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Biomedical subjects

L M Gunne

Publications and source records attributed to L M Gunne.

At least 37 records · Page 2Linked to original sources
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↗
PubMed1985

Experimental tardive dyskinesia.

In ongoing studies of chronic administration of neuroleptics to monkeys (Cebus apella) and rats, the regional distribution of glutamic acid decarboxylase (GAD) and brain levels of homovanillic acid were examined. Reduction of GAD activity, a GABA-synthesizing enzyme, in three specific brain areas (substantia nigra, medial globus pallidus, and nucleus subthalamicus) was related to the development of neuroleptic induced dyskinesias; these reductions were not seen in treated animals who did not develop movement disorders. The neostriatal level of HVA was reduced in dyskinetic monkeys. Such animal models can be useful in the screening process for new antipsychotics and thus potentially aid in the prevention of drug-induced tardive dyskinesia.

Animals↗
PubMed1984

CSF and plasma beta-casomorphin-like opioid peptides in postpartum psychosis.

The authors measured opioid receptor-active components in the CSF of 11 women with postpartum psychosis, 11 healthy lactating women, and 16 healthy women who were not lactating. Activity that eluted with 0.2 M acetic acid 0.7-0.9 times the total volume of the column (fraction II activity) was significantly higher in the CSF of both healthy and psychotic women in the puerperium than in that of the lactating women. Very high levels of fraction II activity were seen in four psychotic patients. Material from these patients was further characterized by electrophoresis and high-performance liquid chromatography: The material migrated as bovine beta-casomorphin. Receptor-active material with the same characteristics was also found in the plasma of these four patients. The authors conclude that certain cases of postpartum psychosis are associated with the occurrence in plasma and CSF of unique opioid peptides probably related to bovine beta-casomorphin.

Adult↗
PubMed1984

Discrete regional distribution of biochemical markers for the dopamine, noradrenaline, serotonin, GABA and acetylcholine systems in the monkey brain (Cebus Apella). Effects of stress.

Brains from Cebus Apella monkeys have been mapped biochemically using a cryo-section technique which enables exact micro-dissectioning of tissue. Two neurotransmitters; noradrenaline (NA) and gamma-amino-butyric acid (GABA) were measured by gas chromatography-masspectrometry technique. In addition biochemical markers reflecting metabolic activity in the dopamine (homovanillic acid, HVA, 3, 4-dihydroxyphenylacetic acid, DOPAC), serotonin (5-hydroxyindoleacetic acid, 5-HIAA), noradrenaline (4-hydroxy-3-methoxy-phenylglycol, HMPG), acetylcholine (choline acetyltransferase, CAT) and GABA (glutamic acid decarboxylase, GAD) transmitter systems were assayed. The distribution of these transmitter markers roughly corresponded to earlier studies in other non-human primates, whereas similar studies on the human brain generally show lower concentrations and enzyme activities. One monkey exposed to severe stress immediately before death deviated from the normal animals with regard to HVA, 5-HIAA, GAD and GABA. For the study of neuroleptic drugs, and notably their neurological side-effects, Cebus Apella monkeys have turned out to be particularly useful. In our laboratory we have employed this species of monkey to develop a model for acute dystonia and tardive dyskinesia (Gunne and Barany 1976, 1979, Barany et al. 1979). As a first step in the topological mapping of brain neuro-chemistry in these animals we here present data from normal monkeys, not treated with neuroleptics. During the ongoing project there was an unplanned "stress experiment" in one monkey, which had a nightly fight with a cage partner and had to be sacrificed the morning after due to severe wounds. The present communication describes a method for obtaining well-defined samples from monkey brains and presents the data on homovanillic acid (HVA), 3.4-dihydroxyphenylacetic acid (DOPAC), 5-hydroxyindoleacetic acid (5-HIAA), noradrenaline (NA), 4-hydroxy-3-methoxy-phenyl glycol (HMPG), choline acetyltransferase (ChAT), glutamic acid decarboxylase (GAD), and gamma-amino-butyric acid (GABA) in discrete regions from 7 drug-naive control monkeys. Also data from the stressed animal are presented.

Animals↗
PubMed1983

Reduction of nigral glutamic acid decarboxylase in rats with neuroleptic-induced oral dyskinesia.

Following eight monthly haloperidol decanoate injections rats showed an increased rate of vacuous chewing movements (VCM's), which gradually disappeared within 4 drug-free months. Another single dose of non-decanoate haloperidol reinstated a second increase in VCM rate which was still significant after 2 months. The glutamic acid decarboxylase (GAD) activity in the substantia nigra of these chronically haloperidol-treated rats was lower than untreated controls. Furthermore, there was a significant negative correlation between individual VCM rates and nigral GAD activity. No corresponding changes occurred in other brain regions. The depression of nigral GAD may reflect a reduced tissue density of GABA-ergic axon terminals within the descending striato-nigral pathway.

Animals↗
PubMed1983

Antidyskinetic action of 3-PPP, a selective dopaminergic autoreceptor agonist, in Cebus monkeys with persistent neuroleptic-induced dyskinesias.

Four Cebus apella monkeys with persistent dyskinetic movements induced by earlier long-term administration of haloperidol were subjected to a trial of the dyskinesia-modifying effects of a novel dopamine autoreceptor agonist 3-PPP (3[3-hydroxyphenyl]-N-n-propyl-piperidine). Three monkeys had choreic dyskinesia involving trunk and extremities whereas one had a buccolingual form including tongue protrusion with choreoathetotic twitching and twisting movements of the tongue. Two monkeys (1 choreic, 1 buccolingual) responded with dose-dependent symptom alleviation to 3-PPP, 1-4 mg/kg, with no signs of concomitant sedation or catalepsy. In the monkey with buccolingual dyskinesia all dyskinetic signs disappeared completely 2 hours after 2 mg/kg of 3-PPP. This animal participated in a separate study where the same doses of 3-PPP but also its enantiomers were given. The (-) enantiomer was a more potent antidyskinetic agent than the (+) enantiomer, the racemate falling between these two. Four mg/kg of the (+) enantiomer precipitated an amphetamine-like excitation and after 4 hours aggravation of dyskinesia was noted. These observations support the notion that the (+) enantiomer has both postsynaptic and presynaptic stimulatory effects, whereas the (-) enantiomer acts as a presynaptic dopamine receptor agonist.

Animals↗
PubMed1983

Application of a primate model for tardive dyskinesia.

Persistent signs of oral dyskinesia (tongue protrusion and facial grimacing) had developed as a result of earlier chronic treatment with neuroleptics in a Cebus apella monkey. When this animal was given single doses of any classical neuroleptic, a transient deterioration of dyskinesia occurred, preceded by a temporary abolishment of dyskinesia sometimes with an attack of acute dystonia. Fluphenazine (5-25 micrograms/kg) causes dose-related deteriorations of dyskinesia. Six different drugs were tested on this monkey for their capacity to elicit aggravation of dyskinetic signs: three antihistamines (brompheniramine, promethazine, diphenhydramine) and three dopamine D2 receptor antagonists (sulpiride, tiapride, metoclopramide). High doses of promethazine and diphenhydramine (5 mg/kg) induced a temporary alleviation of dyskinesia, possibly through sedation. All three D2 receptor antagonists precipitated signs of acute dystonia at some dose levels, but out of the test drugs only metoclopramide caused deterioration of dyskinetic symptoms. According to the present results only metoclopramide stands out as a drug with an inherent propensity to cause tardive dyskinesia.

Animals↗
PubMed1982

Oral dyskinesia in rats following brain lesions and neuroleptic drug administration.

After 10-12 weeks of chronic haloperidol administration rats with frontal cortex ablations or lesions induced by intracerebroventricular infection of 6-hydroxydopamine developed vacuous chewing behavior at a fairly stable frequency (bifrontal ablations had 15-20, 6-hydroxy-dopamine lesioned rats 7-12 chewing movements/min). This behavior persisted for 10 weeks after the last injection of haloperidol decanoate. However, rats with frontal cortex lesions developed a low rate of vacuous chewings (4-8 chewings/min) even without haloperidol administration. Bilateral intrastriatal injections of kainic acid in combination with chronic haloperidol administration did not cause chewing movements in excess of unlesioned haloperidol-treated controls. Pharmacological tests of this animal model for tardive dyskinesia (TD) revealed similarities to human TD, but also differences. Dopamine agonists (apomorphine) and antagonists (haloperidol) both lowered chewing behavior analogous to reported effects on TD and so did gabaculine. The cholinergic drugs physostigmine and pilocarpine, however, increased chewing in rats, while anticholinergics (atropine) reduced it, in contrast to reported effects on human TD.

Acetylcholine↗
PubMed1982

Pharmacokinetics of methadone during maintenance treatment: adaptive changes during the induction phase.

Deuterated methadone (M-d3) and GCMS were used to study the pharmacokinetics of methadone (M) during the induction stage of methadone maintenance treatment (MMT). A pulse dose of M-d3 was given on Days 1 and 25 of two dosage regimens, one with a continuous 30 mg dose (n = 6), and the other with 30 mg for 10 days, followed by 60 mg as the maintenance dose (n = 6). Plasma and urinary levels of M and M-d3 were measured throughout and plasma half-lives, oral bioavailabilities and volumes of distribution were calculated from the data of Days 1-2 and 24-26. The oral bioavailability of a methadone solution was found to be between 81 and 95%: elimination half-life in the beta-phase varied between 19 and 58 h; the volume of distribution was 4.1 +/- 0.65 l/kg; and total body clearance of M was 54-195 ml/min and its renal clearance 3.4-34 ml/min. A consistent finding was a lower urinary pH and increased renal clearance during the first month of treatment. The shorter elimination half-lives in those patients probably caused unacceptably high fluctuation in the body content of M during the 24 h dosage interval, and may have interfered therefore, with its therapeutic effectiveness.

Adaptation, Physiological↗