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Biomedical subjects

A M Janson

Publications and source records attributed to A M Janson.

At least 19 recordsLinked to original sources
PubMed1992

Inhibitory effects of the psychoactive drug modafinil on gamma-aminobutyric acid outflow from the cerebral cortex of the awake freely moving guinea-pig. Possible involvement of 5-hydroxytryptamine mechanisms.

The effects of modafinil on acetylcholine and GABA outflow from the cerebral cortex of awake freely moving guinea pigs provided with an epidural cup were studied. In the dose range of 3-30 mg/kg s.c. modafinil produced a dose dependent significant inhibition of GABA outflow without influencing cortical acetylcholine release. Methysergide (2 mg/kg, i.p.) and ketanserin (0.5 mg/kg, i.p.) but not prazosin (0.14 mg/kg, i.p.) counteracted the inhibitory action of modafinil on cortical GABA outflow. Modafinil both acutely and chronically in the same dose range increased striatal 5-HIAA levels and 5-HT utilization in the rat (acute) and mouse (chronic). The action on cortical GABA release may be dependent on activity at 5-HT2 receptors, since the action of modafinil in this respect is blocked by the non-selective 5-HT antagonist methysergide and the 5-HT2 antagonist ketanserin. The involvement of 5-HT mechanisms in the inhibitory action of modafinil on cortical GABA release is also suggested by the findings that 5-HT metabolism may become increased by modafinil at least in the striatum. The reduction of cortical GABA outflow via 5-HT2 receptors by modafinil is probably related to some of its actions on the central nervous system including behavioural effects.

Acetylcholine↗
PubMed1992

Evidence for a protective action of the vigilance promoting drug modafinil on the MPTP-induced degeneration of the nigrostriatal dopamine neurons in the black mouse: an immunocytochemical and biochemical analysis.

Based on the observations that the psychostimulant drug amphetamine in combination with physiotherapy can promote recovery of brain function after brain injury, we have studied the ability of the vigilance promoting drug Modafinil to counteract 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-(MPTP)-induced degeneration of the nigrostriatal dopamine (DA) neurons of the black mouse. MPTP was given s.c. in a dose of 40 mg/kg and the mice were sacrificed 2 weeks later. The effects of acute and chronic treatment with Modafinil were studied on MPTP-induced DA neurotoxicity. The substantia nigra and neostriatum were taken to both biochemical and histochemical analysis of presynaptic parameters of the nigrostriatal DA neurons, the latter in combination with image analysis. In separate experiments in rats in vivo tests for DA uptake blocking activity were made using intrastriatal microdialysis to study superfusate levels of DA and its metabolites and the 4-alpha-dimethylmetatyramine (H77/77) model to test for a possible ability of Modafinil to protect against H77/77-induced depletion of forebrain DA stores. Chronic treatment with Modafinil in doses of 10 to 100 mg/kg counteracted the MPTP-induced disappearance of nigral TH IR nerve cell body profiles and neostriatal TH IR nerve terminal profiles as evaluated after 2 weeks with image analysis. Chronic treatment with Modafinil (10-100 mg/kg) also dose-dependently counteracted the MPTP-induced disappearance of striatal DA uptake binding sites as evaluated at the same time interval. Also in the dose range 10-100 mg/kg Modafinil counteracts the MPTP-induced depletion of DA stores both in the neostriatum and the substantia nigra. In the acute experiments Modafinil (30 mg/kg) protected against the MPTP-induced depletion of striatal DA, dihydrophenylacetic acid (DOPAC) and homovanillic acid (HVA) levels both when given 15 min before, at the same time and 3 h following the MPTP injection. In the substantia nigra, however, these protective actions of Modafinil were only observed when the drug was coadministered with MPTP. Experiments with microdialysis in intact rats failed to demonstrate any increases of superfusate DA levels in neostriatum with 30 mg/kg of Modafinil. Modafinil in high doses of 2 x 50 mg/kg, however, significantly counteracted the H77/77 induced DA depletion of striatal DA stores. Thus, morphological and biochemical evidence has been obtained that Modafinil in the dose range 10-100 mg/kg protects against MPTP-induced degeneration of the nigrostriatal DA neurons of the black mouse.(ABSTRACT TRUNCATED AT 400 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

Chronic nicotine treatment decreases dopamine D2 agonist binding in the rat basal ganglia.

To elucidate possible actions of nicotine on dopamine D2 receptor binding, the effect of chronic continuous (-)nicotine treatment (osmotic pumps s.c., 0.125 mg kg h-2, 14 days) was studied in the binding of [3H]N-propylnorapomorphine ([3H]NPA) and [125I]sulpride in coronal cryostat sections in the rat. Quantitative autoradiography showed that nicotine decreased the binding of [3H]NPA in the basal ganglia, preferentially in the nucleus accumbens and olfactory tubercle. In contrast, [125I]sulpride binding was not affected. Nicotine decreased the KD value of [3H]NPA by 27% and decreased the Bmax value by 17%, using filter-wiped sections. These results indicate that chronic continuous nicotine treatment affects the D2 receptor and that this effect may be involved in the development of nicotine dependence.

Animals↗
PubMed1991

Chronic nicotine treatment counteracts the decrease in extracellular neostriatal dopamine induced by a unilateral transection at the mesodiencephalic junction in rats: a microdialysis study.

The effect of chronic treatment with (-)-nicotine on the decrease in extracellular dopamine (DA) levels in neostriatum induced by a unilateral transection at the meso-diencephalic junction in rats was studied. At the lesion time, Alzet minipumps filled with (-)-nicotine were implanted subcutaneously. Two weeks later, microdialysis probes were implanted bilaterally into the neostriatum. Perfusates were assayed for DA, acetylcholine (ACh) and metabolites in HPLC systems under basal and KCl stimulated conditions. The unilateral hemitransection produced an ipsilateral decrease in neostriatal extracellular DA, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), but not in ACh levels. Chronic nicotine treatment counteracted the lesion-induced decrease in DA, but had no effect on extracellular DA levels in the contralateral neostriatum or in normal rats. The results support the idea that chronic nicotine treatment may protect against degeneration of central DA neurons.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1991

Chronic continuous nicotine treatment causes decreased burst firing of nigral dopamine neurons in rats partially hemitransected at the meso-diencephalic junction.

Chronic continuous administration of nicotine (0.125 mg/kg/h, 14 days) to male Sprague-Dawley rats with a partial hemitransection at the meso-diencephalic junction caused a significant reduction in burst firing of remaining dopamine (DA) neurons in the zona compacta, substantia nigra, whereas neither the firing rate nor the number of spontaneously active DA cells per track were altered in comparison with saline-treated, hemitransected controls. The reduced functional activity of the remaining DA cells subjected to nicotine treatment provides a physiological correlate to the previously observed, reduced DA utilization in these neurons. It may also help to explain the increased nigral DA cell survival found after chronic nicotine treatment in similar lesion experiments.

Action Potentials↗
PubMed1991

Hypertrophy of dopamine neurons in the primate following ventromedial mesencephalic tegmentum lesion.

Morphological changes in ventral mesencephalic dopamine (DA) neurons of a monkey sustaining a unilateral electrolytic lesion of the ventromedial mesencephalic tegmentum four years earlier were examined. Substantia nigra (A9) DA neurons lateral to the lesion underwent hypertrophic changes. The mean area of these neurons was enlarged by approximately 30% relative to corresponding neurons in the contralateral substantia nigra. Semi-quantitative immunohistochemical measurements of the intensity of tyrosine hydroxylase-like immunoreactivity (TH-li) indicated an increase in the amount of TH-li protein per cell in the hypertrophied neurons. Hypertrophic changes were also observed in ipsilateral A11 DA neurons of the caudal hypothalamus, suggesting that the increase in size was related to transection of the axons of DA neurons as they pass through the midbrain in their projections to target sites. The lesion did not overtly change the density or pattern of the substance P innervation of the substantia nigra, indicating that the striato- and pallido-nigral projections were spared by the lesion. These data suggest that hypertrophy may be a compensatory mechanism of dopaminergic neurons in response to partial lesions of the nigrostriatal system, and thus represent a morphological counterpart to the compensatory biochemical processes effected in response to partial lesions of the striatal dopaminergic innervation.

Animals↗
PubMed1990

Chronic nicotine treatment increases dopamine levels and reduces dopamine utilization in substantia nigra and in surviving forebrain dopamine nerve terminal systems after a partial di-mesencephalic hemitransection.

In order to further study the previously demonstrated protective action of chronic nicotine treatment on lesioned meso-striatal dopamine (DA) pathways, the following study was carried out on DA utilization in these lesioned neurons. Male Sprague-Dawley rats were partially hemitransected at the meso-diencephalic junction and treated with nicotine (0.125 mg.kg-1.h-1) by means of Alzet minipumps implanted subcutaneously for 2 weeks. The overall serum nicotine level obtained was 64.6 +/- 2.7 ng.ml-1. The results demonstrated that partial di-mesencephalic hemitransections produced a marked reduction of DA fluorescence (quantitative histofluorimetry) on the lesioned side in the nucleus caudatus putamen, anterior nucleus accumbens and posterior lateral tuberculum olfactorium. No significant effects were observed on the intact side. Furthermore, studies on changes in DA utilization as evaluated 2 h after tyrosine hydroxylase inhibition showed an augmentation in the alpha-methyl-(+/-)-p-tyrosine methyl ester (alpha-MT)-induced depletion of the DA stores on the hemitransected side in comparison with the operated side of the sham-operated animals. On the hemitransected side chronic nicotine treatment increased DA stores in the DA nerve terminals of the nucleus caudatus putamen and the posterior lateral tuberculum olfactorium. No significant effects were observed on the intact side. Following chronic nicotine treatment a marked and preferential attenuation of the alpha-MT-induced depletion of DA stores was seen in the various DA nerve terminal systems of the forebrain on the hemitransected side. In the substantia nigra reduced DA levels (HPLC) were demonstrated on the hemitransected side, while no effects on the non-operated side were observed. Also an increase of the alpha-MT-induced depletion of the DA stores was seen on the hemitransected side in comparison with the operated side of the sham-operated animals. In contrast, on the non-operated side an attenuation of the alpha-MT-induced depletion of the DA stores was found. Following chronic nicotine treatment the lesion induced reduction of the nigral DA stores on the hemitransected side was counteracted, as was the lesion induced increase in the alpha-MT-induced depletion of DA stores, which was replaced by a reduction of the alpha-MT-induced depletion of the nigral DA stores. However, on the non-operated side an increased DA depletion was observed after alpha-MT treatment in rats treated chronically with nicotine. Chronic nicotine treatment under the present conditions did not significantly alter serum levels of corticosterone and reduced prolactin serum levels in sham-operated rats.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

Chronic nicotine treatment eliminates asymmetry in striatal glucose utilization following unilateral transection of the mesostriatal dopamine pathway in rats.

Partial hemitransection was performed through a knife lesion at the meso-diencephalic level in rats to sever the mesostriatal dopamine system. During the subsequent 2 weeks the animals received 0.125 mg/kg/h of nicotine continuously via an osmotic minipump implanted s.c. To achieve prompt high nicotine levels, 4 i.p. injections of 0.5 mg/kg nicotine were, in addition, given during the first 2 h following the lesion. The total treatment corresponded to a mean plasma level of 50 ng/ml nicotine, measured at the end of the experiment. Control animals received corresponding volumes of 0.9% saline. Quantitative autoradiographic analysis of the glucose utilization in the caudate nucleus using Sokoloff's [14C]2-deoxyglucose method demonstrated a 16% side-to-side difference in the lesioned control animals, whereas the asymmetry was counteracted by the nicotine treatment. Although there was an overall tendency to a lower rate of glucose utilization (by 6%) in the nicotine-treated animals compared to the controls receiving saline only, the difference was not statistically significant. The eliminated asymmetry probably reflects an increased survival of the dopamine neurons and/or of striatal nerve cells on the lesioned side due to protective effects of nicotine resulting from desensitization of nicotinic-type cholinergic receptors following continuous administration of the drug.

Animals↗
PubMed1989

Chronic immobilization stress: evidence for decreases of 5-hydroxy-tryptamine immunoreactivity and for increases of glucocorticoid receptor immunoreactivity in various brain regions of the male rat.

Male rats were exposed to severe 14 day immobilization stress. Body weight, body temperature, food and water intake, behavioral parameters, and serum corticosterone levels were measured during and after the stress period. On the 7th day after cessation of stress the experimental animals together with the control rats were taken to immunocytochemical analysis involving morphometry and microdensitometry of tyrosine hydroxylase (TH), 5-hydroxytryptamine (5-HT), various neuropeptide, and glucocorticoid receptor (GR) immunoreactivities (IRs) in a large number of regions of the central nervous system. In addition, adrenocorticotropic hormone (ACTH) IR was analyzed in the pituitary gland. Seven days following cessation of the chronic stress food intake, total locomotion and forward locomotion had been restored to normal. Serum corticosterone levels appeared to remain increased even 6 days following cessation of the chronic immobilization stress, probably caused by increased release of ACTH. Paraventricular corticotropin releasing hormone (CRF) IR was negatively correlated with the pituitary ACTH IR, indicating that the increase in ACTH release was produced by an increased release of CRF from the hypothalamus. The major immunocytochemical change observed 7 days after cessation of stress was a disappearance of 5-HT IR in the 5-HT cell groups B1, B2, B3, and B7. 5-HT IR in nerve terminals was only affected in the dorsal horn, where 5-HT IR was increased in the substantia gelatinosa. GR IR was found to be significantly increased in monoaminergic cell groups: serotoninergic B7, dopaminergic A12, and noradrenergic A1, A2, and A6. A trend for a reduction of TH IR was observed in nigral DA cells associated with significant reductions in TH IR in striatal DA nerve terminals. Finally, increases in 5-HT and substance P (SP) IR were found in the nerve terminals of the substantia gelatinosa of the cervical spinal cord in the stress group. In the present experimental model evidence has been obtained for a maintained activation of the hypothalamic-pituitary-adrenal axis as evaluated 7 days after cessation of severe chronic immobilization stress. The reduction of 5-HT IR in various 5-HT cell groups indicates a reduction of 5-HT synthesis, which may also be associated with reduced 5-HT release from the nerve terminals, since no depletion was observed in terminal regions and in one case an increase in 5-HT IR was noted (substantia gelatinosa).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

Protective effects of chronic nicotine treatment on lesioned nigrostriatal dopamine neurons in the male rat.

The present results demonstrate that chronic nicotine treatment can in part protect against mechanically-induced and neurotoxin-induced degeneration of nigrostriatal DA neurons. These results indicate that in sufficient doses chronic treatment with nicotine may be considered in the pharmacological treatment of Parkinson's disease. It remains to be demonstrated whether these protective actions can be extended to include also other injured neurons such as the cholinergic neurons, known to be severely affected in Alzheimer's disease.

Animals↗
PubMed1989

Studies of protective actions of nicotine on neuronal and vascular functions in the brain of rats: comparison between sympathetic noradrenergic and mesostriatal dopaminergic fiber systems, and the effect of a dopamine agonist.

Neuroprotective and possible trophic actions of nicotine were studied in two types of experimental models: (1) one in which the meso-striatal dopamine system was subjected to partial hemitransection, and regional glucose utilization (using 2-[3H]deoxyglucose) and blood flow (using [14C]iodoantipyrine) were measured by computer-assisted quantitative autoradiography based on a double-isotope technique; and (2) another where the sympathetic cranial nervous system supplying the brain vasculature was subjected to decentralization, axotomy, and partial or complete ganglionectomy, and the neuronal survival and fiber regeneration were elucidated by fluorescence histochemistry of noradrenaline, tyrosine hydroxylase, and neuropeptide Y. Continuous nicotine infusion for 4 weeks failed to significantly affect the neuronal response to the surgical interference of the sympathetic noradrenergic system. The same nicotine treatment for 2 weeks significantly improved glucose utilization and blood flow in caudate-putamen on the side in which the meso-striatal dopamine system had been transected, thus eliminating the 16% side-to-side asymmetry in the metabolism caused by the axotomy. The dopamine agonist, EMD 23,448, was without significant effect on this asymmetry. The hemitransection produced marked reduction in metabolism and flow also in the ventro-lateral thalamus. In substantia nigra, glucose utilization was markedly elevated--perhaps as a consequence of a regenerative increase in protein synthesis--opposite to a considerable reduction in nigral blood flow. Little or no effect of the hemitransection was seen in hippocampus or nucleus accumbens. In neither of these four regions did nicotine (or EMD 23,448) have any overt influence on glucose metabolism or blood flow. It is concluded that nicotine, mainly through its protective action on the meso-striatal dopaminergic system, is able to improve striatal glucose utilization and associated blood flow, probably reflecting a tendency to amelioration of neurotransmission function of surviving terminals belonging to the nigro-striatal dopamine neurons.

Animals↗
PubMed1988

Chronic nicotine treatment counteracts the disappearance of tyrosine-hydroxylase-immunoreactive nerve cell bodies, dendrites and terminals in the mesostriatal dopamine system of the male rat after partial hemitransection.

Male Sprague-Dawley rats were partially hemitransected at the mesodiencephalic junction and treated with nicotine (nicotine hydrogen (+)-tartrate) using Alzet minipumps implanted subcutaneously. Nicotine was delivered for 2 weeks in a dose of 0.125 mg/kg/h resulting in a serum nicotine level of 50.0 +/- 5.1 ng/ml. Three other groups of rats were analyzed: hemitransected rats receiving saline treatment and sham-operated animals receiving nicotine and saline, respectively. The effects of hemitransection and nicotine rostrally as well as caudally to the lesion were evaluated with image analysis of tyrosine hydroxylase (TH)-immunoreactive (IR) nerve cell body and dendrite profiles in the rostral and caudal substantia nigra and of TH-IR nerve terminal profiles in the striatum. Adjacent sections were taken to Nissl staining. [3H]Nicotine binding in the midbrain and forebrain was studied by means of receptor autoradiography on partially hemitransected rats receiving no treatment. Catecholamine (CA) levels in the frontal cortex were measured using high-performance liquid chromatography (HPLC). Striatal dopamine (DA) function was analyzed studying apomorphine-induced (1.0 mg/kg) ipsilateral rotational behavior. The spontaneous behavior of the rats was evaluated with a hole board. Furthermore, body temperature and body weight were measured. The results demonstrated a lesion-induced disappearance of TH-IR cell body and dendrite profiles in the substantia nigra and of TH-IR nerve terminal profiles in the striatum. Similar findings were seen after Nissl staining. A significant counteraction of this disappearance was found in the nicotine-treated animals. On the lesioned animals a marked reduction of [3H]nicotine binding in the striatum and the substantia nigra was found. In the functional experiments an enhancement of the apomorphine-induced ipsilateral rotational behavior was demonstrated. The degree of rotation was positively correlated with the serum nicotine level. The study on spontaneous activity in the hole board showed a slower restoration of total activity in the hemitransected nicotine-treated rats. All these results are compatible with the hypothesis that the protective action of nicotine on the mesostriatal DA system may be due to a desensitization of excitatory nicotine cholinoceptors located on the nigral DA nerve cells, leading to a reduction of firing rate and reduced energy demands. Such an action of nicotine could be of importance for a possible anti-parkinsonian effect.

Animals↗
PubMed1988

Effects of chronic imipramine treatment on glucocorticoid receptor immunoreactivity in various regions of the rat brain. Evidence for selective increases of glucocorticoid receptor immunoreactivity in the locus coeruleus and in 5-hydroxytryptamine nerve cell groups of the rostral ventromedial medulla.

Glucocorticoid receptor (GR) immunoreactivity (IR) was analyzed semi-automatically in the forebrain and in the lower brain stem of male rats treated for two weeks with imipramine (10 mumol/kg). Serum corticosterone and aldosterone levels were determined by means of radioimmunoassay procedures. The microdensitometric analysis demonstrated a selective increase in the GR IR in the nerve cell nuclei of the locus coeruleus (A6), of the ventral part of the reticular gigantocellular nucleus (B3L) and of the nucleus raphae magnus (B 3 M), whereas a small reduction of GR IR was found in the nucleus raphe obscurus (B2). In the morphometric analysis significant increases in the mean profile area of nuclear GR IR, which may be secondary to the increase in GR IR, were observed in the B 3 M. The serum corticosterone and aldosterone levels were not found to be significantly altered. The selective changes of GR IR may reflect the presence of an altered number of GR in these nerve cell groups and/or an altered translocation of GR to the nuclei. It is of substantial interest that these changes were observed in the presence of unchanged serum levels of corticosterone and aldosterone. It seems possible that adaptive changes in monoamine synapses induced by the chronic imipramine treatment may be responsible for the changes in GR IR found in the noradrenaline (NA) and 5-hydroxytryptamine (5-HT) cell bodies, respectively. The present results open up the possibility that chronic imipramine treatment may help to maintain the glucocorticoid receptor function in the locus coeruleus and in the 5-HT cell groups of the rostral ventromedial medulla of depressed patients.

Aldosterone↗
PubMed1987

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.

Groups of male rats were treated for a period of 14 days with imipramine (10 mumol/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 (B1, B2, B3) and of the nucleus raphe dorsalis (B7) 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 terminals 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 B3 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 B7, 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 B1 was acutely reduced by imipramine.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗