Study of neuropathologic changes in the striatum following 4, 8 and 12 months of treatment with fluphenazine in rats

Jørgensen

1994

Psychopharmacology

Tardive dyskinesia (TD) is a serious side-effect of long-term treatment with neuroleptics. To investigate if TD may be a result of neuroleptic-induced excessive stimulation of striatal glutamate receptors, the effect of the anti-excitotoxic GM1 ganglioside was studied in a rat model of TD. In an acute experiment each of four groups of rats was treated with GM1 20 mg/kg SC+saline IP, saline SC+haloperidol 1.2 mg/kg IP, GM1 SC+haloperidol IP, or saline SC+saline IP. In a subsequent long-term experiment lasting 16 weeks, each of the four groups was treated as in the acute experiment, with the exception that haloperidol was injected IM as decanoate 38 mg/kg every 4 weeks, and the controls received vehicle injections. The behavior was videotaped and scored at intervals during both experiments, including 16 weeks after cessation of the long-term treatment. Haloperidol induced a significant increase in vacuous chewing movements (VCM) and immobility both in the acute and in the long-term experiment. Other categories of behaviour (rearing, moving, sitting) were significantly affected only in the acute experiment. GM1 did not affect any of the acute behavioural effects of haloperidol, but significantly reduced VCM in the long-term experiment. The effects on VCM of haloperidol and GM1 persisted for at least 8 weeks after cessation of the long-term treatment. These results suggest that long-lasting changes in striatal function induced by excessive glutamate receptor stimulation may be a mechanism for the development of VCM in rats and perhaps also for TD in humans.

Section: Discussionmentioning

confidence: 91%

“…The pathophysiological substrate of other wellknown hyperkinetic movement disorders are located here (Albin et ai. 1989), and earlier studies have shown pathological changes in this area after long-term neuroleptic treatment (Jeste et al 1992).…”

mentioning

confidence: 95%

GM1 ganglioside attenuates the development of vacuous chewing movements induced by long-term haloperidol treatment of rats

Jørgensen

1994

Psychopharmacology

“…Following 6 months of treatment with haloperidol, Roberts et al (1995) recently reported a significant decrease in the density of striatal asymmetric synapses. Using a computerized image analysis system, Jeste et al (1992) reported that treatment of rats for 8 months with fluphenazine resulted in a significant decrease in the density of large neurons within the central region of the caudate. They interpreted this as indicating a possible loss of cholinergic neurons.…”

Section: Introductionmentioning

confidence: 99%

Correlation of vacuous chewing movements with morphological changes in rats following 1-year treatment with haloperidol

Allen

et al. 1996

Psychopharmacology

Long-term treatment with the typical antipsychotic drug, haloperidol, can lead to a sometimes irreversible motor disorder, tardive dyskinesia (TD). It has been hypothesized that increased release of glutamate due to prolonged neuroleptic drug treatment may result in an excitotoxic lesion in specific neuronal populations within the basal ganglia, leading to TD. We reported that treatment with haloperidol for 1 month results in an increase in the mean percentage of striatal asymmetric synapses containing a perforated postsynaptic density (PSD) and that these synapses are glutamatergic. Using quantitative immunocytochemistry, we found that depending on how long the animals had been off haloperidol following subchronic (30 d) treatment, there was either a decrease (1 day off) or increase (3-4 days off) in the density of glutamate immunolabeling within the presynaptic terminals of synapses with perforated PSDs. Using a rat model for TD, animals in the current study were treated for 1 year with haloperidol and spontaneous oral dyskinesias (i.e. vacuous chewing movements, VCMs) were recorded. In these long-term treated animals we wanted to determine if there was a correlation between glutamate function, as measured by changes in synapses with perforated PSDs and the density of nerve terminal glutamate immunoreactivity, and VCM behavior. In drug treated rats which demonstrated either a high or low rate of VCMs, there was a significant increase in the mean percentage of asymmetric synapses in the dorsolateral striatum with perforated PSDs in both haloperidol-treated groups compared to vehicle-treated rats. There was a small but significant increase in the density of glutamate immunolabeling within striatal nerve terminals of the high VCM group compared to the low VCM group. There was, however, no difference in the density of glutamate immunolabeling between the high VCM group compared to the vehicle-treated animals. One reason for this lack of difference was partially due to a significant increase in nerve terminal area within the high VCM group compared to either the low VCM- or vehicle-treated groups. The larger nerve terminal size in the high VCM group may be due to a small but sustained increase in glutamate neurotransmitter release with the ability of the terminal to maintain its supply of glutamate, while the terminals in the low VCM group showed evidence of glutamate depletion. This finding would be consistent with the hypothesis that increased glutamatergic activity may be associated with TD.

“…It has been suggested that TD might be a result of neuroleptic-induced excitotoxic changes in striatal neurones (McGeer & McGeer, 1976;DeKeyser, 1991;Andreassen & J0rgensen, 1994). This is supported by findings in rats of histopathological changes in striatum after long-term neuroleptic treatment (Jeste et al, 1992), haloperidol (Hal)-induced increase in striatal glutamate release (Moghaddam & Bunney, 1993;Yamamoto & Cooperman, 1994), and Hal-induced ' Author for correspondence. morphological changes in striatum consistent with enhanced glutamatergic activity (Meshul et al, 1994).…”

Section: Introductionmentioning

confidence: 60%

Inhibition by memantine of the development of persistent oral dyskinesias induced by long‐term haloperidol treatment of rats

Aamo

Jørgensen

1996

British J Pharmacology

1 Tardive dyskinesia (TD) is a serious side-effect of long-term treatment with neuroleptics. To investigate if neuroleptic-induced excessive stimulation of striatal glutamate receptors may underlie TD development, the effect of the NMDA antagonist, memantine (1-amino-3,5-dimethyladamantane), was studied in a rat model of TD. 2 In an acute experiment, six groups of rats were treated daily for 1 week with either vehicle or memantine 20 or 40 mg kg-' day-', and on the seventh day they received one injection of either haloperidol 1.0 mg kg-' i.p. or saline i.p. In a subsequent long-term experiment lasting 20 weeks, the same treatment was continued, except that haloperidol was injected i.m. as decanoate (38 mg kg-' every 4 weeks) and control rats received sesame oil. The behaviour was videotaped and scored at intervals during both experiments, and for 16 weeks after cessation of the long-term treatment. 3 In the acute experiment, haloperidol decreased motor activity and memantine increased moving and tended to attenuate the immobility induced by haloperidol. Memantine also enhanced the haloperidolinduced increase in the putative TD-analogue vacuous chewing movements (VCM). 4 In the long-term experiment, the most marked effect of haloperidol was a gradual increase in VCM and the increase persisted significantly for 12 weeks after cessation of treatment. Memantine dosedependently increased VCM and moving during long-term treatment. However, only one week after stopping treatment, both these effects of memantine disappeared. In contrast to rats previously treated with haloperidol alone, rats co-treated with memantine (both doses) and haloperidol had VCM at the level of controls two weeks after stopping treatment. The blood levels of drugs were within the therapeutic range achieved in human subjects. 5 These results suggest that long-lasting changes induced by haloperidol are prevented by memantine, which supports the theory that excessive NMDA receptor stimulation may be a mechanism underlying the development of persistent VCM in rats and maybe also TD in human subjects.