Xue-Min Gao

Delayed regional metabolic actions of phencyclidine

Phencyclidine (PCP), a psychotomimetic drug of abuse, produces mental changes and manifestations in humans which are reminiscent of schizophrenia, though the mechanism of these actions remains unknown. We report here a biphasic time course of PCP action on regional cerebral glucose metabolism extending over 48 h. A single dose of PCP (8.6 mg/kg) produces an initial increase in glucose metabolism (at 3 h) and a later decrease in glucose metabolism (at 24 h) without a return to baseline until 48 h. A single lower dose of PCP (0.86 mg/kg), a dose which is considered selective for action at the NMDA-PCP receptor, produces no early metabolic change (at 3 h), but replicates the regional hypometabolism albeit less intense at 24 h. The delayed cerebral hypometabolism does not appear to be related to PCP-induced intracellular vacuolization, seen in the retrosplenial cortex. These metabolic changes may be associated with the psychotomimetic effects of PCP and thus may be relevant to psychosis in humans.

The effect of chronic haloperidol treatment on dendritic spines in the rat striatum.

Previous studies have shown that schizophrenics, in comparison to controls, have reduced cortical spine density and smaller striatal spines. The current study in the rat was conducted to determine whether such differences could result from chronic neuroleptic treatment and whether they are correlated with neuroleptic-induced oral dyskinesias. Rats administered 1.5 mg/kg/day of haloperidol (HA) (n = 28) or water (n = 10) were tested for vacuous chewing movements (VCMs). After 6 months, rats were divided into low and high VCM groups; all but seven high VCM rats were sacrificed. These rats (withdrawn group) were withdrawn from HA for 4 weeks. Random electron micrographs of the striatum were analyzed for spine changes. Spine size was not significantly affected by HA (0.193 vs 0.174 microm2, HA and control, respectively) nor correlated with oral dyskinesias (0.191 vs 0.196 microm2, low and high VCM groups, respectively). These results suggest that smaller spines in schizophrenic striatum may be correlated with the disease rather than caused by neuroleptic treatment. Spine density decreased in the HA-treated group (32.7 +/- 9.5) in comparison to controls (53.7 +/- 7.3, P < 0.001) and remained low in the withdrawn group (35.0 +/- 4.2, P < 0.01). Spine density also decreased in both the low (37.3 +/- 9.9, P < 0.01) and the high (28.0 +/- 7.0, P < 0.000) VCM groups in comparison to controls. However, there was no significant difference between high and low VCM groups, suggesting that decreased spine density is independent of oral dyskinesias. These results suggest that the decreased spine density observed in schizophrenic cortex may be a result of neuroleptic treatment.

The dose-response characteristics of rat oral dyskinesias with chronic haloperidol or clozapine administration

SummaryWhether the pathophysiology and treatment of neurolepticinduced oral dyskinesias in rats parallel that for tardive dyskinesia in humans remains a question. To address the issue further, Sprague Dawley rats were treated for 6 months with multiple oral doses of haloperidol (1.5 and 3.0 mg/ kg/day) or clozapine (10, 20, and 30 mg/kg/day) and compared with water treated animals. The rate of oral dyskinesias was monitored at study start and monthly by trained raters who were blind to treatment group. All haloperidoltreated rats developed oral dyskinesias at a significantly higher rate than rats treated with water (p=0.0007) or those treated with clozapine (p=0.0017). Each dose of haloperidol produced significantly higher rates of oral dyskinesias than did any dose of clozapine and did so in an apparent dose-sensitive manner. Clozapine lacked a dose-sensitive relationship with the oral dyskinesias, and failed to show a significant difference in rate from control rats at any dose. Plasma levels of haloperidol with these doses were in the human therapeutic range; with clozapine only the highest dose produced plasma levels in the human therapeutic range. These data show little association between rat oral dyskinesias and clozapine treatment, whereas a strong association is present with haloperidol. The data are, thereby, consistent with the clinical association of tardive dyskinesia with typical neuroleptics like haloperidol but not with the atypical neuroleptic clozapine.

Tiagabine inhibits haloperidol-induced oral dyskinesias in rats

Chronic administration of haloperidol to male Sprague Dawley rats for 6 months at a dosage of 1.5 mg/kg/day produces oral dyskinesias in a significant percent of the treated group. This has been used as an animal model of tardive dyskinesia in several laboratories, because the rat movements display characteristics reminiscent of the human dyskinetic condition. Previously, we have reported a reduction in these haloperidol-induced oral dyskinesias with the coadministration of a direct acting GABA agonist progabide. Here, we have tested an indirect acting GABA agonist, tiagabine, coadministered with haloperidol, for its effect on the oral dyskinesias. At a dosage of 75 mg/kg/day tiagabine significantly inhibited the onset of vacuous chewing movements (VCMs), decreasing the average movement severity from 11.2 ± 2.0 to 4.4 ± 1.4, compared with a placebo rate of 1.3 ± 0.5 (VCMs/5 min). These data support the proposition that an effective, potent GABAmimetic coadministered with haloperidol, will block the onset of rat oral dyskinesias. This conclusion has important implications for the treatment and prevention of tardive dyskinesia in humans.

Drug-induced oral dyskinesias in rats after traditional and new neuroleptics

Tardive dyskinesia (TD) is a serious human side effect of neuroleptic treatment in psychotic disorders. Although the etiology is clear (ie. chronic neuroleptic drugs), its pathophysiology has not yet been satisfactorily explained. This is important not only theoretically but also to inform drug development, allowing the introduction of antipsychotic compounds without TD liability. The development of an animal condition which putatively models these delayed onset dyskinesias, has provided a technique to differentiate between neuroleptic drug effect and dyskinesia correlates. We report here the development of oral dyskinesias in rats in response to a number of different neuroleptics, which have a range of neurochemical and clinical characteristics. Traditional neuroleptics (e.g. haloperidol) produced rat oral dyskinesias, in an open-cage environment. Clozapine, while it produced an increased rate of oral movements, showed a significantly decreased potency in this model. SCH23390 (D1 antagonist) neither produced the oral movements nor modified their onset by coadministration with raclopride. These data replicate and extend other similar studies in the literature. They suggest that clozapine differs from traditional neuroleptics with respect to motor side effects.