Psychopharmacology. Supplementum最新文献

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.

Selective presynaptic dopamine receptor agonists appear to offer promise as putative antipsychotic agents with a low risk of extrapyramidal side-effects, including tardive dyskinesia. However, no such agent with a reasonable degree of selectivity has yet reached the stage of clinical trial. In the present paper the particular pharmacological profile of presynaptic dopamine receptor (autoreceptor) agonists is described, and underlying mechanisms are discussed. Special attention is paid to the compound 3-(3-hydroxyphenyl-N-n-propylpiperidine(3-PPP), especially its levotatory enantiomer. This agent shows affinity for both pre- and postsynaptic dopamine receptors. Its intrinsic activity in different locations varies between virtually zero and 100%, leading to a mixture of agonist and antagonist properties. It is suggested that this variability depends on the adaptive properties of the dopamine receptor.

It is well known that the therapeutic effect of neuroleptics is counterbalanced by the property of these drugs to induce serious neurological side-effects mainly represented by tardive dyskinesia. Several reports indicate that at the experimental level GABA agonists interact with dopamine neurons with effects on behavior, stereotyped and dyskinetic movements induced by either lesions or dopamine agonists. This action on dopamine-related events provides a basis for a possible therapeutic action of GABA agonists in dyskinesia. Previous results with the GABA agonists muscimol and THIP in tardive dyskinesia have not been encouraging. The present paper deals with clinical results obtained with the new GABA agonist progabide both in neuroleptic-induced dyskinesia and in L-dopa-induced dyskinesia from five studies conducted on a total of 57 patients. Twenty-nine patients suffering from neuroleptic-induced dyskinesia have been treated in three studies (two open, one double-blind cross over) with progabide at doses from 900 to 2400 mg/day; clinical evaluation and EMG testing are in favor of a therapeutic effect of progabide on dyskinesia. Twenty-eight patients with L-dopa dyskinesia have been studied in two double blind trials. At variance with studies in tardive dyskinesia progabide was not effective in this kind of dyskinesia but an increase in the "on" time has been observed in both studies. Attempts to treat tardive dyskinesia with various pharmacological tools are reviewed and discussed, showing that at present no established effective treatment exists for this frequent complication of neuroleptic use. The possible mechanism of action of progabide in dyskinesia is discussed in the light of its pharmacological properties. These results suggest that progabide can be useful in the treatment of neuroleptic-induced dyskinesia.

In this paper various new findings on the possible anatomical substrates of tardive dyskinesia will be presented. The results show that the striatum is heterogeneously organized, and the syndromes of biting, gnawing, and licking activities in the rat model involve a complex balance between various dopamine (DA), cholinergic, and GABAergic systems within the striatum and the mesolimbic and mesocortical systems.

A series of experiments is described in which behavioral models and intracerebral dialysis were used to study neurotransmitter release and which illustrate the functional properties of different dopamine receptors. Evidence is presented for the existence of postsynaptic D-1 dopamine receptors, which are preferentially stimulated by apomorphine and inhibited by SCH 23390, and postsynaptic D-2 receptors, which are preferentially stimulated by pergolide and inhibited by sulpiride. On the basis of results obtained following systemic and local treatment with picrotoxin it seems probable that D-2 receptors are located on GABA interneurons in the striatum. Furthermore, lesion studies indicate that the D-1 and D-2 receptors are related to different neuronal pathways. In contrast to postsynaptic dopamine receptors, presynaptic autoreceptors, as studied by recording the decrease in exploratory behavior and dopamine release, seem not to differ in their response to apomorphine and pergolide. Sulpiride selectively inhibits dopamine autoreceptors and is equally potent in inhibiting apomorphine and pergolide autoreceptor-dependent responses. In summary, the data strongly support the existence of functionally important D-1 and D-2 receptors.

In single-dose experiments neuroleptics antagonize dopamine (DA)-agonist-induced stereotypies in animals. The antagonistic potency correlates with their clinical antipsychotic effects. In a series of experiments where DA-agonist-induced stereotyped gnawing in mice and rats was inhibited by neuroleptics it was shown that the antagonistic effect of butyrophenones was greatly attenuated by concomitant treatment with anticholinergics. The effect of phenothiazines was slightly attenuated and that of thioxanthenes and SCH 23390 remained unchanged. After repeated administration a differentiation is also seen in the ability of the antagonists to suppress DA-agonist-induced stereotypies. The differentiation in these experiments is similar to that seen in dopamine D-1 and D-2 receptor binding. The compounds can be classified into three pharmacological subgroups: butyrophenones (e.g., haloperidol) with affinity for D-2 receptors; phenothiazines (e.g., fluphenazine and perphenazine) with affinity for both D-2 and D-1 receptors but with preference for the D-2 receptors; and thioxanthenes (e.g., cis(Z)-flupentixol and cis(Z)-clopenthixol) with equal affinity for D-1 and D-2 receptors, and the selective D-1 antagonist SCH 23390. This compound has the same antistereotypic effect as is seen with the neuroleptics. We have also investigated the effect of the above-mentioned neuroleptics and SCH 23390 after 12 days' treatment and 3-5 days withdrawal. They were given either alone or in combination. When they were given alone a clear differentiation was seen between the groups when mice were tested for methylphenidate antagonism. The thioxanthenes and SCH 23390 retain their ability to antagonize the stereotyped gnawing; the phenothiazines show a reduced effect; and the butyrophenones have almost lost their ability to antagonize the stereotyped behavior.

The role of neuroleptics in causing the tardive dyskinesia syndrome is controversial. To properly assess the contribution of drugs as the etiology of dyskinesias, the effects of aging, the natural history of psychosis, and characteristics of spontaneous dyskinesias must be considered. Though the buccolinguo-masticatory triad is seen more often in tardive than in spontaneous dyskinesias, these two disorders have many symptoms in common. Other dyskinesias, such as idiopathic and tardive dystonia or tardive Tourette's syndrome and dyskinesias in untreated schizophrenia, are poorly understood. Chronic neuroleptic treatment may only precipitate TD in those already predisposed to develop such movement disorders. Tardive dyskinesia is not a unique movement disorder, but rather spans several clinical and epidemiological phenomena which must be considered in a balanced evaluation of how much of the permanent dyskinesias should be attributed to neuroleptic drugs.

The prevalence and distribution of involuntary movements in age-matched chronic schizophrenics treated and not treated with neuroleptics were compared. While exposure to neuroleptic drugs in the past was important, high rates of movement disorder were associated with the severe, untreated illness. Ventricular enlargement correlated with severe movement disorder but not with past neuroleptic exposure. It is suggested that in the context of Schizophrenia neuroleptic drugs may act to promote what are features of the illness for some, and that in the search for predisposing factors illness, as well as treatment variables, is worthy of consideration.

Brain dopamine receptors (type D2) mediate the psychomotor effects of dopamine. The D2 dopamine receptor can exist in either a high-affinity state for dopamine (nanomolar dissociation constant) or in a low-affinity state (micromolar dissociation constant). Both states of the receptor, however, have high affinity for neuroleptics (60 pM for spiperone). The postsynaptic receptor probably operates mainly in the D2 slow state. The presynaptic dopamine receptor, and also the dopamine receptors in the pituitary gland and the area postrema, probably function in the D2 high state. The density of brain D2 dopamine receptors is elevated in schizophrenia. The control densities were 10.5 pmol per g tissue. Half of the schizophrenic tissues (putamen, caudate nucleus, and nucleus accumbens) revealed densities of about 11.9 pmol per g, while the other half of the tissues revealed a density mode of 23.8 pmol per g. The bimodal distribution may support the concept of two types of schizophrenia. Future work must decide which group has more tardive dyskinesia.