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L Gunne

Publications and source records attributed to L Gunne.

13 recordsLinked to original sources
PubMed2002

Naloxone reduces levodopa-induced dyskinesias and apomorphine-induced rotations in primate models of parkinsonism.

Using in situ hybridization, it was found that subchronic treatment with levodopa/benserazide increased preproenkephalin-A and preproenkephalin-B mRNAs in the dopamine-depleted striatum. In order to examine whether dysfunction of the endogenous opioid system may underlie the development of levodopa-induced dyskinesias, the effect of naloxone, an opioid antagonist, on dyskinesias was investigated in two models of parkinsonism in the common marmoset. MPTP-treated monkeys were administered a daily oral dose of levodopa/benserazide which relieved the parkinsonian symptoms but induced severe and reproducible dyskinetic movements. Naloxone (0.1, 0.2 or 0.5 mg/kg) was given subcutaneously (s.c.) during peak-dose dyskinesia, which reduced the dyskinesias significantly using the highest dose, normalized the motor activity, but did not modify the antiparkinson effect. Unilaterally 6-OHDA -lesioned marmosets received apomorphine s.c., which caused a contralateral turning behavior that could be reduced up to 35 percent by concomitant administration of naloxone. Taken together the present results suggest a possible role for the endogenous opioid system in the pathogenesis of levodopa-induced dyskinesia in primates.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2001

Coadministration of (-)-OSU6162 with l-DOPA normalizes preproenkephalin mRNA expression in the sensorimotor striatum of primates with unilateral 6-OHDA lesions.

The substituted phenylpiperidine (-)-OSU6162 is a novel modulator of the dopaminergic systems with low affinity for dopamine D(2) receptors and potent normalizing effects on l-DOPA-induced dyskinesias. We studied the effects of coadministration of (-)-OSU6162 with l-DOPA on the regulation of striatal preproenkephalin (PPE) and prodynorphin (PDyn) mRNA expression in the primate brain by in situ hybridization histochemistry. Common marmoset monkeys sustaining unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway received l-DOPA/carbidopa, l-DOPA/carbidopa plus (-)-OSU6162, or vehicle over 14 days. In vehicle-treated animals, PPE mRNA levels were markedly increased in the sensorimotor territory of the lesioned striatum. By contrast, a rather uniform lesion-induced reduction of PDyn mRNA levels was found in the vehicle group. Subchronic l-DOPA treatment induced a further increase in PPE mRNA expression in a number of sensorimotor and associative subregions of the denervated striatum. Coadministration of (-)-OSU6162 with l-DOPA partially reversed the lesion- and l-DOPA-induced elevation of PPE expression and, by affecting PPE mRNA expression differentially on the intact and lesioned striatum, markedly reduced the side-to-side difference in PPE mRNA expression. The effects on PPE mRNA expression were apparent throughout the rostrocaudal extent of the putamen and the dorsal portions of the caudate nucleus. l-DOPA treatment resulted in an enhancement in PDyn mRNA expression in all functional compartments of the striatum. Coadministration of (-)-OSU6162 had no apparent influence on these l-DOPA-induced changes in PDyn mRNA expression. The present results suggest that (-)-OSU6162 acts primarily by modifying striatal output via the indirect pathway.

Animals↗
PubMed2000

L-DOPA produces strong induction of c-fos messenger RNA in dopamine-denervated cortical and striatal areas of the common marmoset.

Common marmosets (Callithrix jacchus) with near-complete unilateral 6-hydroxydopamine denervation of the dopaminergic input received a single injection of saline or L-DOPA (15mg/kg plus 6.25mg/kg benserazide). Using in situ hybridization, the effects of these treatments on c-fos messenger RNA expression in the cerebral cortex, the striatal complex and the external layer of the pallidum were studied. Moreover, receptor autoradiography was used to determine the levels of dopamine D(1) and D(2) receptors in these areas. In the cerebral cortex, animals treated with L-DOPA displayed a high expression of c-fos messenger RNA restricted to the dopamine-denervated hemisphere. No changes in the levels of cortical D(1) and D(2) receptors were found in the dopamine-denervated hemisphere. L-DOPA treatment also induced a strong expression of c-fos messenger RNA in the striatal complex in the dopamine-denervated hemisphere. The levels of striatal D(2), but not D(1), receptors were increased in the dopamine-denervated hemisphere. In the external pallidum, the major terminal region for D(2) dopamine receptor-containing striatal projection neurons, L-DOPA treatment induced c-fos messenger RNA expression in both the intact and the dopamine-denervated hemispheres.Thus, using c-fos messenger RNA as a biochemical marker of postsynaptic neuronal activation, these results provide evidence that near-complete dopamine depletion causes a profound supersensitization to L-DOPA treatment in the cerebral cortex and in the striatal complex, but not in the external layer of the pallidum, of the primate brain. The cortical response may be unique to the primate brain, but c-fos messenger RNA activation within the striatum has also been reported in the rodent. The effects of L-DOPA probably depend both on a direct activation of supersensitized dopamine receptors by dopamine produced in the few remaining, but hyperactive, dopaminergic nerve terminals and in serotonergic nerve terminals, as well as on indirect actions of L-DOPA related to activation of circuitries connecting cerebral cortex and basal ganglia structures. These results provide novel information on the mechanisms underlying L-DOPA's action in the cerebral cortex, striatum and external pallidum in a primate model of Parkinson's disease.

Animals↗
PubMed1995

Behavioral and neurochemical consequences of ibotenic acid lesion in the subthalamic nucleus of the common marmoset.

Five marmosets were unilaterally lesioned within the subthalamic nucleus (STN) by injection of 10 micrograms ibotenic acid. Seven marmosets served as saline injected controls. The lesioned marmosets showed an increased locomotor activity, occasional tongue protrusions, posture asymmetry, and abnormal movements of the contralateral legs and arms. The animals were sacrificed 21 days after the ibotenic acid injection and markers of gamma-aminobutyric acid (GABA), dopamine (DA), and acetylcholine were studied in a variety brain regions. There was a bilateral increase in the activity of glutamic acid decarboxylase (GAD) in the caudate, putamen, globus pallidus, superior colliculus, and the ventral anterior/ventral lateral (VA/VL) thalamus, whereas GABA concentrations were only increased ipsilaterally in the ventral posterior medial/centromedial/parafasciculus (VPM/CM/Pf) complex of the thalamus. Tyrosine hydroxylase (TH) activity was bilaterally increased in the medial segment of globus pallidus and nucleus accumbens. However, there were also changes restricted to the side contralateral to the lesion. TH activity and DA concentrations were increased contralateral to the lesion in the putamen. Choline acetyltransferase (CAT) activity was bilaterally increased in the medial segment of globus pallidus and hypothalamus. The ibotenic acid induced STN-lesion in the marmoset, thus, seemed to cause a widespread bilateral activation of neurons within the basal ganglia.

Acetylcholine↗
PubMed1991

Intranigral tachykinin NK3 receptor agonist elicits oral movements in rats.

Synthetic agonists for the tachykinin NK1 and NK3 receptors were bilaterally infused at three dose levels (4.2, 0.17, and 0.007 nmol) into each substantia nigra of freely moving rats and oral behaviors were monitored for 30 min postinfusion. It was found that all doses of senktide, an agonist at the NK3 receptor, induced a significant increase of nonobject-directed chewing, vacuous chewing movements (VCM). The highest dose of senktide produced the greatest effect (p less than 0.001) and precipitated wet shakes for about 15 min after infusion. Septide, selective at the NK1 receptor, was without effect on oral behavior. The present results suggest that NK3 receptor-active peptides might be symptom inducers in oral dyskinesia.

Animals↗
PubMed1990

Neuropeptide changes in a primate model (Cebus apella) for tardive dyskinesia.

Tardive dyskinesia has been connected with regional reductions of GABA functions in the basal ganglia. In view of the possibility that peptides are involved in neuroleptic-induced dyskinesias substance P and dynorphin A levels were measured in the basal ganglia of the Cebus apella model for tardive dyskinesia. In addition, regional glutamate decarboxylase activities, dopamine, homovanillic acid and dihydroxyphenylacetic acid levels were monitored. A significant dyskinesia-related decrease in glutamate decarboxylase activity was found in the subthalamic nucleus, the medial segment of globus pallidus and the rostral part of substantia nigra in accordance with earlier findings. Cebus monkeys with an intact GABA system (neuroleptic-treated controls without dyskinesia) showed increased levels of substance P and homovanillic acid in the caudate nucleus. The changes were confined to the caudal part of the body of the caudate and the nucleus accumbens. On the other hand, the dyskinetic monkeys, with a defective GABA system, did not demonstrate a similar substance P rise in the caudate or nucleus accumbens, but showed a depression of homovanillic acid levels in the caudal part of the body of the caudate nucleus. Dynorphin A, dopamine and dihydroxyphenylacetic acid showed no dyskinesia-related changes. In conclusion, the difference in glutamate decarboxylase activity between animals developing dyskinetic symptoms vs those who did not, was reflected by regional changes in substance P and homovanillic acid levels.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1989

Methadone-assisted rehabilitation of Swedish heroin addicts.

During its first 20 years of existence a national Swedish methadone maintenance programme received 174 heroin addicts. Programme policy, with a massive emphasis on vocational rehabilitation, and outcome data are described. In 75% of the cases the subjects abandoned their drug abuse behaviour and took up work while 25% were expelled from the programme due to violation of rules. The stability of the programme was established by 14 yearly check-ups of the percentage working and studying, which remained about 80%. The tendency towards maturing out of addiction was low in Swedish heroin addicts (6%) as evidenced by a special study including a 6-year follow-up of 34 subjects fulfilling admission criteria. Half of this group received methadone, while the other half were randomly assigned controls. The death rate among controls was at least 73 times the expected for the age group studied (20-24 years), while 81% of those receiving methadone became free of drug abuse and vocationally rehabilitated. The control group also showed a high rate of drug abuse-related morbidity. Among 34 female heroin addicted prostitutes 71% abandoned drugs and street prostitution and took up regular work.

Adult↗
PubMed1988

Chronic neuroleptics alter the effects of the D1 agonist SK&F 38393 and the D2 agonist LY171555 on oral movements in rats.

Vacuous oral movements (OMs) in rats chronically administered haloperidol (HAL), fluphenazine (FLU), or no drug were studied following injections of one of three doses of either a D1 agonist (SK&F 38393) or a D2 agonist (LY171555). Oral movements were observed via closed-circuit television and simultaneously recorded using a computerized video analysis system which measured the distance between two fluorescent dots painted above and below the rat's mouth. SK&F 38393 induced a dose-dependent increase in tremorous oral movements and repetitive chewing movements in the controls; this effect was more pronounced in rats treated with chronic HAL or FLU, both during chronic neuroleptic treatment and even more so when they were tested after drug withdrawal following 5 or 14 months of chronic neuroleptic administration. Conversely, LY171555 produced an inhibition of oral activity at all dose levels in controls. This inhibition was attenuated during chronic administration of HAL or FLU, but returned to control levels (without any signs of supersensitivity) when the animals were retested shortly after discontinuation of neuroleptics. These results indicate that heightened oral movements in rodents following chronic neuroleptic administration can be more clearly induced by D1 than by D2 receptor activation.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1987

Opposite effects of a D1 and a D2 agonist on oral movements in rats.

Oral movements in rats administered one of three doses of either a D1 agonist (SK&F 38393) or a D2 agonist (LY171555) were observed via closed-circuit television and simultaneously recorded using a computerized video analysis system which measured the distance between two fluorescent dots painted above and below the rat's mouth. The D1 agonist SK&F 38393 induced a dose-dependent increase in tremorous oral movements, tongue protrusions, and, at the highest dose, increased repetitive chewing movements. Conversely, the D2 agonist LY171555 produced an inhibition or oral activity at all dose levels. At the lowest dose tested this appeared to reflect a non-specific decrease in activity, for there was an inhibition of all categories of behavior measured, as well as of all amplitudes of computer-scored movements and slow, sluggish movements were recorded. But higher doses of LY171555 induced hyperactivity and stereotyped, repetitive head movements whereas chewing movements, tremorous oral movements, and tongue protrusions were still decreased. D1 and D2 dopamine receptors appear to have opposite effects on oral movements.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗