Effects of the noradrenaline neurotoxin DSP 4 on monoamine neurons and their transmitter turnover in rat CNS

Summary Regional effects of DSP 4 on monoamine neurons have been analyzed by chemical assay of endogenous monoamines and their metabolites in rat CNS. The results confirmed that the neurotoxic action of DSP 4 is predominantly on noradrenaline nerve terminal projections originating fromlocus coeruleus, with the most marked effects on terminal fields localized most distant from the noradrenaline perikarya. DSP 4 treatment (10 days) caused no alteration of the regional DA levels, except in cingulate cortex, where a moderate increase (+ 40 %) was observed, possibly at least partially related to a sprouting of dopamine nerve terminals following the noradrenaline denervation. 5-hydroxytryptamine levels were generally unaltered after DSP 4, except for an about 10–25% reduction in cerebral cortex and hippocampus. There was with time a certain noradrenaline recovery, most likely related to regeneration of noradrenaline nerve terminals, although this process was relatively slow (months). Analysis of catecholamine decline after tyrosine hydroxylase inhibition and metabolite/monoamine ratios, as indices for transmitter utilization rate, indicated an increased noradrenaline turnover in terminals spared by DSP 4, while dopamine turnover appeared to be reduced in many regions (i.a. cerebral cortex, striatum, accumbens, olfactory tubercle and spinal cord), most pronounced in cingulate cortex. The results indicate that noradrenaline neurons have a facilitatory action on dopamine neurons. The DSP 4 treatment did not cause any significant effect on 5-hydroxytryptamine turnover in any of the individual regions analyzed.     

Synthesis and utilization of catecholamines in the rat superior cervical ganglion following changes in the nerve impulse flow

Summary The nerve impulse flow to the noradrenaline nerve cell body region of the superior cervical ganglion and to the noradrenaline nerve terminals of the salivary glands was decreased and increased by decentralization and preganglionic electrical stimulation, respectively. The concentrations of dopamine, noradrenaline, and their primary deaminated metabolites (DOPAC, DOPEG) in the ganglion were not changed during the first day after the decentralization but were increased following preganglionic stimulation, particularly that of DOPAC. The disappearances of dopamine and noradrenaline after-methyltyrosine and the disappearance of noradrenaline after inhibition of the dopamine--hydroxylase were not changed by decentralization or stimulation. The accumulation of dopamine following inhibition of the dopamine--hydroxylase was somewhat lowered by decentralization and was markedly enhanced by stimulation. In the noradrenaline nerve terminals of the salivary glands, preganglionic sympathetic stimulation decreased and increased the concentration of noradrenaline and dopamine, respectively. Thus, nerve impulses stimulated the tyrosine hydroxylase activity in the cell body region and the axon terminals of the noradrenaline neurons but they increased the utilization of noradrenaline only in the terminals.     

Influence of descending bulbospinal monoamine neurons on axonal transport of acetylcholine and cholinergic enzymes

Summary The influence of descending bulbospinal monoamine (MA) neurons on the intra-axonal transport of acetylcholine (ACh) and related enzymes (cholineacetyltransferase, CAT, and ACh-esterase, AChE) in rat sciatic nerve was studied in crush experiments following intracisternal injections of specific neurotoxins. The injection of 6-hydroxydopamine (6-OH-DA) and 5, 6-dihydroxytryptamine (5, 6-diOH-TA) (50g×2) caused a degeneration of catecholamine (CA) and 5-hydroxytryptamine (5-HT) nerve terminals, respectively, and a combination of the two neurotoxins caused a loss of virtually all MA terminals in the lumbar spinal cord. The results of the neurotoxin injections were controlled by the Falck-Hillarp fluorescence method. The effect of neurotoxin treatment on the enzyme activities in the sciatic nerve was very small. The ACh levels of uncrushed nerves and in nerves proximal to a crush performed 12 hours before dissection decreased following either 6-OH-DA or 5, 6-diOH-TA. However, the combined treatment with both 6-OH-DA and 5, 6-diOH-TA had no influence on ACh accumulation and transport, as compared to the control group.In a previous study we have shown that mid-thoracic spinal cord transection increased AChE-transport while ACh-transport was decreased. The results of this study indicate that the bulbospinal MA neurons may be involved (perhaps indirectly) in the regulation of ACh levels and transport in motor neurons, but less important for the modulation of the cholinergic enzymes.     

Release of dopamine from central noradrenaline and dopamine nerves induced by a dopamine-β-hydroxylase inhibitor

Summary The effect of the dopamine--hydroxylase inhibitor bis-(4-methyl-1-homopiperazinylthiocarbonyl)-disulphide (FLA-63) on the release of dopamine and noradrenaline was studied in regions of the rat central nervous system rich in dopamine or noradrenaline nerve terminals. The release was investigated by analyzing the accumulation of the 3-0-methylated catecholamines after inhibition of the monoamine oxidase by nialamide. In the dopamine-rich corpus striatum, the concentration of dopamine was unchanged but its release was enhanced after treatment with FLA-63. The noradrenaline concentration and release were markedly reduced. In the areas containing mainly noradrenaline nerve terminals, dopamine accumulated but did not stoichiometrically replace the missing noradrenaline. There was a pronounced release of dopamine from the noradrenaline nerves after the dopamine--hydroxylase inhibiticn. This release may, at least partly, explain why noradrenaline is not stoichiometrically replaced by dopamine.     

Effects of 5,6-dihydroxytryptamine on nerve terminal serotonin and serotonin uptake in the rat brain

One intraventricular injection of 5,6-dihydroxytryptamine (5,6-DHT) caused the disappearance of fluorescent histochemically detectable 5-hydroxytryptamine (5-HT)-containing terminals and a loss in 5-HT uptake sites. There was an almost complete disappearance of 5-HT-containing nerve terminals in periventricularly located diencephalic areas and in the spinal cord 10–15 days after 75 μg of 5,6-DHT. The noradrenaline and dopamine innervation patterns in the hypothalamus, septum, basal ganglia, and spinal cord appeared normal, except in a narrow zone of the caudate nuclei facing the lateral ventricles, where there was a marked reduction in dopamine fluorescence. These changes were accompanied by 50–87% reductions in the uptake of [³H]5-HT by thin slices of cortex, hypothalamus and spinal cordin vitro. In contrast, the uptake ofL-[³H]noradrenaline was close to normal in hypothalamus and spinal cord slices, and about 35% reduced in the cortex slices. These results are consistent with the idea that intraventricularly administered 5,6-DHT causes extensive axonal degeneration of central serotonin neurones, and that noradrenaline and dopamine neurones are largely unaffected after one injection of 75 μg.     

Dihydalazine inhibits tyrosine hydroxylasein vivo in the rat

Summary The effect of dihydralazine on monoamine metabolism in the rat was investigated. Dihydralazine, 5 mg/kg i.v., reduced noradrenaline (NA) in the heart. After pretreatment with phenoxybenzamine an NA depletion was evident also in the brain. Dihydralazine did not affect the utilization of NA or dopamine in the brain as judged by the disappearance rates of these amines following synthesis inhibition by-methyl-p-tyrosine. However, dihydralazine reduced the synthesis of monoamines as evidenced by a decreased accumulation of the monoamine precursor dihydroxyphenylalanine (and 5-hydroxytryptamine) subsequent to treatment with NSD 1015.It is concluded that dihydralazine inhibits central tyrosine hydroxylase (and tryptophan hydroxylase) in the rat.     

The stimulatory action of phosphodiesterase inhibitors on the flexor reflex of the hind limb in the spinal rat

Summary We studied the action of the following phosphodiesterase inhibitors (PDEIs): rolipram (4-[3-cyclopentoxy-4-methoxyphenyl]-2-pyrrolidione), Ro 20-1724 (4-[3-butoxy-4-methoxybenzyl]-2-imidazolidione), 1-methyl-3-isobutylxanthine (IMBX) and theophylline on flexor reflex activity of the hind limb in the spinal rat. Potentiation of this reflex is thought to be due to enhancement of either 5-hydroxytryptaminergic or-adrenergic transmission in the spinal cord.All the inhibitors potentiated flexor reflex activity in a dose-dependent manner in the following order of potency: rolipramRo 20-1724>IBMX> theophylline. Their stimulatory action in this model paralleled their known potency in inhibiting phosphodiesterase (PDE). Neither the 5-hydroxytryptamine (5-HT) antagonist cyproheptadine nor the-adrenoceptor blocker phenoxybenzamine prevented potentiation of flexor reflex activity by PDEIs. It is suggested that (1) the PDEIs potentiate flexor reflex activity through a novel spinal mechanism which does not involve-adrenoceptors or 5-HT receptors in the spinal cord but rather is related to the inhibition of PDE localized postsynaptically; (2) flexor reflex activity in the spinal rat can be a useful experimental preparation to estimate thein vivo effects of known PDEIs.     

The effects of 4-aminopyridine on the spinal cord: Rhythmic discharges recorded from the peripheral nerves

The effects of an intravenous injection (20 mg/kg) of 4-aminopyridine (4-AP) were initially investigated in acute low spinal cats (Th 13), in whichl-DOPA had induced fictive locomotion after paralysis. 4-AP first accelerated the locomotor rhythm and could also change markedly the pattern of activation of some muscle nerves. Shortly after, the locomotor activity was replaced by synchronous rhythmic discharges (2.5–8.5 Hz) in flexor and extensor muscle nerves of the same limb girdle. Similar rhythmic activity was recorded after 4-AP alone (5–20 mg/kg) in the acute decerebrate spinal cat. Whilst the mean rate of the rhythmic activity could differ in the two limb girdles, discharges generated in one girdle appeared to be strongly influenced by those generated in the other. After a complete section of the spinal cord (Th13), the activity persisted in both the rostral and caudal segments although the interactions between the two disappeared. The persistence of the rhythmic activity caudal to the section underscores its spinal origin. In the chronic spinal rat, such rhythmic activity could still be induced in the lumbo-sacral cord despite degeneration of descending pathways. It appears that large doses of 4-AP exert potent effects on the spinal cord which can override other patterns of activity and synchronize the electrical activity of many neuronal elements.     

Catecholamine and 5-hydroxytryptamine synthesis and metabolism following intracerebroventricular injection of dibutyryl cyclic AMP

Summary Two to seven days after bilateral implantation of polyethylene tubings into the lateral ventricles rats were injected intracerebroventricularly with dibutyryl cAMP or dibutyryl cGMP. The accumulation of dopa and 5-hydroxytryptophan after inhibition of the aromatic amino acid decarboxylase with 3-hydroxybenzylhyrazine HCl, served as a measure of catecholamine and 5-hydroxytryptamine synthesisin vivo.A dose of 100g dibutyryl cAMP per rat but not dibutyryl cGMP increased the accumulation of dopa in all brain regions by 70 to 130%. Both nucleotides stimulated the formation of 5-hydroxytryptophan in the dopamine-rich part of the limbic system and diencephalon and in addition dibutyryl cAMP increased 5-hydroxytryptophan in C. striatum and cerebellum.Dibutyryl cAMP (25–200g per rat) did not change the dopamine levels in the dopamine-rich parts of the brain but decreased the noradrenaline level of the C. striatum in a dose-dependent manner. The same doses of dibutyryl cAMP elevated the 5-hydroxytryptamine level in brain stem and the level of 5-hydroxyindole acetic acid in diencephalon and the limbic system. The disappearance of noradrenaline but not of dopamine after inhibition of catecholamine synthesis with-methyl-p-tyrosine methylester HCl was accelerated in most brain regions.The data are compatible with the view that dibutyryl cAMP stimulates tyrosine and tryptophan hydroxylase directly. In addition, dibutyryl cAMP appears to enhance the utilization of noradrenaline but not that of dopamine. The increased utilization of 5-hydroxytryptamine may be restricted to the diencephalon and the limbic system.     

An in vitro functionally mature mouse spinal cord preparation for the study of spinal motor networks

An in vitro isolated whole spinal cord preparation has been developed in ‘motor functionally mature' mice; that is mice of developmental maturity sufficient to weight-bear and walk. In balb/c mice this stage occurs at around postnatal day 10 (P10). Administration of strychnine elicited synchronous activity bilaterally in lumbar ventral roots. Rhythmic alternating locomotor-like activity could be produced by application of a combination of serotonin (5-HT), N-methyl- -aspartate (NMDA), and dopamine in animals up to P12. Using a live cell–dead cell assay, it is demonstrated that there are primarily viable cells throughout the lumbar spinal cord. The viability of descending pathways was demonstrated with stimulation of the mid-thoracic white matter tracts. In addition, polysynaptic segmental reflexes could be elicited. Although usually absent in whole cord preparations, monosynaptic reflexes could invariably be elicited following longitudinal midline hemisection, leading to the possible explanation that there might be an active crossed pathway producing presynaptic inhibition of primary afferent terminals. The data demonstrate that this functionally mature spinal cord preparation can be used for the study of spinal cord physiology including locomotion.     

Biogenic amines and metabolites in spinal cord of patients with Parkinson's disease and amyotrophic lateral sclerosis

Summary In four human controls, four cases of Parkinson's disease and three cases of amyotrophic lateral sclerosis analysis of dopamine, noradrenaline, serotonin and the metabolites 3,4-dihydroxyphenylacetic acid, homovanillic acid and 5-hydroxyindoleacetic acid was performed in various segments of postmortem spinal cord. In controls the concentrations of dopamine are about 1/3 to 1/4 that of noradrenaline; the significantly highest content of noradrenaline was found in the lumbar, and dopamine in thoracic, lumbar and sacral segments of the spinal cord. Intersegmental distribution of monoamines was only present in spinal cord of controls, while in the spinal cord of parkinsonian patients such a difference was not found.Otherwise, biogenic amine and metabolite concentrations in spinal cord segments of parkinsonian patients did not differ significantly from those in the control subjects. However, it cannot be excluded that these segments are sensitive to drugs including neuroleptics and combined L-DOPA treatment.In subjects with amyotrophic lateral sclerosis significantly lower concentrations of noradrenaline in the cervical and thoracic, and of dopamine and homovanillic acid in the thoracic and lumbar segments were found in comparison with controls. The concentrations of serotonin and 5-hydroxyindoleacetic acid in the thoracic segments of amyotrophic lateral sclerosis were significantly lower than that of controls. Differences in the inter-segmental distribution of noradrenaline in lumbar, lumbar-sacral, and serotonin in lumbar segments of spinal cord were found in this group.     

Selective blockade of brainα 2-autoreceptors by yohimbine: Effects on motor activity and on turnover of noradrenaline and dopamine

Summary The motor activity of groups of three mice was increased by yohimbine at doses up to 3 mg/kg intraperitoneally. The turnover of dopamine and noradrenaline in the mouse brain, as assessed by the disappearance of catecholamines following treatment with the tyrosine hydroxylase inhibitor-methyltyrosine, was accelerated by yohimbine with a peak effect after 10 mg/kg intraperitoneally. Prazosin (3 mg/kg i.p.) completely antagonized the stimulatory effect of yohimbine on motor activity and on dopamine turnover but it somewhat potentiated the stimulatory effect on the turnover of noradrenaline. Amphetamine reversed the prazosin-induced hypomotility, indicating that prazosin can selectively block postsynaptic ₁-receptors.Yohimbine did not stimulate motor activity following 10 mg/kg and it retarded the turnover of dopamine following 30 mg/kg. These actions might be due to blockade of postsynaptic-receptors by yohimbine.The data indicate that yohimbine at low doses stimulates motor activity and dopamine turnover by selectively blocking ₂-autoreceptors leading to increased release of noradrenaline and subsequent activation of postsynaptic ₁-receptors.     

Autonomic dysreflexia in tetraplegic patients: Evidence for α-adrenoceptor hyper-responsiveness

A controlled study of acute pharmacological intervention was designed to determine whether decreased sympathetic nerve activity in tetraplegic patients results in increased responsiveness of -adrenoceptors which might contribute to vascular hyperreactivity and the clinical scenario of autonomic dysreflexia. The study took place in a university teaching hospital and included six male tetraplegic patients and six age-matched normal male controls. All tetraplegics were 5 months or longer post-traumatic spinal cord injury and all had experienced symptoms of autonomic dysreflexia on at least one occasion. The dorsal foot vein diameter was recorded with a tonometer during local infusions of noradrenaline 0.125–256 ng/min given through a short intravenous needle. In tetraplegic patients, there was a significant shift to the left of the dose—response curve indicating increased venous responsiveness to noradrenaline. The concentration of noradrenaline required to cause a 50% reduction of the resting vein diameter was decreased in tetraplegics (1.6 ng/min, geometric mean) compared to normal controls (10.9 ng/min,p < 0.02). -Adrenoceptor responsiveness in dorsal foot veins is increased in patients with tetraplegia. Hypersensitivity of vascular -adrenoceptors may contribute to autonomic dysreflexia in patients with high spinal cord injury.     

Effects ofp-chlorophenylalanine and a monoamine oxidase inhibitor on the 5-hydroxytryptamine in the spinal cord after transection

Summary Treatment with the monoamine oxidase inhibitor nialamide (500 mg/kg i.p., 2.5 and 5 h) produced in the caudal and cranial half of the spinal cord an increase in 5-hydroxytryptamine which was of the same magnitude in intact rats and in rats acutely spinalized midthoracically. Similar results were obtained after reserpine pretreatment. The nialamide-induced increase in 5-hydroxytryptamine caudal to a transection was slightly reduced after 2 days and completely inhibited after 3 weeks.Treatment with the tryptophan hydroxylase inhibitorp-chlorophenylalanine (319 mg/kg i.p., 24 h) or its methylester HCl (400 mg/kg i.p., 24 h) reduced the concentration of 5-hydroxytryptamine in the spinal cord by about 70 per cent in both halves of the intact cord and in the cranial half of the cut cord but by only about 30 per cent caudal to an acute transection. The nialamide-induced increase in 5-hydroxytryptamine of a transected spinal cord was inhibited to the same extent cranial and caudal to the lesion 24 h after treatment withp-chlorophenylalanine.In conclusion, the changes in 5-hydroxytryptamine concentrations induced byp-chlorophenylalanine are dependent on nerve impulses in contrast to those induced by nialamide. Thep-chlorophenylalanine does not have to be incorporated into newly synthesized tryptophan hydroxylase in order to inhibit the enzyme.     

The role of intraneuronal amine levels in the feedback control of dopamine,noradrenaline and 5-hydroxytryptamine synthesis in rat brain

Summary The influence of varying brain levels of dopamine, noradrenaline and 5-HT on their respective synthesis rates has been investigated. The first step in monoamine synthesis was studiedin vivo by measuring the accumulation of dopa and 5-hydroxytryptophan after inhibition of the aromatic L-amino acid decarboxylase. Variations in monoamine levels were obtained by combined treatment with inhibitors of the decarboxylase (NSD 1015 or Ro 4-4602) and of monoamine oxidase (pargyline).An increase in monoamine levels by pargyline was found to inhibit the synthesis of dopamine, noradrenaline and 5-HT. Conversely, a decrease in monoamine levels induced by the decarboxylase inhibitor Ro 4-4602 appeared to stimulate dopamine and noradrenaline synthesis but had no effect on 5-HT synthesis.The influence of varying levels of dopamine and noradrenaline on the synthesis of these amines could still be demonstrated after blockade of dopamine receptors and of-adrenergic (noradrenaline) receptors by haloperidol, suggesting that the mechanism involved in this feedback control is mediated via end-product inhibition of tyrosine hydroxylase. On the other hand, the stimulating influence of haloperidol on the synthesis of catecholamines does not seem to be directly related to changes in catecholamine levels.It is concluded that the short-term control of catecholamine synthesis presumably involves two independent feedback mechanisms, one intraneuronal mechanism operating via end-product inhibition, and one synaptic mechanism mediated via dopamine and noradrenaline receptors, respectively. Both pre- and postsynaptic receptors may be involved in the latter mechanism.     

4-Aminopyridine enhances motor evoked potentials following graded spinal cord compression injury in rats

Although several experimental and clinical studies have demonstrated the ability of 4-aminopyridine (4-AP) to restore electrophysiological and/or behavioral function following chronic spinal cord injury, the mechanism by which this occurs remains unclear. Demonstration of efficacy in rat spinal cord injury has not been reported, evidently because even relatively mild spinal cord contusions that produce only minor permanent locomotor disturbances abolish hind limb myoelectric motor evoked potentials (mMEPs). In this study, mMEPs were recorded acutely 25 days following graded thoracic spinal cord compression in rats. mMEP amplitudes were significantly enhanced by a single, 2 mg/kg i.v. dose of 4-AP. mMEPs were increased in all rats showing some evoked responses initially, and also in some animals which had no responses prior to treatment. 4-AP was further found to increase the maximum following frequency of mMEPs in both normal and injured rats from about 0.1 Hz to between 1 and 10 Hz. These data suggest that 4-AP might act by enhancing synaptic efficacy, as well as enhancing conduction in spinal axons whose myelination has been rendered dysfunctional by trauma.     

Intrathecal noradrenaline restores 5-methoxy-N,N-dimethyltryptamine induced antinociception abolished by intrathecal 6-hydroxydopamine

Summary Intrathecal administration of 6-hydroxydopamine (6-OHDA) abolished the antinociceptive effects of acute administration of 5-methoxy-N,N-dimethyltryptamine (5-MeODMT, 1 mg/kg, s.c.) in the hot-plate, tail-flick and shock titration tests of nociception. The antinociceptive effects of 5-MeODMT, abolished by the prior intrathecal 6-OHDA treatment, were restored by intrathecal administration (2 or 1 g) of noradrenaline (NA), immediately prior to 5-MeODMT, in all three tests of nociception. Biochemical analysis confirmed severe NA depletions (95 percent loss) in the lumbar and thoracic regions of the spinal and much lesser dopamine depletions (25–35 percent loss). Intrathecal 5,7-dihydroxytryptamine (5,7-DHT) attenuated 5-MeODMT induced antinociception in the tail-flick test and combined NA+5-Me ODMT induced antinociception in the hot-plate and tail-flick tests. Intrathecal administration of 5,7-DHT caused a severe depletion of 5-hydroxytryptamine in the lumbar region of the spinal cord. The present findings demonstrate further the modulatory role of NA upon serotonergic systems in nociception and indicate the necessity of NA availability for induction of 5-MeODMT analgesia.     

Effect of synthetic substance P on monoaminergic mechanisms in brain

Summary Synthetic substance P has been discovered to stimulate significantly the formation of dopa in the limbic, striatum, hemisphere and diencephalon regions of the brain and the lower brain stem. There was no effect upon 5-hydroxytryptophan formation or on tryptophan or tyrosine levels. After inhibition of monoamine synthesis by N-(DL-seryl)-N²-(2, 3, 4-trihydroxybenzyl)hydrazine, substance P significantly accelerated the disappearance of dopamme, noradrenaline and 5-hydroxytryptamine.Substance P appears to stimulate monoaminergic neurons in the brain and to serve as an excitatory transmitter in nerve terminals impinging upon dopaminergic cell bodies. A similar stimulation of noradrenaline and 5-hydroxytryptamine indicate a similar transmitter role for noradrenergic and serotonergic neurons.These data strengthen questions about the possible clinical influence of substance P in disease states involving monoaminergic mechanisms including Parkinsonism and schizophrenia.     

Effects of acute and chronic treatment with imipramine on 5-hydroxytryptamine nerve cell groups and on bulbospinal 5-hydroxytryptamine/substance P/thyrotropin releasing hormone immunoreactive neurons in the rat. A morphometric and microdensitometric analysis

Summary Groups of male rats were treated for a period of 14 days with imipramine (10mol/kg) given twice daily. Separate groups of rats received a single dose treatment using the same dose and experimental design as for the repeated treatment. Employing the avidin-biotin immunoperoxidase technique for immunohistochemistry 5-hydroxytryptamine (5-HT)-, substance P (SP)- and thyrotropin releasing hormone (TRH)-like immunoreactivities (IRs) were visualized in consecutive coronal sections of the brain stem and of the spinal cord. The IRs were studied by means of morphometric and microdensitometric procedures using automatic image analysis on profiles representing nerve terminal networks of the ventral horn of the cervical and lumbar enlargements of the spinal cord as well as their coexistence (5-HT/SP and 5-HT/TRH). With the same technique 5-HT IR was measured in the 5-HT nerve cell groups of the medulla oblongata (B 1, B 2, B 3) and of the nucleus raphe dorsalis (B 7) of the midbrain. In addition 5-HT and 5-hydroxyindolacetic acid (5-HIAA) levels were measured in the ventral and dorsal horns of the cervical and lumbar enlargements of the spinal cord using high performance liquid chromatography (HPLC). In the same parts of the spinal cord SP IR was studied by means of radioimmunoassay (RIA).The microdensitometric studies showed that chronic, but not acute, imipramine treatment selectively increased SP IR in the 5-HT/SP/TRH costoring nerve terminals of the medial part of the ventral horn in both the cervical and the lumbar enlargements. Furthermore, quantitative analysis of the entity of coexistence in the 5-HT nerve terminal networks of these areas showed that all the 5-HT nerve terminals contained SP and TRH IRs and that this phenomenon remained after acute and chronic imipramine treatment. The microdensitometric studies on the 5-HT nerve cell groups of the medulla oblongata and of the nucleus raphe dorsalis demonstrated that chronic, but not acute, imipramine treatment selectively increased 5-HT IR in the nerve cell bodies of the lateral part of group B 3 as evaluated from the median grey values. Acute, but not chronic, imipramine treatment significantly increased the field area of 5-HT IR of nerve cell bodies in group B 7, reflecting an increase in the mean profile area of the 5-HT IR nerve cell body profiles. Instead, the mean profile area of 5-HT IR cell bodies of group B 1 was acutely reduced by imipramine.The biochemical studies demonstrated that chronic imipramine treatment selectively reduced 5-HT utilization in the ventral horn of the spinal cord and selectively increased SP IR in the dorsal horn of the lumbar enlargement.In view of these observations it is suggested that chronic imipramine treatment specifically increases SP IR in the 5-HT/SP/TRH costoring nerve terminals of the ventral horn probably related to reduced SP release and reduced 5-HT utilization in these terminals. The results obtained in group B 7 may be explained by a regulation by the³H-imipramine raphe binding sites of fast axonal transport, an influence which may have therapeutic consequences. This mechanism may also be responsible for the increase in 5-HT IR seen upon chronic imipramine treatment in the lateral part of the 5-HT nerve cell body group B 3. Such an effect may lead to a metabolic down-regulation of group B 7, having a possible role for the antidepressant activity of imipramine. The reduction of the mean profile area of 5-HT IR cell bodies of group B 1 seen in the acute treatment can possibly be caused by, noradrenaline (NA) uptake inhibition in inhibitory NA terminals innervating the B 1 group. These results also illustrate the heterogeneities in the responses of the 5-HT nerve cell groups to antidepressant treatment. The ability of chronic imipramine treatment to increase SP IR in the dorsal horn of the lumbar enlargement may reflect the existence of a monoamine-SP interaction in the substantia gelatinosa due to the NA and/or 5-HT uptake blocking activity of imipramine. The existence of such an interaction may help to explain the antinociceptive effect of chronic imipramine treatment.Part of the paper was presented at the 17th International Congress of the International Society of Psychoneuroendocrinology, Bergen, June 29–July 4, 1986.     

Can 4-aminopyridine modulate dysfunctional gait networks in Parkinson's disease?

Gait dysfunction and postural instability represent a major therapeutic challenge in Parkinson's disease (PD). Gait disability in PD has been historically attributed to striato-nigral degeneration, however there is emerging evidence that multiple neurotransmitter deficits contribute to mobility impairment in PD. 4-aminopyridine (4-AP), a potent neurotransmitter modulator, has a wide range of favorable effects on gait in patients with neurological conditions including multiple sclerosis, spinal cord injury and cerebellar ataxia. In this Review we identify the neurobiological pathways involved in gait dysfunction in PD and discuss the mechanisms of action of 4-AP and its effect on gait related neuronal networks. The proposed mechanisms that may facilitate 4-AP favorable effect on gait in Parkinson's disease include 1) neurotransmitter release (dopamine, glutamate, acetylcholine and noradrenaline) 2) modulation of neuronal network oscillations and 3) increased cortical excitation. Recent clinical trials of 4-AP in neurological conditions associated with gait disorders will be highlighted and the importance of studying non-dopaminergic medications such as 4-AP in PD patients with gait impairment will be emphasized.