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The substituted benzamide drugs YM 09151-2 and clebopride potently inhibited apomorphine-induced stereotyped behaviour in the rat and caused displacement of the specific binding of [3H]spiperone to D-2 binding sites on striatal membranes in low nanomolar concentrations. Other substituted benzamide drugs including metoclopramide, sultopride and flubepride also inhibited stereotyped behaviour to a greater or lesser degree, but were less potent in displacing [3H]spiperone from D-2 sites. YM 09151-2 and clebopride only weakly displaced specific binding of [3H]piflutixol to D-1 sites on rat striatal membranes, and only weakly inhibited striatal dopamine stimulated adenylate cyclase activity, when compared with cis-flupenthixol. The other substituted benzamide drugs did not displace [3H]piflutixol or inhibit dopamine stimulation of adenylate cyclase activity in the concentration range used. Clebopride and YM 09151-2 were highly lipophilic with apparent partition coefficient (log P') values equivalent to those of classical neuroleptic compounds, such as cis-flupenthixol. In contrast, the other substituted benzamide drugs were markedly less lipophilic. A log P' value of approximately 2 was required before inhibition of adenylate cyclase activity or displacement of [3H]piflutixol binding occurred. However, in excess of this value there was no correlation between either inhibition of adenylate cyclase activity or displacement of [3H]piflutixol binding and the lipophilicity of the various compounds. We conclude that potent lipophilic substituted benzamide drugs, like other members of the substituted benzamide series, are selective D-2 receptor antagonists. Inherent steric factors within the drug series would appear to dictate activity at D-1 and D-2 sites, although lipophilicity may contribute to actions in these environments.

The characteristics of [3H]spiperone binding to human lymphocytes have been examined. The haloperidol displaceable component of [3H]spiperone binding to human lymphocytes was not saturable, and stereoselective displacement by the isomers of butaclamol was not observed. There was no correlation between the ability of known dopamine active drugs to cause displacement of the ligand and their rank order of potency. Chloroquine, a drug with no dopaminergic action, was the most potent displacing agent examined. Fragmentation of the cells caused a marked decrease in the haloperidol displaceable component of [3H]spiperone binding, and saturable binding to the lymphocyte membrane fragments was not observed. Lysis of cells after equilibrium incubation with [3H]spiperone caused a marked reduction in the haloperidol displaceable component of ligand binding. Association of [3H]spiperone with lymphocytes was unaffected by the metabolic inhibitor iodoacetate, or by replacement of sodium ions by lithium ions in the incubation medium, suggesting that such association did not involve an active uptake process. We cannot confirm the existence of dopamine receptors on the surface of human lymphocytes. We suggest that the apparent association of [3H]spiperone with lymphocytes is due to some passive uptake process causing accumulation of the ligand within the cells.

Summary Rats were treated continuously for up to 20 months with either haloperidol (1.4–1.6 mg/kg/day), sulpiride (102–109 mg/kg/day) or clozapine (24–27 mg/kg/day). Bmax for specific mesolimbic binding of3H-spiperone,3H-N,n-propylnorapomorphine or3H-piflutixol did not differ in tissue taken from animals treated for up to 12 months with haloperidol, sulpiride or clozapine by comparison to age-matched control rats. Mesolimbic dopamine (50 ΜM)-stimulated adenylate cyclase activity was not altered in any drug treatment group. Spontaneous locomotor activity was transiently decreased during treatment with haloperidol for 1 or 3 months, but not by chronic sulpiride or clozapine treatment. Locomotor activity was not consistently increased in any drug treatment group. After 20 months of continuous drug treatment, focal bilateral application of dopamine (12.5 or 25 Μg) into the nucleus accumbens caused equivalent increases in locomotor activity in control rats and in animals receiving haloperidol, sulpiride or clozapine.

Administration of haloperidol (1.4–1.6 mg/kg/day) for up to 12 months or sulpiride (102–109 mg/kg/day) for between 6 and 12 months increased the frequency of purposeless chewing jaw movements in rats. N,n-propylnorapomorphine (NPA) (0.25–2.0 mg/kg SC) did not induce hypoactivity in haloperidol-treated rats at any time; sulpiride treatment for 9 and 12 months caused a reduction in the ability of NPA to induce hypoactivity. Haloperidol, but not sulpiride, treatment enduringly inhibited low dose apomorphine effects (0.125 mg/kg SC). After 12 months, sterotypy induced by high doses of apomorphine (0.5–1.0 mg/kg) was exaggerated in haloperidol-, but not sulpiride-treated rats.

Patients with depressive motor retardation, neuroleptic induced parkinsonism or Parkinsons disease were tested on movement tasks requiring control of simultaneous movements This was in order to determine whether these three groups of patients, who all show slowing of movements, also share the distinctive impairment of simultaneous movement control that is observed in Parkinsons disease. Though all three patient groups showed equivalent slowing on the motor tasks that were studied, the patterns of impairment were different Only the patients with parkinsonism, either neuroleptic induced or from Parkinsons disease, showed additional slowing of a rapid ballistic elbow flexion movement when it was performed simultaneously with a rapid squeeze of the ipsilateral hand Only patients with parkinsonism showed a significant increase in dual task interference on a bimanual bead and tapper task, compared with controls. The bead and tapper interference in patients with depressive motor retardation was between that of controls and parkinsonism Having a bimanual skill had a large effect on the subjects dual task interference on this task. The measures of dual task interference for the two tasks did not correlate with one another; difficulty running simultaneous motor programs does therefore not explain the interference that is observed when tapping is performed while the other hand simultaneously performs a dextrous motor task. Only patients with parkinsonism showed increased fatigue on the tapping task The patients with depressive motor retardation did have elevated scores on a clinical rating of parkinsonism Nevertheless there are clearly defined differences between the movement disorder observed in patients with depression, and that observed in parkinsonism. The patterns of impairments in patients with neuroleptic parkinsonism were very similar to those of Parkinsons disease