD). Pharmacological, neuroimaging, and animal-model findings suggest imbalances in monoaminergic (dopaminergic, serotonergic, and noradrenergic) neurotransmission in ADHD. We have examined monoaminergic candidate genes for possible genetic association with ADHD in the Irish population, focusing particularly on genes of the dopaminergic and serotonergic systems. We have observed that several of these genes are associated with ADHD, including DAT1, DBH, DRD4, DRD5, and 5HT1B. Here, we present what appears to be a systematic overtransmission of paternal alleles at candidate genes associated with ADHD. For the nine genes included in the analysis, the overall odds ratio for paternal transmission was 2, compared with 1.3 for maternal transmission (paternal vs. maternal chi 2=9.6; P=.0019). Transmission to females, from either parent, was significantly stronger than to males. Possible reasons for this preferential transmission include imprinting and ascertainment bias, although results of further analyses show that the latter is unlikely.     

Serotonergic abnormalities in the central nervous system of seizure-naive genetically epilepsy-prone rats.

Seizure predisposition in Genetically Epilepsy-Prone Rats (GEPRs) is characterized by abnormal sensitivity to a number of seizure provoking stimuli. The GEPR model is composed of two independently derived colonies with each exhibiting a characteristic convulsive pattern. In response to a standardized sound stimulus, GEPR-3s exhibit moderate or clonic convulsions while GEPR-9s exhibit more severe tonic extensor convulsions. In order to further characterize the neurochemical abnormalities that underlie seizure predisposition in GEPRs, the current study examined serotonin concentrations in 14 discrete brain areas of controls, GEPR-3s and GEPR-9s. In all areas examined, serotonin concentrations were lower in either one or both GEPR types than in seizure resistant controls. In 6 of the 14 areas both GEPR-3s and GEPR-9s had levels significantly lower than controls. In an additional 7 areas GEPRs had serotonin concentrations of similar magnitude which were significantly lower than control when the GEPR values were combined. In cerebellum, GEPR-3s had significantly lower serotonin concentration than either controls of GEPR-9s while in the striatum, GEPR-9s had significantly lower serotonin levels than either GEPR-3s or controls. In summary, GEPRs have widespread deficits in serotonin concentration and that these abnormalities appear to contribute to the seizure predisposition that characterizes these animals.     

Response of central monoaminergic neurons to lisuride: comparison with LSD.

The response of brain serotonergic (dorsal raphe), noradrenergic (locus coeruleus) and dopaminergic (pars compacta, substantia nigra) neurons to lisuride hydrogen maleate, a non-hallucinogenic ergot, was studied in the rat using extracellular single cell recording techniques. As has been previously reported for LSD, minute intravenous infusions of lisuride (1–5 μg/kg) produced a complete but reversible suppression of raphe unit spontaneous firing. A similar depressant response was noted when lisuride was applied to raphe units by microiontophoresis. In contrast, locus coeruleus neurons were accelerated by the drug at somewhat higher doses (25–50 μg/kg). Pars compacta neurons demonstrated a predominately depressant response to lisuride but many of the cells tested were only partially suppressed and a few units were accelerated. It is suggested that the marked alterations in central monoamine turnover which have been observed with lisuride are directly paralled by changes in impulse flow in monoaminergic neurons. The fact that lisuride has powerful suppressant effects on central serotonergic neurons but no psychotomimetic actions in man challenges the “serotonin theory” of hallucinogensis; however, other pharmacological properties may account for lisuride's lack of hallucinogenic effects. Further studies with lisuride may provide insight into those drug characteristics critical to the presence or absence of hallucinogenic action.     

Neuronal-vascular relationships in the raphe nuclei, locus coeruleus, and substantia nigra in primates.

A fluorescence histochemical and electron microscopic study of the monoaminergic cell groups in the squirrel monkey and Rhesus monkey brains has revealed the direct apposition of blood vessels to perikarya and dendrites of monoaminergic neurons. Capillaries and small arterioles or venules, ranging from 8-50 microns in diameter, showed perikarya and dendrites abutting the basement membrane without evidence of glial interposition. This neuronal-vascular relationship was present in 20% to 30% of the small vessels in the serotonergic nuclei raphe dorsalis and centralis superior and in the noradrenergic locus coeruleus. Such contacts were clearly present but observed less frequently in the dopaminergic substantia nigra pars compacta and in the serotonergic nuclei raphe obscurus, pallidus, magnus, and pontis. We postulate that monoamine-containing neurons apposed to blood vessels in certain regions of the brain may be influenced directly by hormones or other substances in blood.     

Neurotransmitter abnormalities in genetically epileptic rodents

A growing body of evidence supports a pathophysiological role for norepinephrine (NE) and serotonin in the regulation of seizures in the genetically epilepsy-prone rat (GEPR). Other evidence indicates that gamma-aminobutyric acid (GABA) and taurine may also participate in the seizure regulation process. Innate deficits in NE and serotonin appear to be causes of the genetically determined seizure-prone states of the GEPR, whereas abnormalities in GABAergic systems and taurine metabolism may represent inadequate attempts of the central nervous system to compensate for the seizure-prone state in these rats. In audiogenic seizure-susceptible (AGS) mice, evidence suggests a role for dopamine as well as GABA and possibly serotonin. NE may contribute to the regulation of seizures in AGS mice, but consistent evidence for a primary role for this monoamine is lacking. It is suggested that there is no single common neurotransmitter abnormality underlying genetic seizure disorders in humans or other animals and that the GEPR and the AGS mouse may both serve as good models for study of the neurochemical abnormalities that underlie the different human epilepsies.     

Inferior colliculus neuronal response abnormalities in genetically epilepsy-prone rats: evidence for a deficit of inhibition

The genetically epilepsy-prone rat (GEPR) is abnormally susceptible to induction of seizures by acoustic stimulation. The inferior colliculus (IC) is critically important to audiogenic seizure susceptibility. The GEPR is more susceptible to induction of audiogenic seizures at 12 kHz than at other pure tone frequencies. IC neurons in the GEPR exhibit significantly elevated response thresholds and broader tuning characteristics than normal. These findings along with previous neurophysiological and anatomical data suggest that a hearing deficit occurs in the GEPR. IC neurons in the GEPR exhibit a significantly elevated incidence of a response pattern with a peak of activity at the beginning and end of the stimulus, the onset-offset response. This response pattern occurs at 12 kHz and at characteristic frequency with high stimulus intensities and may represent an afterdischarge phenomenon. The onset-offset pattern may be a manifestation of central mechanisms developed to compensate for reduced peripheral auditory input that appears to be involved in the hearing deficit of the GEPR. Such compensatory mechanisms may involve alterations of the actions of neurotransmitters of the brain-stem auditory nuclei. GABA is implicated as an inhibitory transmitter in the IC. Iontophoretic application of GABA or a benzodiazepine produces significantly less inhibition of IC neurons of the GEPR than of the normal rat. Endogenous sound-induced (binaural) inhibition which is suggested to be GABA-mediated is also significantly reduced in IC neurons of the GEPR. Iontophoresis of the GABAA antagonist, bicuculline, often converts normal response patterns in the IC to onset-offset responses seen with high incidence in GEPR IC neurons, suggesting that the decreased effectiveness of GABA may lead to the onset-offset prevalence. This reduced effectiveness of inhibition may be unable to compensate for the rise in the putative excitatory transmitter, aspartate, in IC during high intensity acoustic stimulation in the GEPR. These altered transmitter actions may be important mechanisms subserving initiation of audiogenic seizures in the genetically epilepsy-prone rat.     

Neuronal Activation in the Central Nervous System of Rats in the Initial Stage of Chronic Kidney Disease-Modulatory Effects of Losartan and Moxonidine

The effect of mild chronic renal failure (CRF) induced by 4/6-nephrectomy (4/6NX) on central neuronal activations was investigated by c-Fos immunohistochemistry staining and compared to sham-operated rats. In the 4/6 NX rats also the effect of the angiotensin receptor blocker, losartan, and the central sympatholyticum moxonidine was studied for two months. In serial brain sections Fos-immunoreactive neurons were localized and classified semiquantitatively. In 37 brain areas/nuclei several neurons with different functional properties were strongly affected in 4/6NX. It elicited a moderate to high Fos-activity in areas responsible for the monoaminergic innervation of the cerebral cortex, the limbic system, the thalamus and hypothalamus (e.g. noradrenergic neurons of the locus coeruleus, serotonergic neurons in dorsal raphe, histaminergic neurons in the tuberomamillary nucleus). Other monoaminergic cell groups (A5 noradrenaline, C1 adrenaline, medullary raphe serotonin neurons) and neurons in the hypothalamic paraventricular nucleus (innervating the sympathetic preganglionic neurons and affecting the peripheral sympathetic outflow) did not show Fos-activity. Stress- and pain-sensitive cortical/subcortical areas, neurons in the limbic system, the hypothalamus and the circumventricular organs were also affected by 4/6NX. Administration of losartan and more strongly moxonidine modulated most effects and particularly inhibited Fos-activity in locus coeruleus neurons. In conclusion, 4/6NX elicits high activity in central sympathetic, stress- and pain-related brain areas as well as in the limbic system, which can be ameliorated by losartan and particularly by moxonidine. These changes indicate a high sensitivity of CNS in initial stages of CKD which could be causative in clinical disturbances.     

Inhibition of Monoamine Oxidase Within Monoaminergic Neurons in the Rat Brain by (E)-β-Fluoromethylene-m-Tyrosine (MDL 72394)

The irreversible inhibition of the monoamine oxidase (MAO) activity within monoaminergic neurons in the rat brain 24 h after single or repeated administration of (E)-beta-fluoromethylene-m-tyrosine (FMMT, MDL 72394) was examined. The enzyme activity was determined by incubating synaptosome-rich homogenates of hypothalamus or striatum with low concentrations of 5-[14C]hydroxytryptamine (5-HT), [14C]noradrenaline (NA), or [14C]dopamine (DA) in the absence and presence of the selective amine uptake inhibitors citalopram (5-HT), maprotiline (NA), and GBR 12909 (DA). After a single subcutaneous injection of FMMT, the inhibition of MAO within the noradrenergic and dopaminergic neurons was significant but only slightly greater than that outside these neurons. The opposite relationship was observed for the serotonergic neurons. After 7 days' treatment of rats with carbidopa, 20 mg/kg p.o., + FMMT once daily, the preference for the inhibition of MAO within the noradrenergic and dopaminergic neurons was accentuated further. The inhibition outside the serotonergic neurons was still greater than within these neurons. The NA uptake inhibitor CPP 199 antagonized the selective inhibition of MAO within the noradrenergic neurons, which indicates that this preference is due to the accumulation of the active metabolite (E)-beta-fluoromethylene-m-tyramine by the NA transporter.     

Brain Monoamines and Optokinetic Performances in Pigmented and Albino Rats

The aim of this study was two-fold: 1) To provide in DA-HAN rats the basic brain monoamine data useful for later investigations of the neurochemical effects of sensory alterations and 2) to assess whether there is a relationship between the monoaminergic pattern in medial vestibular nuclei and optokinetic performances. We comparatively studied the regional brain monoamine distribution and the optokinetic performances in pigmented DA-HAN and albino Sprague-Dawley rats. As expected, the optokinetic responses and vestibulo-ocular reflex gain were by far more efficient in DA-HAN rats. Norepinephrine (NE), dopamine (DA), serotonin (5-HT) and their metabolites were determined in retina, brainstem nuclei and dopaminergic areas. DA-HAN rats exhibited an increased noradrenergic activity in the medial vestibular nuclei, locus cœruleus and anteroventral cochlear nucleus, an extended decrease of serotonergic activity in brainstem nuclei and increased DA stores with a reduced dopaminergic activity in most dopaminergic areas. These data confirm and extend the general findings that biochemical data obtained in one strain cannot be extrapolated to another strain. The possible role of the morphological neuronal abnormalities and functional impairment induced by albinism has been discussed especially in medial vestibular nucleus, cochlear nuclei and retina. Alternatively, behavioral factors may also explain some of the observed neurochemical differences.     

Continuous increase of epileptogenic effects following application of proteolytic enzymes (buccal ganglia of Helix pomatia)

Epileptic activity of neurons consists of paroxysmal depolarization shifts (PDS) which can be induced presumably in any nervous system by application of an epileptogenic drug. The spontaneous appearance of epileptic activity, however, is based on a largely unknown process which increases susceptibility to epileptic activity (seizure susceptibility in man). It is presently shown that the treatment of ganglia with proteolytic enzymes (Pronase) decreases the effective concentration of epileptogenic drugs, i.e. increases seizure susceptibility. Since proteolytic enzymes are known to primarily affect glial cells a contribution of glia to seizure susceptibility is discussed.     

Anatomical changes of the GABAergic system in the inferior colliculus of the genetically epilepsy-prone rat

The number of GABAergic neurons as determined by GAD immunocytochemistry and total neurons as determined from Nissl preparations were counted and classified at the light microscopic level in the inferior colliculus (IC) of the genetically epilepsy prone rat (GEPR) and the non-epileptic Sprague-Dawley (SD) strain of rat. GAD-positive neurons are abundant in the IC and a significant increase in the number of GAD-positive neurons occurs in the GEPR as compared to the SD in all three subdivisions. However, the most pronounced difference occurs in the ventral lateral portion of the central nucleus, where there is a selective increase in the small (200%) and medium-sized (90%) GABAergic somata (10-15 microns in diameter and 15-25 microns in diameter, respectively). As determined from Nissl preparations an increase in total numbers of neurons also occurs. Thus, a 100% increase in the number of small neurons and a 30% increase in the number of medium-sized neurons occur in the adult GEPR as compared to the SD rat. A statistically significant increase in the numbers of small neurons also occurred in the IC of the young GEPR. At 4 days of age, a 55% increase in the number of small neurons was found, and at 10 days of age this increase was 105%. The numbers of the medium and large neurons were similar in the older group of rats. These data suggest that the increase in cell number observed in the adult GEPR is not compensatory to the seizure activity, but may either be genetically programmed or be a failure of cell death. Based on other studies of genetic models of epilepsy, we propose that the additional GABAergic neurons may disinhibit excitatory projection neurons in the IC.     

Epileptic seizures in a heterogeneous excitatory network with short-term plasticity

Epilepsy involves a diverse group of abnormalities, including molecular and cellular disorders. These abnormalities prove to be associated with the changes in local excitability and synaptic dynamics. Correspondingly, the epileptic processes including onset, propagation and generalized seizure may be related with the alterations of excitability and synapse. In this paper, three regions, epileptogenic zone (EZ), propagation area and normal region, were defined and represented by neuronal population model with heterogeneous excitability, respectively. In order to describe the synaptic behavior that the strength was enhanced and maintained at a high level for a short term under a high frequency spike train, a novel activity-dependent short-term plasticity model was proposed. Bifurcation analysis showed that the presence of hyperexcitability could increase the seizure susceptibility of local area, leading to epileptic discharges first seen in the EZ. Meanwhile, recurrent epileptic activities might result in the transition of synaptic strength from weak state to high level, augmenting synaptic depolarizations in non-epileptic neurons as the experimental findings. Numerical simulation based on a full-connected weighted network could qualitatively demonstrate the epileptic process that the propagation area and normal region were successively recruited by the EZ. Furthermore, cross recurrence plot was used to explore the synchronization between neuronal populations, and the global synchronization index was introduced to measure the global synchronization. Results suggested that the synchronization between the EZ and other region was significantly enhanced with the occurrence of seizure. Interestingly, the desynchronization phenomenon was also observed during seizure initiation and propagation as reported before. Therefore, heterogeneous excitability and short-term plasticity are believed to play an important role in the epileptic process. This study may provide novel insights into the mechanism of epileptogenesis.     

Amino acid neurotransmitter alterations in three sublines of Rb mice differing by their susceptibility to audiogenic seizures

The levels of inhibitory amino acids (Tau, Gly), or excitatory amino acids (Glu, Asp) and Gln, precursor of GABA, have been determined, under resting conditions, in 17 brain areas of 3 sublines of inbred Rb mice displaying different responses to an acoustic stimulus. Rb1 mice were clonictonic seizure-prone, Rb2 mice were clonic seizure-prone and Rb3 mice were seizure resistant. Profile of distribution in the brain of each one of these amino acids differed. Maximum to minimum level ratio was higher for Tau (3.8) than for Glu or Asp or Gln (2). The level of Gly was similar in 13 out of the 17 areas examined. Multiple inter-subline differences were recorded for each amino acid. These differences have been analyzed considering the seizure susceptibility or severity of the three Rb sublines. Common lower levels (approximately –20%: Rb1/Rb3, Rb2/Rb3) of Gln in Temporal Cortex may be implicated in seizure susceptibility. Seirure severity (Rb1/Rb2) seems to correlate, in some areas, with additional lower amounts of GABA already reported and, to a lower extent, of Asp (–19% in striatum, inferior colliculus and cerebellum), of Tau and Gly; a tendency for a rise in Gln content was observed in certain others (10–20% in olfactory bulb, thalamus, hypothalamus, substantia nigra, and frontal, temporal and occipital cortex). The data and correlations recorded provide guidelines for further investigations for synaptosomal and metabolic alterations in the three sublines of the same strain of Rb mice.Abbreviations used GABA 4-aminobutyrate - Tau taurine - Gly glycine - Asp aspartate - Glu glutamate - Gln glutamine - GEPR genetically epilepsy-prone rat - OB olfactory bulbs - OT olfactory tubercles - Sr striatum - Se septum - Hy hypothalamus - Hi hippocampus - Th thalamus - A amygdala - SC superior colliculus - IC interior colliculus - SN substantia nigra - FCx frontal cortex - TCx temporal cortex - OCx occipital cortex - C cerebellum - P pons - Ra raphe     

Influence of the alpha-2 agonist oxaminozoline (S3341) on firing rate of central noradrenergic and serotonergic neurons in the rat. Comparison with clonidine

The firing rate of central locus coeruleus (LC) noradrenergic neurons and dorsal raphe (DR) serotonergic neurons was recorded in rats anaesthetized with chloral hydrate. The iontophoretic application or the i.v. perfusion of S3341, a new antihypertensive drug or clonidine decreased the frequency of discharge of LC neurons. Depending on the mode of administration clonidine was 54-63 times more potent than S3341. The selectivity of action of both drugs on alpha-2 vs. alpha-1 adrenoceptors was confirmed using yohimbine and prazosin: yohimbine completely blocked the inhibitory effect of S3341 or clonidine while prazosin did not prevent this effect. S3341 and clonidine regularly reduced the firing rate of DR neurons during i.v. perfusion but not during iontophoretic application. From these experiments is it concluded that S3341 and clonidine have a direct inhibitory effect on LC neurons via stimulation of alpha-2 autoreceptors and that both drugs have an indirect inhibitory effect on DR neurons, probably via impairment of noradrenergic transmission. Clinical studies show that S3341 induces much less sedative side effects than clonidine. In view of the great difference in the potency of these drugs to inhibit the firing rate of monoaminergic neurons which are known to be involved in sleep mechanisms, it is possible that the electrophysiological effects reported here relate to the sedative effects of these drugs.     

Specific Neurochemical Derangements of Brain Projecting Neurons in Apolipoprotein E-Deficient Mice

Abstract: Apolipoprotein E (apoE)-deficient mice provide a useful system for studying the role of apoE in neuronal maintenance and repair. Previous studies revealed specific memory impairments in these mice that are associated with presynaptic derangements in projecting forebrain cholinergic neurons. In the present study we examined whether dopaminergic, noradrenergic, and serotonergic projecting pathways of apoE-deficient mice are also affected and investigated the mechanisms that render them susceptible. The densities of nerve terminals of forebrain cholinergic projections were monitored histochemically by measurements of acetylcholinesterase activity, whereas those of the dopaminergic nigrostriatal pathway, the noradrenergic locus coeruleus cortical projection, and the raphe-cortical serotonergic tract were measured autoradiographically using radioligands that bind specifically to the respective presynaptic transporters of these neuronal tracts. The results obtained revealed that synaptic densities of cholinergic, noradrenergic, and serotonergic projections in specific brain regions of apoE-deficient mice are markedly lower than those of controls. Furthermore, the extent of presynaptic derangement within each of these tracts was found to be more pronounced the further away the nerve terminal is from its cell body. In contrast, the nerve terminal density of the dopaminergic neurons that project from the substantia nigra to the striatum was unaffected and was similar to that of the controls. The rank order of these presynaptic derangements at comparable distances from the respective cell bodies was found to be septohippocampal cholinergic > nucleus basalis cholinergic > locus coeruleus adrenergic > raphe serotonergic ? nigrostriatal dopaminergic, which interestingly is similar to that observed in Alzheimer's disease. These results suggest that two complementary factors determine the susceptibility of brain projecting neurons to apoE deficiency: pathway-specific differences and the distance of the nerve terminals from their cell body.