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Biomedical subjects

L M Gunne

Publications and source records attributed to L M Gunne.

At least 19 recordsLinked to original sources
PubMed1992

Regional changes in 2-deoxyglucose uptake associated with neuroleptic-induced tardive dyskinesia in the Cebus monkey.

The neural mechanisms that mediate a primate model of tardive dyskinesia have been investigated using the 2-deoxyglucose (2-DG) uptake technique. Three groups of Cebus monkeys were used. Some of the animals received long-term neuroleptic treatment. These animals were allotted to one of two groups depending on whether they developed tardive dyskinesia or not. A third group of animals served as untreated controls. The neuroleptic-treated dyskinetic animals showed reduced uptake of 2-DG in the medial segment of the globus pallidus and in the ventral anterior (VA) and ventral lateral (VL) nuclei of the thalamus relative to that seen in the equivalent structures in the neuroleptic-treated nondyskinetic and untreated control animals. The data are interpreted as suggesting that tardive dyskinesia is mediated by underactivity of the pathways from the subthalamic nucleus to the medial pallidal segment and the substantia pars nigra pars reticulata, which in turn result in a loss of gamma-aminobutyric acid-ergic inhibition of the VA and VL thalamic nuclei. This suggests that tardive dyskinesia shares a common underlying neural mechanism with other hyperkinesias such as chorea and ballism.

Animals↗
PubMed1990

Mortality in heroin addiction: impact of methadone treatment.

The mortality within a cohort of 115 street heroin addicts was studied for 5-8 years using the Kaplan-Meier survival estimate technique. This differed markedly from the relatively low mortality of 166 comparable heroin addicts given methadone maintenance treatment (MT). The street addicts' mortality rate was 63 times that expected, compared with official statistics for a group of this age and sex distribution. When 53 patients in MT were involuntarily expelled from treatment, due to violation of programme rules, they returned to the high mortality of street addicts (55 times that expected). A group of 34 rehabilitated patients who left MT with medical consent retained the low mortality of MT patients (their mortality rate was 4 times that expected). Despite this great improvement in survival, even patients in MT showed a moderately elevated mortality (8 times that expected), mainly due to diseases acquired before entering the treatment programme. It is concluded that MT exerts a major improvement in the survival of heroin addicts.

Adult↗
PubMed1989

Reduced glutamate decarboxylase activity in the subthalamic nucleus in patients with tardive dyskinesia.

Glutamate decarboxylase (GAD) activity was measured in the nuclei of the basal ganglia in patients with neuroleptic-induced tardive dyskinesia (TD) and controls matched for age and premortem state. In five TD patients, who all had a sudden death, a significant decrease in GAD activity was found in the subthalamic nucleus (STN). The lowered GAD activity in the STN may represent a biochemical substrate for neuroleptic-induced TD.

Aged↗
PubMed1989

Chronic neuroleptic effects on spatial reversal learning in monkeys.

Cebus apella monkeys were chronically administered the antipsychotic drug fluphenazine decanoate for periods ranging from 3.5 to 5.5 years. In the present study, four of these monkeys and two controls were tested for cognitive abilities on a spatial learning task, which consisted of an original discrimination and four reversals of that discrimination. No effect of fluphenazine administration was seen in the rate of learning the original discrimination, but the carryover of learning across discrimination reversals was significantly reduced by fluphenazine. After overtraining on the original discrimination, the controls showed the normal difficulty in learning the first reversal. The fluphenazine-treated monkeys showed no such disruption. On subsequent reversals, the controls showed continually improving performance, so that on the third and fourth reversals they had near-perfect scores. On the other hand, the fluphenazine-treated monkeys showed no change over the four reversals. Unlike normal monkeys, their learning did not improve with practice. Although simple forms of learning seem to be relatively unaffected by chronic fluphenazine administration, more complex learning is disrupted.

Animals↗
PubMed1989

Intranigral infusion of enkephalins elicits dyskinetic biting in rats.

Leu- and Metenkephalin (Lenk and Menk) and their more stable analogues D-Ala-Leu- and D-Ala-Metenkephalin (DALenk and DAMenk) as well as D-Ala-D-Leu- and D-Ala-D-Metenkephalin (DADLenk and DADMenk) were infused bilaterally into substantia nigra in awake rats and oral movements were recorded for 90 min. DADLenk and DADMenk elicited dose-dependent biting dyskinesias with a chewing rate of about 90 jaw movements/min. DALenk produced a similar but weaker effect, whereas DAMenk, Lenk and Menk were ineffective in the doses given. These findings suggest a possible enkephalinergic mechanism underlying neuroleptic-induced tardive dyskinesias.

Aggression↗
PubMed1989

Chronic melperone administration does not enhance oral movements in rats.

Melperone and haloperidol were compared in a rat model for tardive dyskinesia. Drugs were given chronically for 12 months with the drinking water and the frequency of oral movements was measured at monthly intervals. Haloperidol (0.2 and 0.4 mg/kg/d) produced an increase in vacuous chewing movements, whereas melperone (2.4, 5.1 and 11.0 mg/kg/d) did not differ from untreated controls.

Animals↗
PubMed1989

Rhythmic jaw movements induced by ethanol in rats.

Intraperitoneal administration of an anaesthetic dose of ethanol, 3.0 mg/kg, produced rapid rhythmic jaw movements (RJM) in rats. The peak effect (90 RJM/min.) occurred after 5 min., and all movements ceased after about 15 min. Clozapine, (4.4 mg/kg intraperitoneally) completely abolished this RJM phenomenon, whereas halopridol (0.5 mg/kg intraperitoneally), apomorphine (1.0 mg/kg subcutaneously) and atropine (10 mg/kg intraperitoneally) reduced it. It is suggested that the postulated brain stem masticatory pattern generator is activated or released from inhibition during induction of ethanol anaesthesia. Apparently this masticatory movement pacemaker is amenable to pharmacological manipulation, as shown by the present experiments.

Animals↗
PubMed1988

Oral movements induced by interference with nigral GABA neurotransmission: relationship to tardive dyskinesias.

Previous studies have shown that the emergence of spontaneous dyskinetic behaviors, such as vacuous chewing movements, following several months of neuroleptic treatment in the rat, is correlated with depletion of nigral GABA. To explore the specificity of this relationship, we acutely interfered with nigral GABA transmission pharmacologically, by microinfusing either the GABA receptor antagonist, bicuculline, or the GABA-depleting agent, isoniazid, bilaterally into substantia nigra. We found that both acute treatments induced vacuous chewing movements in rats. Moreover, the time to onset of action of each of these drugs corresponded to the onsets of their respective effects on GABA transmission. In addition, we found that the application of muscimol into the target field of the nigrotegmental projection, which has been shown to block gnawing elicited by nigral GABA receptor stimulation, completely abolished elicitation of vacuous chewing movements by intranigral isoniazid. In contrast, bilateral microinfusions of muscimol into the nigrocollicular target region, in the deep layers of superior colliculus, blocked elicitation of gnawing by intranigral muscimol, but completely spared elicitation of vacuous chewing movements by intranigral isoniazid. We conclude that qualitatively different dyskinetic syndromes can be produced by bidirectional perturbations of nigral GABA function and are differentially mediated by nigrotegmental and nigrotectal projections. These syndromes may represent animal models of distinct components of extrapyramidal side effects of chronic neuroleptic administration.

Animals↗
PubMed1988

Neurobiochemical changes in tardive dyskinesia.

There is evidence for the view that both up- and downregulation of nigral GABA may give rise to dyskinetic movements. Intranigral infusion of GABA agonists causes stereotyped licking and gnawing in rats, while intranigral GABA antagonists produce vacuous chewing movements. It is hypothesized that during long-term neuroleptic treatment there may be a succession of changes within striatonigral GABA neurons: down-regulation caused by neuroleptic drugs may increase receptor sensitivity, and this may lead to overcompensation and withdrawal dyskinesia during periods of cessation of drug treatment. Reduced nigral GAD activity may be a marker of irreversible brain damage and has not been observed in all chronic experiments, but only in individuals with long-standing or irreversible dyskinesia. Changes within the GABA system seem to be accompanied by changes in the striatal and nigral levels of substance P.

Animals↗
PubMed1987

Effects of buprenorphine in heroin addicts.

Twelve heroin addicts on the 8th day after withdrawal, and 8 healthy volunteers were given a single i.m. injection of buprenorphine 0.6 mg and their subjective response rated on 10 psychological variables. Pre-injection rating differed significantly between addicts and controls on 7 variables out of 10. Following buprenorphine more subjective changes were noted in the control group which became more calm, depressed, more aware of the environment, sleepy, tired, intoxicated, dizzy and nauseated. The drug addicts reported changes only in 2 variables (less tense and dysphoric) but otherwise showed no significant changes. These findings support the notion that buprenorphine induces low or normalizing effects in heroin addicts. This drug might thus be suitable for maintenance therapy in opiate addiction.

Adult↗
PubMed1986

Spontaneous chewing movements in rats during acute and chronic antipsychotic drug administration.

Single intraperitoneal doses of various antipsychotic drugs (clozapine 6, 12, 25 mg/kg, sulpiride 100 mg/kg, haloperidol 0.5, 1.0, 2.0 mg/kg, fluphenazine 0.5, 1.0, 2.0 mg/kg) induced a depression of the spontaneous chewing movement (SCM) rate in rats during the first 6-8 hours. Haloperidol and fluphenazine elicited a rebound increase in SCM on day 2-5, while clozapine and sulpiride did not. Atropine (5 mg/kg) reduced the SCM rate. During chronic administration for 10 months clozapine (50 mg/kg/day) caused no changes in the SCM rate. Sulpiride (120 mg/kg/day) gave a marginal rise above control levels, while thioridazine (40 mg/kg/day), chlorpromazine (30 mg/kg/day), fluphenazine (0.6 mg/kg/day) and haloperidol (0.4 mg/kg/day) produced highly significant increases in SCM rates. It is suggested that the present animal model may prove useful for monitoring the risk of tardive dyskinesia with individual drugs.

Animals↗
PubMed1986

CSF levels of receptor-active endorphins in schizophrenic patients: correlations with symptomatology and monoamine metabolites.

Cerebrospinal fluid (CSF) levels of an opioid receptor-active, chromatographically separated endorphin fraction (Fraction I) were measured in 45 schizophrenic patients and 18 healthy volunteers. Significantly increased levels of Fraction I differentiated the patient group from controls, with no difference being found between newly admitted untreated and chronic previously neuroleptic-treated subjects. Fraction I levels did not correlate with age, weight, height, duration of illness, total time hospitalized, or age when symptoms first appeared. No differences were found between patients with or without a family history of schizophrenia. Fraction I levels were negatively correlated with "hallucinations" and "indecision" on the Comprehensive Psychopathological Rating Scale. Increased levels of Fraction I were associated with low levels of the dopamine metabolite homovanillic acid in drug-free schizophrenics. This relationship was not present after neuroleptic treatment or in healthy controls. No relationship was found between Fraction I and the serotonin metabolite 5-hydroxyindoleacetic acid. Neuroleptic treatment did not significantly change Fraction I levels; when only patients above the control range were considered, however, a significant decrease was observed. The data support our previous hypothesis of an increased opioid activity in schizophrenia and further indicate a concomitant dysfunction of brain endorphin and dopamine activity in schizophrenic patients.

Adolescent↗
PubMed1985

Pathophysiology of tardive dyskinesia.

Animal models of persisting tardive dyskinesia have been developed in two species (rats and monkeys). Dyskinetic animals chronically treated with neuroleptics had significant decreases in glutamic acid decarboxylase and GABA in the substantia nigra, the medial globus pallidus, and the subthalamic nucleus, whereas animals without dyskinesias which had been treated similarly had a normal distribution of these biochemical parameters. These changes remained 2 months after neuroleptics were discontinued, and at that point there was a reduced turnover of striatal dopamine in the dyskinetic monkeys. These findings suggest that reduced GABA function in the substantia nigra may play a role in tardive dyskinesia.

Animals↗