Lars M. Gunne

Naloxone-induced reversal of schizophrenic hallucinations.

In a single-blind pilot study 0.4 mg naloxone i.v. was found temporarily to reduce or abolish auditory hallucinations in four cases of chronic schizophrenia whereas saline was without effect. In one of these patients there was a similar reversal also of her visual hallucinations. Two additional cases who denied hearing voices before the injections, reported no subjective effects.

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 (VCMs), 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.

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 injection 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.

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 rats 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.

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.

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.

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.

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 rats 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.

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

Summary. 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.

A monitoring test for the liability of neuroleptic drugs to induce tardive dyskinesia

Two Cebus apella monkeys with haloperidol-induced tardive dyskinesia have been studied. Substitution of chlorpromazine, thioridazine, clozapine, melperone, or fluphenazine for the daily haloperidol administration temporarily reduced the signs of tardive dyskinesia. In a monkey with low-grade symptoms, persisting for more than 100 days after with-drawal of haloperidol, neuroleptic drugs induced a typical sequence of events: first the dyskinetic movements were abolished, but 1–3 days after administration of a single dose of a neuroleptic drug there was a rebound worsening of symptoms. It was noticed that this aggravation of symptoms corresponded in magnitude and duration to the approximate liability of each compound to induce tardive dyskinesia in man. It is therefore suggested that this animal model could be used to monitor neurological side effects in neuroleptic drugs.