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S18327 (1-[2-[4-(6-fluoro-1, 2-benzisoxazol-3-yl)piperid-1-yl]ethyl]3-phenyl imidazolin-2-one), a novel, potential antipsychotic displaying marked antagonist properties at alpha(1)- and alpha(2)-adrenergic receptors: II. Functional profile and a multiparametric comparison with haloperidol, clozapine, and 11 other antipsychotic agents.

S18327 was dose-dependently active in several models of potential antipsychotic activity involving dopaminergic hyperactivity: inhibition of apomorphine-induced climbing in mice, of cocaine- and amphetamine-induced hyperlocomotion in rats, and of conditioned avoidance responses in rats. Furthermore, reflecting its high affinity at serotonin(2A) sites, S18327 potently blocked phencyclidine-induced locomotion and 1-[2, 5-dimethoxy-4-iodophenyl]-2-aminopropane-induced head-twitches in rats. In models of glutamatergic hypoactivity, S18327 blocked hyperlocomotion and spontaneous tail-flicks elicited by the N-methyl-D-aspartate antagonist dizocilpine. The actions of S18327, together with its binding profile at multiple monoaminergic receptors (15 parameters in total), were compared with those of clozapine, haloperidol, and 11 other antipsychotics by multiparametric analysis, and the resulting dendrogram positioned S18327 close to clozapine. Consistent with a clopazine-like profile, S18327 generalized to a clozapine discriminative stimulus and evoked latent inhibition in rats, blocked aggression in isolated mice, and displayed anxiolytic properties in the ultrasonic vocalization and Vogel procedures in rats. Relative to the above paradigms, only markedly (>20-fold) higher doses of S18327 were active in models predictive of potential extrapyramidal side effects: induction of catalepsy and prolactin secretion, and inhibition of methylphenidate-induced gnawing in rats. S18327 showed only modest affinity for histaminic and muscarinic receptors. Multiparametric analysis of these data distinguished S18327 from both haloperidol (high extrapyramidal potential) and clozapine (high histaminic and muscarinic affinity). In conclusion, S18327 displays a broad-based pattern of potential antipsychotic activity at doses appreciably lower than those eliciting extrapyramidal side effects. In this respect, S18327 closely resembles clozapine, but it is chemically distinct and displays weak affinity for histaminic and muscarinic receptors.

Adrenergic Antagonists↗

S33084, a novel, potent, selective, and competitive antagonist at dopamine D(3)-receptors: II. Functional and behavioral profile compared with GR218,231 and L741,626.

The selective dopamine D(3)-receptor antagonist S33084 dose dependently attenuated induction of hypothermia by 7-hydroxy-2-dipropylaminotetralin (7-OH-DPAT) and PD128,907. S33084 also dose dependently reduced 7-OH-DPAT-induced penile erections (PEs) but had little effect on 7-OH-DPAT-induced yawning and hypophagia, and it did not block contralateral rotation elicited by the preferential D(3) agonist quinpirole in unilateral substantia nigra-lesioned rats. In models of potential antipsychotic activity, S33084 had little effect on conditioned avoidance behavior and the locomotor response to amphetamine and cocaine in rats, and weakly inhibited apomorphine-induced climbing in mice. Moreover, S33084 was inactive in models of potential extrapyramidal activity in rats: induction of catalepsy and prolactin secretion and inhibition of methylphenidate-induced gnawing. Another selective D(3) antagonist, GR218,231, mimicked S33084 in inhibiting 7-OH-DPAT-induced PEs and hypothermia but neither hypophagia nor yawning behavior. Similarly, it was inactive in models of potential antipsychotic and extrapyramidal activity. In distinction to S33084 and GR218,231, the preferential D(2) antagonist L741,626 inhibited all responses elicited by 7-OH-DPAT. Furthermore, it displayed robust activity in models of antipsychotic and, at slightly higher doses, extrapyramidal activity. In summary, S33084 was inactive in models of potential antipsychotic and extrapyramidal activity and failed to modify spontaneous locomotor behavior. Furthermore, it did not affect hypophagia or yawns, but attenuated hypothermia and PEs, elicited by 7-OH-DPAT. This profile was shared by GR218,231, whereas L741,626 was effective in all models. Thus, D(2)-receptors are principally involved in these paradigms, although D(3)-receptors may contribute to induction of hypothermia and PEs. S33084 should comprise a useful tool for further exploration of the pathophysiological significance of D(3)- versus D(2)-receptors.

Animals↗

[Symptomatology of movement disorders in children].

Abnormal involuntary movements are common symptoms in children. The neuroanatomical basis for these movement disorders is the extrapyramidal system. Although present at rest they may be more intensive during the will - depending motor activity and increased under stress. They are almost absent during sleep. The underlying causal factors of involuntary movement disorders include metabolic disorders, progressive neurodegenarative diseases, central nervous system infection. The symptomatology of chorea, athetosis, dystonia, tremor, myoclonus and tics are discussed. Special attention is paid to differential diagnosis of myoclonus, chorea and tics as well as to movement disorders and epilepsy.

Child↗

Swallowing in ALS and motor neuron disorders.

The dysphagia of ALS is characterized by an impaired oral stage of swallowing, which has a direct impact on the seemingly more robust pharyngeal stage. Increased duration of the volitional stage (PPRT) of swallowing, including DT and lingual motility deficits, appear to be the major contributors to the dysphagia. The abnormal temporospatial events during the oral stage of swallowing have a direct and significant effect on the more automatic, pharyngeal stage. Specifically, abnormal lingual movement may result in pharyngeal residue that is aspirated after the swallow is completed and respiration is resumed. ALS patients with bulbar involvement demonstrate more severe swallowing problems (such as aspiration); however, the current work indicates that predominantly nonbulbar ALS patients may also demonstrate dysphagia. The semisolid material was more effective than liquids in eliciting temporospatial abnormalities of swallowing in the nonbulbar group. Thus, more viscous materials may be most sensitive for eliciting behaviors indicative of the onset of bulbar dysfunction in patients who otherwise appear nonbulbar, or different neurophysiologic mechanisms are involved in swallowing the distinct types of substances.

Adult↗

Extrapyramidal effects of SSRI antidepressants.

(1) About a hundred detailed reports of extrapyramidal adverse effects linked to a "selective" serotonin reuptake inhibitor (SSRI) antidepressant have been published. (2) The effects include acute dystonia, akathisia, and onset or aggravation of parkinsonism. Late-onset dyskinesias are rare. (3) All SSRIs have been implicated. (4) The annual incidence is unclear. It has been estimated at about 1-2 cases per 1 000 patients. (5) In patients with Parkinson's disease, SSRIs are an alternative to tricyclic antidepressants but can worsen the disease itself.

Dyskinesias↗

[Effect of manganese on the brain extrapyramidal development of rat offspring].

The effect of manganese (Mn) exposure on the behavior and extrapyramidal system of offspring were studied. Pregnant rats and their offspring in the experimental group were exposed to manganese from drinking water containing 2 g/L (low Mn-exposed group) or 10 g/L (high Mn-exposed group) of MnCl2 respectively. The latent period for running from the center field to any arm of Elevated Plus Arm Maze of both low and high Mn-exposed group was significantly reduced. But the latent period for reaching the platform above the water in Morris Water Maze of the Mn-exposed group was not different from that of control group. There was a significant increase in the areas, glial fibrillary acid protein(GFAP) immunoreactivity and the average proportional densities of GFAP-positive elements in nucleus caudate and accumbens in the high Mn-exposed group, and a significant reduction in the tyrosine hydroxylase immunoreactivity (TH) and average proportional densities of TH-positive elements in substantia nigra, ventral tegmentum area of midbrain and nucleus caudate in the high Mn-exposed group.

Animals↗