Collateral sprouting and reduced activity of the rat mesocortical dopaminergic neurons after selective destruction of the ascending noradrenergic bundles

The properties of the mesocortical dopaminergic neurons projecting to the pregenual and anterior supragenual cortices were examined 3–6 months after the degeneration of ascending noradrenergic pathways caused by bilateral multiple or single microinjections of 6-hydroxydopamine made laterally to the pedunculus cerebellaris superior. In all rats and in all cortical areas examined, noradrenaline levels were reduced by more than 75%. A similar decrease in noradrenaline levels was obtained in the ventral tegmental area. As indicated by the increases in cortical levels of dopamine and in [³H]dopamine specific uptake sites as well as by histochemical analysis, these lesions induced a collateral sprouting of the mesocortical dopaminergic neurons. The intensity of the effect varied from one animal to another and even from one anteromedial hemicortex to another. When present, the increase in dopamine levels was observed in all the cortical areas investigated. As suggested by the decreased ratio of the amount of dihydroxyphenylacetic acid to dopamine in the cortex, the activity of the mesocortical dopaminergic neurons was reduced in the rats with lesions. This effect was even seen in rats in which the cortical levels of dopamine were only slightly increased. Both the collateral sprouting and the reduced activity of the mesocortical dopaminergic neurons were related to the degeneration of the noradrenergic neurons and not to a non-specific effect of 6-hydroxydopamine, since both phenomena did not occur in rats pretreated with desipramine, a treatment which prevented the decline in noradrenaline levels.Thus, a lesion of the ascending noradrenergic pathways can lead to sprouting of dopaminergic neurons in the cortex and a reduced activity of these dopaminergic neurons. The respective role of the disappearance of the noradrenergic innervation in the cerebral cortex and in the ventral tegmental area in the collateral sprouting and in the reduced activity of the mesocortical dopaminergic neurons is discussed.     

Substance P-like immunoreactivity in nerves associated with the vascular system of guinea-pigs

Substance P-like immunoreactivity was localized by an indirect immunohistochemical technique in whole mounts and sections of blood vessels from the guinea-pig. There was a widespread association of nerve fibres that had substance P-like immunoreactivity with blood vessels, extending into all vascular beds. The relative densities of supply of different vessels were assessed visually and a rating scale used to compare them. Large elastic arteries close to the heart had dense networks of immunoreactive nerves associated with them. The density decreased as more peripheral beds were approached, except that there was a particularly dense network of nerves with arteries of the splanchnic beds. Arteries to myocardial, central nervous system, renal, reproductive and skeletal muscle beds all had substance P-immunoreactive nerves associated with them to varying extents. The venae cavae near the heart were densely supplied, but there were few fibres with their more peripheral extensions. Some large veins (e.g. pulmonary, hepatic portal and superior mesenteric) had a few fibres with them, but veins of peripheral vascular beds had very few or no immunoreactive nerve fibres. Substance P-like immunoreactivity in vascular nerves was markedly reduced in guinea-pigs that were injected with capsaicin but was unaffected by the injection of 6-hydroxydopamine. It is concluded that the vascular substance P-immunoreactive nerves are likely to be of sensory origin.     

Neurochemical correlates of behavioural responses to frustrative nonreward in the rat: implications for the role of central noradrenergic neurones in behavioural adaptation to stress

Summary We tested whether the stress of nonreward has neurochemical effects on noradrenergic neurones which resemble those reported for other forms of stress. Rats trained to run in a straight runway for food reward were subjected to either 1 or 10 extinction trials. Half the rats in each group were injected before the start of acquisition with IP 6-hydroxydopamine to deplete peripheral noradrenaline stores. All animals were killed immediately after their final test in the runway, together with untrained controls. Noradenaline depletion had no behavioural or neurochemical effects. The rate of extinction in the 10-trial group, which was indexed by the slope of the linear regression of running time on trial, correlated negatively with both alpha₂ and beta-adrenoceptor number (Bmax). There were no differences between groups in cerebral cortical noradrenaline content, or alpha₂ or beta-adrenoceptor binding. These results substantially conflict with those predicted from Stone's hypothesis relating beta-adrenoceptor sensitivity to the behavioural response to stress. A further finding was that alpha₂, but not beta-adrenoceptor number, negatively correlated with levels of noradrenaline in the tissue, suggesting that noradrenaline is less involved in the regulation of beta than in that of alpha₂-adrenoceptors.     

Norepinephrine-containing terminals in kitten visual cortex: Laminar distribution and ultrastructure

The laminar distribution of monoamine-containing terminals in the visual cortex (areas 17 and 18) of 6- to 8-week-old kittens was studied with a modified glyoxylic acid histofluorescence method. The ultrastructure of monoamine-containing terminal boutons in cortical tissues fixed with glyoxylic acid perfusion followed by immersion in potassium permanganate was also studied in serial sections. In both coronal and sagittal planes, rich innervation of catecholamine-containing fibers and terminals was found throughout all 6 cortical layers. Intensely fluorescent stem fibers, which are preterminal fibers in the white matter, entered layer VI from the white matter after veering abruptly towards the cortical surface. While the stem fibers ran towards the surface, many collateral terminal fibers branched out in all directions in the middle layers; a dense plexus of catecholamine fibers and terminals was found mostly in layers II and III. Reaching the superficial layer, the stem fibers gave off terminal fibers which ran parallel to the surface.Monoamine-containing terminal boutons were identified by electron microscopy as small bulges which contained dense-cored vesicles. About 10% of the monoamine-containing boutons showed the usual synaptic membrane specialization suggesting synapse formation. Another 10% of the monoamine boutons showed only some characteristic features such as widening of the associated intermembrane space, and aggregation and contact of cored vesicles with the presynaptic membrane. The remaining 80% of the monoamine boutons failed to show any of the above described properties. The 2 types of monoamine boutons with classical synaptic features were seen in all layers, particularly II and III, but not in layer VI. The most frequent target of monoamine boutons in all 6 layers seemed to be dendritic shafts. The few axo-spiny and axo-somatic contacts observed occurred in the superficial and deep layers, respectively. The circumstantial evidence suggested that the monoamine visualized in the current study of either histofluorescence or electron microscopy was in fact norepinephrine rather than dopamine and serotonin.The rich innervation of all cortical layers with catecholamine-containing boutons is consistent with noradrenaline being a factor in modifying the plasticity of neurons in the visual cortex.     

The effects of lesions to ascending noradrenergic neurons on discrimination learning and performance in the rat

Three experiments examined the effect of central noradrenergic depletion on the acquisition and performance of a temporal discrimination in auditory or visual modalities. In Experiment 1, 6-hydroxydopamine-induced lesions of the dorsal noradrenergic bundle significantly retarded acquisition compared to a similarly lesioned ventral noradrenergic bundle-group, two sham-operated and one unoperated control group. In Experiment 2, the acquisition impairment produced in the dorsal noradrenergic bundle group was replicated, for both auditory and visual modalities, by lesions depleting hippocampal and neocortical noradrenaline by over 80%. In rats subsequently switched to discriminations involving the unfamiliar modality, the dorsal-bundle lesion also impaired acquisition several weeks after surgery. Experiment 3 showed significantly impaired performance in rats with dorsal bundle lesions when training prior to surgery had not resulted in better than chance performance. In rats previously trained to criterion, the dorsal bundle lesion transiently, but non-significantly, impaired performance. In rats performing better than chance, but not having reached criterion, there were no significant effects of the dorsal bundle lesion. Subsequent manipulations of deprivation and difficulty of discrimination in general failed to distinguish between the dorsal bundle lesion and sham-groups, suggesting that the acquisition impairment did not result from simple sensory or motivational effects. Reducing the interstimulus interval did impair the dorsal bundle group more than controls. However, there was no evidence of altered "distractibility" in the lesioned group when the alternative modality was introduced as a distractor. The results are discussed in terms of other acquisition deficits shown by rats with central noradrenaline depletion and their significance for determining the functions of the projections from the locus caeruleus via the dorsal noradrenergic bundle to the neocortex and hippocampus.     

New dopaminergic terminal fields in the motor, visual (area 18b) and retrosplenial cortex in the young and adult rat. Immunocytochemical and catecholamine histochemical analyses

New dopaminergic terminal fields have been visualized in the rat cerebral neocortex, using two morphological methods based on distinct properties of the dopaminergic system: presence of the first synthetic enzyme, tyrosine hydroxylase, and high-affinity uptake of amines. Tyrosine hydroxylase was used as an immunocytochemical marker after destruction of the cortical noradrenergic system, induced either neonatally by 6-hydroxydopamine or later on by DSP4, and controlled by the absence of dopamine beta-hydroxylase immunoreactivity. The uptake and storage of exogenous amines in tissue sections, in the presence of selective high-affinity transport inhibitors, enabled the specific visualization of the dopaminergic system with fluorescence histochemistry. A dopaminergic innervation of low density was observed along a dorsal sagittal strip which extended from the genu of corpus callosum until about 2 mm behind the splenium and encompassed several distinct cytoarchitectonic areas in the sensorimotor and visual cortex (medial and lateral agranular field, area 18b), as well as in discrete zones of the retrosplenial granular 29c,b, and agranular 29d areas. The distribution of these dopaminergic fields suggested a columnar organization. Several characteristics of the dopaminergic innervation were similar to that of the superficial anterior cingulate cortex (area 24): the laminar distribution to the superficial I-III layers, the secondarily developed varicose aspect in catecholamine fluorescence histochemistry and the delayed postnatal ingrowth in contrast with the early prenatal dopaminergic input to the prefrontal cortex. These similarities suggested that the subpopulation of dopaminergic neurons which provides projections to the anterior cingulate cortex could also contribute to the motor and visual cortex and thus play a role in sensorimotor integration. The predictive value of these results in the ascent of the phylogenetic scale are further considered.     

Noradrenergic and non-noradrenergic nerves containing small granular vesicles in Auerbach's plexus of the guinea-pig: evidence against the presence of noradrenergic synapses

The appearance and distribution of varicosities containing small granular vesicles in Auerbach's plexus of the guinea-pig ileum, distal colon and rectum has been studied with the electron-microscope. Two types of varicosity were recognised. The first type was located predominantly at the surface of the plexus and did not form synapses on intrinsic neurons. This type became labelled with 5-hydroxydopamine, a specific marker for noradrenergic axons, and was destroyed by 6-hydroxydopamine and extrinsic denervation, procedures which lead to degeneration of noradrenergic nerves in the gut. The second type formed axodendritic and axosomatic synapses on intrinsic neurons and the morphology of its synaptic vesicles differed subtly from that of the first type. The second type was unaffected by 5-hydroxydopamine, 6-hydroxydopamine, or extrinsic denervation. It is concluded that the two types of small granular vesicle-containing varicosities belong to different neurons and that the first type is noradrenergic. Noradrenergic varicosities do not, therefore, form synapses in Auerbach's plexus. This conclusion is in accord with the electrophysiological findings. The second type of small granular vesicle-containing varicosity is not noradrenergic although it was formerly thought to be so. It is intrinsic to the gut and is resistant to the serotoninergic neurotoxin, 5,6-dihydroxytryptamine.     

Avoidance conditioning in rats following changes in activity of the noradrenergic and cholinergic systems of the brain

Bilateral coagulation of the ventral noradrenergic pathways of the brain in male rats of the Wistar strain disrupted the conditioned passive avoidance response after unconditioned stimulation with a current of 0.75 mA. Injecting 10 mg/kg galantamine into these rats 20 min before training and increasing the unconditioned stimulus to 3 mA improved subsequent avoidance responses. Injecting galantamine under analogous conditions into normal rats impaired this reaction. Disruption of the conditioned avoidance response following the operation may be due to a change in the intracentral interrelation of the noradrenergic and cholinergic systems of the brain.Translated from Fiziologicheskii Zhurnal SSSR imeni I. M. Sechenova, Vol. 68, No. 3, pp. 297–302, March, 1982.     

The effects of lesions of lateral tegmental noradrenergic neurons on components of sexual behaviour and pseudopregnancy in female rats

Lesions (electrolytic and neurotoxic, using 6-hydroxydopamine) have been made of the projections of medullary noradrenergic neurons in the ascending ventral noradrenergic pathway in female rats. The lesions caused major depletion of noradrenaline in sub-cortical structures, notably the hypothalamus. In behavioural tests, these lesions selectively impaired sexual receptivity, measured as lordosis responses, but did not abolish proceptivity (soliciting). The impaired behaviour is critically dependent on somatosensory stimulation generated by the male during a mount. So, too, is pseudopregnancy since stimulation of the uterine cervix during coitus is essential for the prolongation of luteal life which underlies it. The ability to induce a pseudopregnant state was also abolished by the same ventral noradrenergic pathway lesion.These data, together with supportive evidence from experiments using procaine anaesthesia, have led us to suggest an important function of subcortically projecting noradrenergic neurons in the central transmission and/or processing of somatosensory information in neuroendocrine systems. We also present data suggesting that the effects of noradrenergic neuron activity are dependent on dopaminergic mechanisms more directly concerned with the control of motivated behaviour and anterior pituitary function.     

Benzodiazepine receptors in the rat hippocampal formation: action of catecholaminergic, serotoninergic and commissural denervation

The problem of benzodiazepine receptor localization in the rat hippocampal formation has been approached using several methods of selective deafferentation, followed by [3H]flunitrazepam binding studies. The intraventricular injection of 6-hydroxydopamine reduced, after 14 days, the norepinephrine content of the hippocampal formation by 68.4%, and decreased the number of binding sites by 32%, without change in affinity. The intraventricular injection of 5,6 dihydroxytryptamine reduced the serotonin content by 61.5% but did not alter the [3H]flunitrazepam binding. The intraventricular bilateral injection of 0.5 micrograms kainic acid selectively destroyed the pyramidal neurons in area CA3 of both hippocampi and produced an increase of 28% in [3H]flunitrazepam binding, without change in affinity. These results are discussed in relation to our previous observations about benzodiazepine receptor changes after fimbria-fornix transection. The reduction in [3H]flunitrazepam binding after administration of 6-hydroxydopamine suggests the possible localization of the benzodiazepine receptors on adrenergic presynaptic terminals. The increase in binding sites after destruction of CA3 pyramidal cells, which are the site of origin of commissural fibers, is tentatively interpreted as resulting from the sprouting of mossy fibers that replace the associational-commissural projections.     

Interaction of noradrenergic and cholinergic systems in regulation of ocular dominance plasticity

We studied interactions among the noradrenergic (NA) and the muscarinic cholinergic (ACh) systems in the regulation of ocular dominance plasticity in kitten visual cortex. The cortex was bilaterally infused with 6-hydroxydopamine (6-OHDA) for a week. Upon termination of the 6-OHDA infusion, one hemisphere was infused with a muscarinic ACh agonist, bethanechol, through the same, chronically implanted cannula for the second week together with monocular lid suture. The other hemisphere received an infusion of the vehicle solution alone. (1) Only in the hemisphere infused with bethanechol at relatively high concentrations did we obtain a clear shift in ocular dominance. We also found that the effect of bethanechol was concentration-dependent. (2) By comparing necessary concentrations of bethanechol and NA for the respective maximal effects, we noted that the former was at least 100-fold less effective than the latter in restoring the plasticity. (3) The cortical infusion of bethanechol did not restore the plasticity to the propranolol-pretreated cortex; the ocular dominance distribution remained virtually unchanged. This result was interpreted as suggesting that functioning beta-adrenoreceptors are needed for the cortical effect of activating the muscarinic ACh receptors to become detectable. (4) The expected shift in ocular dominance following monocular deprivation was partially suppressed, when highly concentrated scopolamine, a muscarinic ACh antagonist, was used, indicating that the involvement of the ACh system in this matter was indirect. The concentration of scopolamine needed for the half-maximum effect was 172-fold higher than that of propranolol. We thus conclude that the involvement of the muscarinic ACh system in ocular dominance plasticity is secondary to that of the NA-beta-adrenoreceptor system.     

Alteration of central alpha 2- and beta-adrenergic receptors in the rat after DSP-4, a selective noradrenergic neurotoxin

A peripheral injection of DSP-4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine] produced a marked, selective, and lasting depletion of norepinephrine in certain regions of the rat central nervous system. This depletion at 10 days after injection was associated with regional alterations in some, but not all, adrenergic binding sites (receptors) as determined by in vitro [3H]prazosin (alpha 1), [3H]p-aminoclonidine (alpha 2), and [3H]dihydroalprenolol (beta) binding. The neocortical alpha 1-receptor was not changed. The alpha 2-receptor in several regions was altered as indicated by an increase in ligand affinity; additionally, the density of this receptor was slightly decreased in some regions. Depending on the region, the beta-receptor either increased in density or was unchanged. The increased density of this receptor in neocortex corresponded to an increased activity of isoproterenol-sensitive adenylate cyclase. These two changes were not affected by subchronic treatment with desipramine, a norepinephrine uptake inhibitor. The changes were, however, partially or completely reversed by subchronic administration of clenbuterol, a centrally-acting beta-receptor agonist. The dopaminergic receptor in various regions was unaltered as assessed by in vivo and/or in vitro binding of [3H]spiperone. The in vivo binding of this ligand also indicated that the serotoninergic receptor in frontal neocortex was unchanged. Assessment of adrenergic receptors in neocortex at 50 days after injection indicated only the above affinity change of the (presumably postsynaptic) alpha 2-receptor. The alpha 1-receptor remained unaltered. The density of the beta-receptor had normalized, as had the activity of isoproterenol-sensitive adenylate cyclase. Implicit in these findings is the following rank order of receptor sensitivity to chronic norepinephrine depletion: alpha 2 greater than beta greater than alpha 1. The use of DSP-4 has clear advantages over other methods of depleting central norepinephrine. This neurotoxin can be administered by intraperitoneal injection, the depletion of norepinephrine can be readily checked by absence of the post-decapitation reflex, and the changes in other neurotransmitter concentrations are relatively minor or nonexistent. The alteration of alpha 2- and beta-receptors, as a consequence of DSP-4 treatment, may form the basis of a new animal model of adrenergic receptor supersensitivity. Such a model may clarify the importance of these central receptors to physiological and behavioral processes.     

Feeding response to regulatory challenges after 6-hydroxydopamine injection into the brain noradrenergic pathways

Previous studies have demonstrated that intra-mesencephalic 6-hydroxydopamine (6-OH-DA) injection into the ascending noradrenergic bundles produces hyperphagia in rats. In the present study, 6-OH-DA-injected, hyperphagic rats responded like normals to manipulation of certain factors concerned with the short-term regulation of feeding. First, norepinephrine-depleted animals and controls ate similar amounts after insulin challenge. Second, adulterating the diet with quinine, saccharin or a very palatable cheese resulted in only small and nonsignificant differences in intake in the 6-OH-DA rats and controls. However, a third experiment demonstrated that the long-term regulation of calorie balance was functioning suboptimally in the 6-OH-DA-injected rats. These animals took twice as long as controls to reduce their intake to isocaloric levels after being given a calorically concentrated diet. Thus, a disruption in the efficient calorie regulating mechanism may be a factor leading to overeating after norepinephrine loss. In addition, this study further supports the notion that hyperphagia and finickiness are dissociable.     

Interaction between the noradrenergic and serotonergic systems in locomotor hyperactivity and striatal expression of Fos induced by amphetamine in rats

It is classically considered that Amphetamine acts by increasing extracellular dopamine levels. However, some data suggest a relevant role of other neurochemical systems. The striatum is of particular interest to the study of this question. We have investigated the involvement of the noradrenergic and serotonergic systems and their possible interaction in the striatal responses to Amphetamine using a double behavioral and immunohistochemical approach (i.e., changes in locomotor activity and striatal expression of Fos). In normal rats, Amphetamine induced locomotor hyperactivity and striatal expression of Fos. Pretreatment with the ₁-adrenergic-receptor antagonist Prazosin or lesion of the serotonergic system significantly reduced the locomotor hyperactivity and striatal Fos expression induced by Amphetamine. Administration of Prazosin to rats with serotonergic denervation did not produce any further reduction in the Amphetamine-induced locomotor hyperactivity or striatal Fos expression compared with that observed in rats with serotonergic denervation only. Amphetamine did not induce a detectable increase in Fos expression in dopamine-denervated striata, and elicited intense rotation towards the dopamine-denervated side. This suggests that striatal dopamine release is essential in the Amphetamine-induced effects on striatal neurons. However, the noradrenergic system plays an important role, and the serotonergic system is necessary for mediating the effects of the Amphetamine-induced noradrenergic stimulation. Concurrent stimulation of dopaminergic and serotonergic receptors appears necessary to regulate Amphetamine-induced responses in the striatal neurons.     

Changes in body weight and food-related behaviour induced by destruction of the ventral or dorsal noradrenergic bundle in the rat

Three experiments contrasted the effects of 6-hydroxydopamine-induced lesions of the ventral noradrenergic and dorsal noradrenergic projections, predominantly to hypothalamus and cortex, respectively, upon body weight changes and food-related behaviour in the rat. In general, ventral noradrenergic bundle lesions enhanced weight gain and these effects were exaggerated by the provision of palatable cheese to the standard chow diet. In contrast, lesions of the dorsal noradrenergic bundle produced minor changes in body weight. Associated with the effects of ventral noradrenergic bundle lesions were hyperphagia, enhanced suppression of intake of food adulterated with quinine, (at high concentration), a small attenuation of food neophobia, and enhanced acquisition, but not performance, of the eating response to tail-pinch stimulation. These ventral noradrenergic bundle lesions failed to alter basal activity levels, amphetamine anorexia or the diurnal pattern of eating or activity. In contrast, lesions of the dorsal noradrenergic bundle did not produce either hyperphagia or enhanced rejection of food adulterated with quinine. However, there was a strong attenuation of food neophobia and a retarded acquisition (but unimpaired performance) of eating in response to tail-pinch stimulation.

The results are discussed in connection with previous studies of ventral and dorsal noradrenergic bundle lesions, with the effects of ventromedial hypothalamic lesions and with the underlying behavioural and physiological processes that mediate these contrasting effects of different neuroanatomical patterns of central noradrenaline depletion.     

Reciprocal relations between monoaminergic brain systems as a factor in pharmacological compensation of behavioral disturbances induced in animals by 6-hydroxydopamine

Institute of Biological Physics. Academy of Sciences of the USSR, Pushchino. (Presented by Academician of the Academy of Medical Sciences of the USSR A. V. Val'dman.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 107, No. 1, pp. 52–54, January, 1989.     

alpha 1- and beta-adrenergic receptors are co-regulated during both noradrenergic denervation and hyperinnervation

Changes in the density of alpha 1- and beta-adrenergic receptors were studied following denervation of rat cerebral cortex and hyperinnervation of cerebellum and motor trigeminal nucleus, caused by neonatal 6-hydroxydopamine treatment. Four well-defined thalamic projection zones to cortex were studied separately using tissue punch methodology. Both alpha 1- and beta-adrenergic receptors were unevenly distributed in motor, sensory, visual and auditory cortex. The density of alpha 1-adrenergic receptors correlated better with the norepinephrine content of the punches (r = 0.62) than did the density of beta-adrenergic receptors (r = 0.38). Noradrenergic denervation increased both alpha 1- and beta-adrenergic receptor density in almost all cortical areas studied, however the percentage increase was larger for beta- than alpha 1-adrenergic receptors. The change in receptor density was largest in visual cortex and smallest in somatosensory cortex for both receptor sub-types. Noradrenergic hyperinnervation caused a 15-18% decrease in both alpha 1- and beta-adrenergic receptor density in the motor trigeminal nucleus of the pons, but did not change the density of either receptor type in the cerebellum. In general, following either noradrenergic denervation or hyperinnervation the change in alpha 1-adrenergic receptor density was correlated (r = 0.64, P less than 0.005) with the change in beta-adrenergic receptor density in each region, suggesting that these different receptor sub-types are under similar control mechanisms.     

A study of the organization of the locus coeruleus projections to the lateral geniculate nuclei in the albino rat

The lateral geniculate nuclei of the rat are known to receive an innervation from catecholamine-containing neurons. In the present study the origin, axonal projections and terminal distribution of this innervation was studied. The lateral geniculate nuclei contain a356 ± 20 ng norepinephrine/g and64 ± 7 ng dopamine/g tissue; the latter is within the range expected for dopamine as a precursor in a region innervated by a norepinephrine-containing terminal system. When separate norepinephrine-containing cell groups located at various brain stem levels are ablated or their axonal projections destroyed, only lesions in the locus coeruleus produce a significant decrease in the norepinephrine content of the lateral geniculate nuclei. Injections of horseradish peroxidase into the lateral geniculate nuclei result in retrograde transport of horseradish peroxidase only to the noradrenergic neurons of the locus coeruleus. The labelled neurons are pretent throughout the rostrocaudal and dorsoventral axes of both the ipsilateral (60%) and contralateral (40%) nucleus. Autoradiographic and fluorescence histo-chemical experiments indicate that axons that ascend from the locus coeruleus reach the lateral geniculate nuclei via the dorsal tegmental catecholamine-containing bundle and the medial forebrain bundle. These fibers enter the ventral lateral geniculate nucleus from the zona incerta and the dorsal lateral geniculate nucleus from the superior thalamic radiation, thalamic reticular nucleus, and lateral posterior nucleus. Contralateral fibers from the locus coeruleus cross in the posterior commissure, supraoptic and pontine decussations and join the ipsilateral projections to the lateral geniculate nuclei. The bilateral locus coeruleus innervation of the nuclei is comprised of a highly branched network of varicose axons. Neither the ipsilateral nor the contralateral projections appear to be topographically organized; instead, a single fiber may have collateral axons that branch throughout large areas of the nuclei. This innervation is moderately dense in the ventral, and very dense in the dorsal, lateral geniculate nucleus.The study indicates that both the dorsal and ventral lateral geniculate nuclei receive a diffuse catecholamine-containing innervation which arises solely from the norepinephrine-containing neurons of the locus coeruleus. The innervation of each lateral geniculate nucleus is bilateral, with noradrenergic neurons located throughout both the ipsilateral and the contralateral locus coeruleus contributing to ascending pathways that terminate as a diffuse, plexiform innervation interspersed among other afferents to the lateral geniculate nuclei. It is speculated that such a diffuse noradrenergic innervation might depress the spontaneous activity of neurons in the lateral geniculate nuclei, while preserving or enhancing their responsiveness to afferent optic stimulation.     

Failure of MK-801 to suppress D1 receptor-mediated induction of locomotor activity and striatal preprotachykinin mRNA expression in the dopamine-depleted rat

N-methyl-D-aspartate receptor antagonism exerts suppressive influences over dopamine D1 receptor-mediated striatal gene expression and locomotor behavior in the intact rat. The present study examined the effects of the N-methyl-D-aspartate receptor antagonist MK-801 on locomotor activity and striatal preprotachykinin mRNA expression stimulated by the D1 agonist (+/-)6-chloro-7, 8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide in rats with bilateral dopamine lesions. Two months after neonatal dopamine lesions with 6-hydroxydopamine, rats were challenged with (+/-)6-chloro-7, 8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (1.0 mg/kg) 15 min after administration of the N-methyl-D-aspartate receptor antagonist MK-801 (0.1 mg/kg). In the intact rat, MK-801 prevented the induction of striatal preprotachykinin mRNA by D1 agonism. Similarly, direct infusion of (+/-)6-chloro-7, 8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (3.0 microg) into the intact striatum produced an increase in locomotor activity that was suppressed by MK-801 (1.0 microg) co-infusion. In the dopamine-depleted rat, MK-801 (0.1 mg/kg) administered prior to (+/-)6-chloro-7, 8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (1.0 mg/kg) increased, rather than suppressed, striatal preprotachykinin mRNA levels. Intrastriatal infusion of MK-801 (1.0 microg) failed to inhibit D1-mediated induction of motor activity in dopamine-depleted animals. Together, these data provide further support that N-methyl-D-aspartate receptor antagonists lose their ability to block D1-mediated behavioral activation following dopamine depletion. The activation, rather than suppression, of tachykinin neurons of the direct striatonigral pathway may play a facilitatory role in this mechanism.