Biomedical subjects
Publications and source records attributed to J Bannet.
Chronic schizophrenic patients with first- or second-degree schizophrenic relatives were evaluated for memory function. Wechsler memory scale scores were significantly correlated between index cases and relatives (r = 0.56, p less than 0.05), suggesting that poor memory function in schizophrenia may represent a familial subtype.
Drug holidays have been proposed as a preventive strategy against the development of tardive dyskinesia. Three animal studies in which dopamine receptor hypersensitivity after chronic neuroleptic treatment was used as a model for tardive dyskinesia failed to find any reduction in dopamine receptor hypersensitivity with intermittent, as opposed to continuous, treatment. Since most neuroleptics have a long half-life in vivo, we hypothesized that truly drug-free periods may not have been achieved in previous studies. Droperidol, an ultrashort-acting butyrophenone neuroleptic, was administered to rats for 22 days in twice-daily injections or one injection every 48 hours. At 60 hours after the last dose there was no difference in apomorphine-induced stereotypy between continuously treated and intermittently treated animals. Thus, even totally drug-free periods do not reduce the development of dopamine receptor hypersensitivity.
A vasopressin derivative or placebo was administered to 21 chronic schizophrenia patients for 3 weeks in a randomized crossover double-blind design. The patients were divided into those above and below the median on baseline memory measured by the Wechsler memory scale. Vasopressin treatment did not improve memory either in those patients with below median baseline memory or in the group as a whole.
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The ability of beta-adrenergic receptors to adapt to reductions in stimulation might be impaired in depressed or schizophrenic patients. To test this hypothesis 12 normal controls, 12 depressed patients resistant to tricyclic antidepressants, and 8 chronic schizophrenic patients were treated with propranolol 160 mg/day for 10 days. A previous study had reported that this dose regimen led to a rise in lymphocyte beta-adrenergic receptors in normal volunteers. Blood was sampled before propranolol treatment and 60 hr after the last propranolol dose. There were no significant differences between any of the groups in lymphocyte beta-adrenergic receptors after 10 days of propranolol treatment.
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Chronic treatment with dopamine (DA) agonists has been reported in various paradigms to cause supersensitivity of DA receptors or, contradictorily, subsensitivity of DA receptors. The present study administered 15 mg/kg bromocriptine for 7 days and measured both striatal spiperone binding and apomorphine (AP)-induced stereotypy. A significant decrease in AP-induced stereotypies was observed after chronic bromocriptine treatment, but without a significant parallel decrease in striatal spiperone binding. These results probably do not represent a true agonist-induced subsensitivity, but possibly show that residual bromocriptine in vivo may antagonize AP-induced stereotypy. Since some reports have suggested that L-Dopa may specifically reverse the increases in DA receptor number induced by chronic haloperidol, we also studied the effect of 7 days of L-Dopa treatment after 6-week chronic haloperidol treatment of mice. While chronic haloperidol significantly increased striatal spiperone binding, subsequent L-Dopa treatment did not reverse this biochemical supersensitivity. It is concluded that agonist induction of subsensitivity in the DA system is difficult to reproduce and may depend on highly specific dosage conditions and treatment schedules.
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Mean DA receptor number in rats rises markedly after chronic haloperidol treatment, and this rise is accompanied by a significantly increased variance. The rise in DA receptor number has been proposed as a molecular model of human tardive dyskinesia. Since human tardive dyskinesia may involve pharmacogenetic susceptibility, ten inbred mouse strains were treated for 3 weeks with haloperidol and caudate DA receptor number was determined 4 days after cessation of feeding. Some strains showed much larger rises in DA receptor number than others, supporting the notion that genetic factors may be involved in the susceptibility to large DA receptor responses to chronic haloperidol.
Previous studies of the haloperidol-induced increase in dopamine (DA) receptor number have not emphasized the existence of individual differences. The present study evaluated DA receptor number in individual rat and mouse caudates after haloperidol or drug-free feeding. After 3 months of haloperidol treatment of rats there was a 78% increase in caudate DA receptor number, accompanied by a significantly increased variance in the number of DA receptors in haloperidol-treated compared with control rats. Although three inbred mouse strains (Balb/C, C3H, and CBA) also showed significant increases in DA receptor number after 3 months of haloperidol treatment, no increased variance was observed after haloperidol treatment. Wild-type mice from a genetically heterogenous population showed increases in DA receptor number after chronic haloperidol treatment accompanied by a significantly increased variance in receptor number of the drug-treated group. These findings suggest that pharmacogenetic factors may be important in determining the magnitude of DA receptor response to long-term neuroleptic treatment.
Intermittent haloperidol treatment in mice increased 3H-spiroperidol binding to the same degree as continual haloperidol feeding. The results do not support the concept that drug holidays can reduce the incidence of tardive dyskinesia.
Increased 3H-spiperone binding after chronic neuroleptic treatment has been proposed as a molecular model of tardive dyskinesia. Sulpiride has been claimed to be an atypical neuroleptic that might not produce tardive dyskinesia. The effect of chronic sulpiride was, therefore, compared to that of chronic haloperidol on striatal 3H-spiperone binding. 3 weeks of haloperidol feeding caused a 28% increase in 3H-spiperone binding, whereas even very high dose sulpiride had no effect on spiperone binding. These findings support the concept that sulpiride may be a unique neuroleptic with regard to long-term effects on dopamine receptors.
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