Effects of risperidone and haloperidol on tachykinin and opioid precursor peptide mRNA levels in the caudate-putamen and nucleus accumbens of the rat.

We investigated whether the two output pathways of the striatum are differently affected by the novel atypical drug risperidone and the conventional typical antipsychotic drug haloperidol. To this end, changes in mRNA levels of preproenkephalin-A, preproenkephalin-B, and preprotachykinin were determined in the rat striatum following chronic drug treatment for 14 days, using quantitative in situ hybridization. Furthermore, we studied the contribution of the dopamine D2 and serotonin 5-HT2A antagonist components of risperidone in establishing its effects on neuropeptide mRNA levels in the striatum. The results showed that both risperidone and haloperidol had major effects on the preproenkephalin-A mRNA and thus on the indirect striatal output route, whereas they had minor effects on preproenkephalin-B and preprotachykinin mRNA, contained by the direct output route. When both drugs were administered in the same dose, preproenkephalin-A mRNA was much more elevated by haloperidol than by risperidone. However, when doses of risperidone and haloperidol were modified to attain comparable dopamine D2 receptor occupancy, the drugs had comparable effects on preproenkephalin-A mRNA levels. It was further found that 5-HT2A/C receptor blockade with ritanserin had only modest effects on preproenkephalin-B and preprotachykinin mRNA levels and did not affect preproenkephalin-A mRNA levels. We conclude that risperidone and haloperidol, administered in the same dose, differently affect the striatal output routes. Furthermore, the results suggest that the effects of risperidone on neuropeptide mRNA levels are fully accounted for by its D2 antagonism and that no indication exists for a role of 5-HT2A receptor blockade in this action.

Detailed mapping of serotonin 5-HT1B and 5-HT1D receptor messenger RNA and ligand binding sites in guinea-pig brain and trigeminal ganglion: clues for function.

The similar pharmacology of the 5-HT1B and 5-HT1D receptors, and the lack of selective compounds sufficiently distinguishing between the two receptor subtypes, have hampered functional studies on these receptors. In order to provide clues for differential functional roles of the two subtypes, we performed a parallel localization study throughout the guinea-pig brain and the trigeminal ganglia by means of quantitative in situ hybridization histochemistry (using [35S]-labelled riboprobes probes for receptor messenger RNA) and receptor autoradiography (using a new radioligand [3H]alniditan). The anatomical patterns of 5-HT1B and 5-HT1D receptor messenger RNA were quite different. While 5-HT1B receptor messenger RNA was abundant throughout the brain (with highest levels in the striatum, nucleus accumbens, olfactory tubercle, cortex, hypothalamus, hippocampal formation, amygdala, thalamus, dorsal raphe and cerebellum), 5-HT1D receptor messenger RNA exhibited a more restricted pattern; it was found mainly in the olfactory tubercle, entorhinal cortex, dorsal raphe, cerebellum, mesencephalic trigeminal nucleus and in the trigeminal ganglion. The density of 5-HT(1B/1D) binding sites (combined) obtained with [3H]alniditan autoradiography was high in the substantia nigra, superior colliculus and globus pallidus, whereas lower levels were detected in the caudate-putamen, hypothalamus, hippocampal formation, amygdala, thalamus and central gray. This distribution pattern was indistinguishable from specific 5-HT1B receptor labelling in the presence of ketanserin under conditions to occlude 5-HT1D receptor labelling; hence the latter were below detection level. Relationships between the regional distributions of the receptor messenger RNAs and binding sites and particular neuroanatomical pathways are discussed with respect to possible functional roles of the 5-HT1B and 5-HT1D receptors.

Autoradiographic mapping of 5-HT1B- and 5-HT1D receptors in human brain using [3H]alniditan, a new radioligand.

[3H]alniditan, a new potent non-indole serotonin 5-HT1B/1D agonist, was used as a radioligand to characterize 5-HT1B and 5-HT1D receptor (previously termed 5-HT1D beta and 5-HT1D alpha) in various regions of the human brain. Quantitative receptor autoradiography was applied for high anatomical resolution and sensitivity. Highest densities of 5-HT1B/1D receptors were found in the substantia nigra and in the globus pallidus. High to moderate densities were measured in the caudate nucleus, putamen, nucleus accumbens, central gray and hippocampal formation. Very low densities were detected in various cortical regions. In the cerebellum no [3H]alniditan binding was detected. Selective 5-HT1B receptor labeling was achieved using [3H]alniditan in the presence of 300 nM of ketanserin (sufficient to block 5-HT1D receptor labeling). The identity of the 5-HT1B binding sites under these conditions was corroborated by the pIC50 of sumatriptan, which corresponded to its affinity for cloned human 5-HT1B receptors expressed in cells. Surprisingly, the distribution of selective 5-HT1B receptor labeling was completely identical to the distribution of labeling of 5-HT1B + 5-HT1D receptors. The present data indicate that [3H]alniditan is a suitable radioligand for measuring 5-HT1B/1D receptor in the human brain and that the 5-HT1B binding sites are predominant in the presently investigated regions of the human brain.

Alniditan, a new 5-hydroxytryptamine1D agonist and migraine-abortive agent: ligand-binding properties of human 5-hydroxytryptamine1D alpha, human 5-hydroxytryptamine1D beta, and calf 5-hydroxytryptamine1D receptors investigated with [3H]5-hydroxytryptamine and [3H]alniditan.

Alniditan is a new migraine-abortive agent. It is a benzopyran derivative and therefore structurally unrelated to sumatriptan and other indole-derivatives and to ergoline derivatives. The action of sumatriptan is thought to be mediated by 5-hydroxytryptamine (5-HT)1D-type receptors. We investigated the receptor-binding profile in vitro of alniditan compared with sumatriptan and dihydroergotamine for 28 neurotransmitter receptor subtypes, several receptors for peptides and lipid-derived factors, ion channel-binding sites, and monoamine transporters. Alniditan revealed nanomolar affinity for calf substantia nigra 5-HT1D and for cloned h5-HT1D alpha, h5-HT1D beta and h5-HT1A receptors (Ki = 0.8, 0.4, 1.1, and 3.8 nM, respectively). Alniditan was more potent than sumatriptan at 5-HT1D-type and 5-HT1A receptors. Alniditan showed moderate-to-low or no affinity for other investigated receptors; sumatriptan showed additional binding to 5-HT1F receptors. Dihydroergotamine had a much broader profile with high affinity for several 5-HT, adrenergic and dopaminergic receptors. In signal transduction assays using cells expressing recombinant h5-HT1D alpha, h5-HT1D beta, or h5-HT1A receptors, alniditan (like 5-HT) was a full agonist for inhibition of stimulated adenylyl cyclase (IC50 = 1.1, 1.3, and 74 nM, respectively, for alniditan). Therefore, in functional assays, the potency of alniditan was much higher at 5-HT1D receptors than at 5-HT1A receptors. We further compared the properties of [3H]alniditan, as a new radioligand for 5-HT1D-type receptors, with those of [3H]5-HT in membrane preparations of calf substantia nigra, C6 glioma cells expressing h5-HT1D alpha, and L929 cells expressing h5-HT1D beta receptors. [3H]Alniditan revealed very rapid association and dissociation binding kinetics and showed slightly higher affinity (Kd = 1-2 nM) than [3H]5-HT. We investigated 25 compounds for inhibition of [3H]alniditan and [3H]5-HT binding in the three membrane preparations; Ki values of the radioligands were largely similar, although some subtle differences appeared. Most compounds did not differentiate between 5-HT1D alpha and 5-HT1D beta receptors, except methysergide, ritanserin, ocaperidone, risperidone, and ketanserin, which showed 10-60-fold higher affinity for the 5-HT1D alpha receptor. The Ki values of the compounds obtained with 5-HT1D receptors in calf substantia nigra indicated that these receptors are of the 5-HT1D beta-type. We demonstrated that alniditan is a potent agonist at h5-HT1D alpha and h5-HT1D beta receptors; its properties probably underlie its cranial vasoconstrictive and antimigraine properties.

Endogenous dopamine limits the binding of antipsychotic drugs to D3 receptors in the rat brain: a quantitative autoradiographic study.

[3H]7-hydroxy-N,N-di-n-propyl-2-aminotetralin was used as a radioligand for the autoradiographic measurements of dopamine D3 receptors in rat and human brain. Preincubation of the brain sections was necessary to obtain binding of the radioligand in the islands of Calleja and in the nucleus accumbens, but not in cerebellar lobules 9/10 of the rat. D3 receptors were also totally occluded in unwashed sections of the human striatum. The radioligand binding to D3 receptors was maximal after preincubating the sections for at least 10 min. Pretreatment of the animals with reserpine or tetrabenazine, which results in a severe depletion of endogeneous monoamines, strongly reduces the occlusion of D3 receptors in unwashed brain sections. The occlusion of dopamine D3 receptors in brain sections suggests that the in vivo access to D3 receptors may be locally inhibited by endogenous dopamine. The in vitro binding affinities of 12 antipsychotic drugs for D2 and D3 receptors were evaluated in competition binding experiments, using both rat and cloned human receptors. Most of the compounds showed only a slightly lower affinity for D3 than for D2 receptors in vitro. Affinities of the antipsychotic drugs for cloned human D21 and D3 receptors were very close to their affinities for the rat receptors. In vivo occupancy of these receptors in the rat brain was measured ex vivo by quantitative autoradiography, 2 hours after subcutaneous drug administration. For most compounds, occupancy of D3 receptors, as compared to D2 receptor occupancy, was lower than expected from the corresponding in vivo affinity ratios. For the new antipsychotic risperidone, in vivo occupancy of D3 receptors was measured both in the islands of Calleja and in the cerebellar lobules 9/10. This compound was three times less potent for the occupancy of D3 receptors in the islands of Calleja than in the cerebellum, an area lacking endogenous dopamine (ED50 = 28 and 10 mg kg-1, respectively). Based on the observations in the rat brain, it may reasonably be supposed that therapeutic dosages of antipsychotic drugs will induce in patients only a minor occupancy of D3 receptors in brain areas containing high dopamine concentrations. The role of dopamine D3 receptors as a target of antipsychotic drugs may therefore be less important than previously thought.

Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding.

Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). An ex vivo autoradiography technique was applied to determine the receptor occupancy by the drugs administered in vivo. Of particular interest are the central 5HT2A receptors and D2-type receptors. Predominant 5HT2A receptor antagonism is supposed to add to an atypical profile of the antipsychotics (treatment of the negative symptoms, low incidence of extrapyramidal side effects). D2 antagonism is required the treatment of positive symptoms. A contribution of the new dopamine receptor subtypes D3 and in particular D4 receptors has been proposed. In vitro, all compounds, except the 'typical' antipsychotics haloperidol and fluspirilene, showed higher affinity for 5HT2A than for D2 receptors. Subnanomolar affinity for human 5HT2A receptors was observed for ORG-5222, sertindole, risperidone, 9-OH-risperidone and ziprasidone. Fluspirilene, ORG-5222, haloperidol, ziprasidone, risperidone, 9-OH-risperidone and zotepine displayed nanomolar affinity for human D2 receptors. Sertindole and olanzapine were slightly less potent. Pipamperone, clozapine and seroquel showed 2 orders of magnitude lower D2 affinity in vitro. Clozapine, but even more so pipamperone, displayed higher affinity for D4 than for D2 receptors. For most other compounds, D4 affinity was only slightly lower than their D2 affinity. Seroquel was totally devoid of D4 affinity. None of the compounds had nanomolar affinity for D1 receptors; their affinity for D3 receptors was usually slightly lower than for D2 receptors. In vivo, ORG-5222, risperidone, pipamperone, 9-OH-risperidone, sertindole, olanzapine, zotepine and clozapine maintained a higher potency for occupying 5HT2A than D2 receptors. Risperidone and ORG-5222 had 5HT2A versus D2 potency ratio of about 20. Highest potency for 5HT2A receptor occupancy was observed for ORG-5222 followed by risperidone and olanzapine. Ziprasidone exclusively occupied 5HT2A receptors. ORG-5222, haloperidol, fluspirilene and olanzapine showed the highest potency for occupying D2 receptors. No regional selectivity for D2 receptor occupancy in mesolimbic versus nigrostriatal areas was detected for any of the test compounds. Risperidone was conspicuous because of its more gradual occupancy of D2 receptors; none of the other compounds showed this property. The various compounds also displayed high to moderate occupancy of adrenergic alpha 1 receptors, except fluspirilene and ziprasidone. Clozapine, zotepine, ORG-5222 and sertindole occupied even more alpha 1 than D2 receptors. Clozapine showed predominant occupancy of H1 receptors and occupied cholinergic receptors with equivalent potency to D2 receptors. A stronger predominance of 5HT2A versus D2 receptor occupancy combined with a more gradual occupancy of D2 receptors differentiates risperidone and its 9-OH-metabolite from the other antipsychotic compounds in this study. The predominant 5HT2A receptor occupancy probably plays a role in the beneficial action of risperidone on the negative symptoms of schizophrenia, whereas maintenance of a moderate occupancy of D2 receptors seems adequate for treating the positive symptoms of schizophrenia. A combined 5HT2A and D2 occupancy and the avoidance of D2 receptor overblockade are believed to reduce the risk for extrapyra

In vitro receptor binding and in vivo receptor occupancy in rat and guinea pig brain: risperidone compared with antipsychotics hitherto used.

Risperidone was compared with antipsychotics hitherto used for in vitro receptor binding using animal brain or cloned (human) receptors and in vivo receptor occupancy in rat and guinea pig brain following acute treatment. Both in vitro and in vivo, risperidone, 9-OH-risperidone, SM-9018, clozapine and clocapramine showed higher affinity for 5-HT2A- than for D2-receptors, whereas mosapramine, haloperidol, bromperidol and nemonapride had a slight to strong preference for D2- compared to 5-HT2A-receptors. In vivo, risperidone showed the highest potency for 5-HT2A-receptor occupancy; To obtain the same extent of D2-receptor occupancy, a 19-times higher dosage was required. 9-OH-Risperidone, the principal active metabolite of risperidone, showed a receptor occupancy profile comparable to that of risperidone. No regional selectivity for D2-receptor occupancy in mesolimbic vs nigrostriatal areas was detected for any of the compounds. Risperidone differed from the other compounds by the remarkably shallow slope of its D2-receptor dose-occupancy curve. A greater predominance of 5-HT2A-receptor vs D2-receptor occupancy and a more gradual occupancy of D2-receptors differentiate risperidone from the other compounds. Both properties probably assist in preventing an extensive blockade of D2-receptors, the cause for extrapyramidal symptoms (EPS). The predominant 5-HT2A-receptor occupancy most likely underlies risperidone's beneficial effects on the negative symptoms of schizophrenia and an adequately low D2-receptor occupancy adds to the treatment of positive symptoms with a low liability of EPS.

Evidence for two neurochemical divisions in the human nucleus accumbens.

The neurochemical anatomy of the human nucleus accumbens was studied by comparing the distributional patterns of [3H]DAMGE (mu opioid receptor), [3H]bremazocine (kappa opioid receptor), [3H]SCH-23390 (D1-like dopamine receptor), [3H]7-OH-DPAT (D3 dopamine receptor) binding, preproenkephalin mRNA and acetylcholinesterase activity in sections of post mortem human striatum. Our results demonstrate the presence of at least two neurochemically distinct divisions within the human nucleus accumbens, which may be homologous to the 'shell' and 'core' divisions of the nucleus as found in the rat.

Risperidone: a novel antipsychotic with balanced serotonin-dopamine antagonism, receptor occupancy profile, and pharmacologic activity.

The interaction of risperidone, 9-hydroxyrisperidone (the principal active metabolite), and clozapine with neurotransmitter receptors was investigated in vitro using animal brain tissue homogenates and cloned human receptors expressed in cells and ex vivo using quantitative receptor autoradiography in rat and guinea pig brain sections. In vitro, risperidone and 9-hydroxyrisperidone had similar binding profiles, and their highest affinity was for 5-HT2A receptors (cloned human, Ki 0.4 nM); affinities for other 5-HT-receptor subtypes were at least 100 times lower. Risperidone bound to 5-HT2A receptors with 20 times greater affinity than clozapine and 170 times greater affinity than haloperidol. Clozapine primarily bound to histamine H1 receptors and haloperidol to dopamine D2 receptors. The binding affinity of risperidone and 9-hydroxyrisperidone for the D2 family of receptors (D2L, D2S, D3, D4) was one order of magnitude lower than their affinity for 5-HT2A receptors. Risperidone bound to D2 and D3 receptors with 50 and 20 times greater affinity than clozapine and was only 2 to 3 times less potent than haloperidol. All compounds bound with similar affinities to D4 receptors (Ki 5-9 nM), and their affinities for D1 receptors were 100 times lower than for D4 receptors. The ex vivo receptor occupancy profile of the compounds matched the in vitro receptor binding profile. A conspicuous property of risperidone, not seen for the other compounds, was the shallow occupancy curve at D2 receptors in the striatum and mesolimbic brain area. Moreover, it was observed that antagonism of strong D2-receptor stimulation by apomorphine in rats was achieved at less than 50% D2 occupancy by the antipsychotics.(ABSTRACT TRUNCATED AT 250 WORDS)

Survey on the pharmacodynamics of the new antipsychotic risperidone.

This review reports on the pharmacodynamics of the new antipsychotic risperidone. The primary action of risperidone is serotonin 5-HT2 receptor blockade as shown by displacement of radioligand binding (Ki: 0.16 nM), activity on isolated tissues (EC50: 0.5 nM), and antagonism of peripherally (ED50: 0.0011 mg/kg) and centrally (ED50: 0.014 mg/kg) acting 5-HT2 receptor agonists in rats. Risperidone is at least as potent as the specific 5-HT2 receptor antagonist ritanserin in these tests. Risperidone is also a potent dopamine D2 receptor antagonist as indicated by displacement of radioligand binding (Ki: 1.4 nM), activity in isolated striatal slices (IC50: 0.89 nM), and antagonism of peripherally (ED50: 0.0057 mg/kg in dogs) and centrally acting D2 receptor agonists (ED50: 0.056-0.15 mg/kg in rats). Risperidone shows all effects common to D2 antagonists, including enhancement of prolactin release. However, some central effects such as catalepsy and blockade of motor activity occur at high doses only. Risperidone is 4-10 times less potent than haloperidol as a central D2 antagonist in rats and it differs from haloperidol by the following characteristics: predominant 5-HT2 antagonism; LSD antagonism; effects on sleep; smooth dose-response curves for D2 antagonism; synergism of combined 5-HT2/D2 antagonism; pronounced effects on amphetamine-induced oxygen consumption; increased social interaction; and pronounced effects on dopamine (DA) turnover. Risperidone displays similar activity at pre- and postsynaptic D2 receptors and at D2 receptors from various rat brain regions. The binding affinity for D4 and D3 receptors is 5 and 9 times weaker, respectively, than for D2 receptors; interaction with D1 receptors occurs only at very high concentrations. The pharmacological profile of risperidone includes interaction with histamine H1 and alpha-adrenergic receptors but the compound is devoid of significant interaction with cholinergic and a variety of other types of receptors. Risperidone has excellent oral activity, a rapid onset, and a 24-h duration of action. Its major metabolite, 9-hydroxyrisperidone, closely mimics risperidone in pharmacodynamics. Risperidone can be characterized as a potent D2 antagonist with predominant 5HT2 antagonistic activity and optimal pharmacokinetic properties.

Occupancy of central neurotransmitter receptors by risperidone, clozapine and haloperidol, measured ex vivo by quantitative autoradiography.

Risperidone (Risperdal) is a novel antipsychotic drug, with beneficial effects on both positive and negative symptoms of schizophrenia, and with a low incidence of extrapyramidal side effects (EPS). These particular properties have been attributed to the predominant and very potent serotonin 5-HT2 receptor antagonism of the drug combined with less potent dopamine D2 antagonism. In order to provide data on the degree to which various central neurotransmitter receptors are occupied in vivo, we performed ex vivo receptor occupancy studies with risperidone in comparison with clozapine and haloperidol in rats and guinea pigs. Various types of receptors, to which the compounds were known to bind to in vitro, were investigated precisely using receptor autoradiography in sections of the same rat brain except for histamine H1 receptors that were measured in the guinea-pig cerebellum. Risperidone (2 h after s.c. treatment) occupied 5-HT2 receptors at very low doses (ED50 = 0.067 mg/kg). Nearly full occupancy (> 80%) was achieved before H1, D2, alpha 1 and alpha 2 receptors became occupied (ED50 = 0.45, 0.66, 0.75 and 3.7 mg/kg, respectively). Clozapine displayed occupancy of H1 and alpha 1 receptors at low doses (ED50 = 0.15 and 0.58 mg/kg, respectively) and of 5-HT2, 5-HT1C, D2, alpha 2, cholinergic muscarinic and 5-HT1A receptors at higher doses (ED50 = 1.3, 1.8, 9.0, 9.5, 11 and 15 mg/kg, respectively). Haloperidol occupied D2 and alpha 1 receptors at low doses (ED50 = 0.13 and 0.42 mg/kg, respectively) and 5-HT2 receptors at a higher dose (ED50 = 2.6 mg/kg). Occupancy of receptor types occurred with similar ED50-values in various brain areas, e.g. D2 receptors in striatum and mesolimbic areas. The ED50-values for the ex vivo measured occupancy of 5-HT2 and D2 receptors were in good agreement with ED50-values for functional effects putatively mediated by these central receptors. The dose-dependent occupancy of D2 receptors proceeded more gradually with risperidone (slope in the caudate-putamen: 0.85) than with clozapine (slope: 1.44) or haloperidol (slope: 1.51). It has previously been suggested that partial D2 receptor occupancy may suffice to control the positive symptoms of schizophrenia, whereas higher D2 receptor occupancy would induce extrapyramidal symptoms (EPS). The dose ratio for high (75%) vs. low (25%) D2 receptor occupancy in the caudate-putamen, was 37.3 for risperidone, 8.4 for clozapine, and 7.9 for haloperidol.(ABSTRACT TRUNCATED AT 400 WORDS)

An in vivo study of the influence of the surface roughness of implants on the microbiology of supra- and subgingival plaque.

In nine patients with fixed prostheses supported by endosseous titanium implants, 2 titanium abutments (transmucosal part of the implant) were replaced by either an unused standard abutment or a roughened titanium abutment. After 3 months of habitual oral hygiene, plaque samples were taken for differential phase-contrast microscopy, DNA probe analysis, and culturing. Supragingivally, rough abutments harbored significantly fewer coccoid micro-organisms (64 vs. 81%), which is indicative of a more mature plaque. Subgingivally, the observations depended on the sampling procedure. For plaque collected with paper points, only minor qualitative and quantitative differences between both substrata could be registered. However, when the microbiota adhering to the abutment were considered, rough surfaces harbored 25 times more bacteria, with a slightly lower density of coccoid organisms. The presence and density of periodontal pathogens subgingivally were, however, more related to the patient's dental status than to the surface characteristics of the abutments. These results justify the search for optimal surface smoothness for all intra-oral and intra-sulcular hard surfaces for reduction of bacterial colonization and of periodontal pathogens.

Interaction of antipsychotic drugs with neurotransmitter receptor sites in vitro and in vivo in relation to pharmacological and clinical effects: role of 5HT2 receptors.

In the introductory section an overview is given of the strategies which have been proposed in the search for side-effect free antipsychotics. Special attention is paid to the role of predominant 5HT2 receptor blockade over D2 blockade. Whereas D2 receptor blockade seems to be essential for the treatment of positive symptoms of schizophrenia, it also underlies the induction of extrapyramidal side effects (EPS). Predominant 5HT2 receptor blockade may reduce the EPS liability and can ameliorate negative symptoms of schizophrenia. We further report a nearly complete list of neuroleptics that are on the European market and eight new antipsychotics that recently entered clinical trial, 5HT2 and D2 receptor binding affinity (Ki values) and the rank order in affinity for various neurotransmitter receptor subtypes are also discussed. For the eight new antipsychotics and for six reference compounds the complete receptor binding profile (including 33 radioligand receptor binding and neurotransmitter uptake models) is reported. Furthermore, for a series of 120 compounds the relative affinity for D2 receptors and D3 receptors (a recently cloned new dopamine receptor subtype) is compared. Finally, original findings are reported for the new antipsychotic risperidone and for haloperidol and clozapine on the in vivo occupation of neurotransmitter receptors in various brain areas after systemic treatment of rats or guinea pigs. The receptor occupation by the drugs was measured ex vivo by quantitative receptor autoradiography. The receptor occupancy was related to the motor activity effects of the test compounds (measurements were done in the same animals) and to the ability of the drugs to antagonize various 5HT2 and D2 receptor mediated effects. With risperidone a high degree of central 5HT2 receptor occupation was achieved before other neurotransmitter receptors became occupied. This probably co-underlies the beneficial clinical properties of the drug. Antagonism of the various D2 receptor-mediated effects was achieved at widely varying degrees of D2 receptor occupancy, from just about 10% to more than 70%. For therapeutic application it may be of prime importance to carefully titrate drug dosages. Antipsychotic effects may be achieved at a relatively low degree of D2 receptor occupancy at which motor disturbances are still minimal. With drugs such as risperidone that produce shallow log dose-effect curves, differentiation between the various D2 receptor mediated effects may be made more easily, allowing EPS-free maintenance therapy of schizophrenic patients.

Influence of temperature and foil hardness on interocclusal tactile threshold.

Determinations of interocclusal tactile threshold levels so far have involved neither appropriate psychophysical approaches nor an assessment of the mechanical and thermal properties of the foils used. Twenty subjects (12 females) aged 18 to 50 (mean age 35) were tested for their absolute threshold level (RL). Both the method of limits and the staircase method were applied to determine the active or passive RL. For the active RL assessment, foils of different thicknesses were placed between edge-to-edge opposed incisors during gentle biting. Inner ear receptors of the blindfolded subjects were blocked by broad band noise applied through earphones, because vibrations induced by occlusal contact and conducted through bone might be perceived by these receptors. The foils presented were aluminum (Al), tin (Sn), polyester (PE) and calibrated steel (St) (thickness ranging from 8 to 50 microns) which offer different physical and thermal properties. The range of RL of the group varied between 8 microns for aluminum to 46 microns for polyester for 50% correct assessments. Increasing the foil temperature from room temperature (20 degrees C) to body temperature (35 degrees C) significantly increased the RL for conducting materials (one-way blocked ANOVA). These results indicate that temperature exchange takes place while presenting conducting foils at 20 degrees C (cold stimulus) interocclusally, which influences the RL by activating thermosensitive receptors. The passive RL determination with classical von Frey-hairs resulted in a mean axial RL of 3.0 g. Both psychophysical RL assessments (method of limits, staircase method) gave reproducible and similar results as ascertained by ANOVA. Furthermore, a positive correlation was established between active and passive RL (Pearson correlation test).(ABSTRACT TRUNCATED AT 250 WORDS)

The importance of visual feedback on the accuracy of jaw and finger positioning in man.

The anatomical position of the mandible means that direct visual feedback is not possible. To clarify the role of visual information, several jaw- and finger-positioning tasks were designed, both in a 'free-movement' and an 'isolated' (arm or head fixed) state, with or without a visual feedback display of the target position. The subjects had to position the mandible or the index finger of the preferred hand on to a movable metal bar and to maintain a defined position coinciding with the target level provided on an oscilloscope screen. The position signal was tape recorded and computer analysed off-line. Digital filtering differentiated between the drift and the oscillations around the target (root mean square). The results demonstrated a lack of precision in the free-movement, finger-positioning task after withdrawal of visual feedback. For jaw opening and closing muscles, position control was less impaired when a visual feedback display was abolished. It was suggested that the efficiency of jaw positioning is not primarily determined by visual feedback.

Autoradiographic evidence for the occlusion of rat brain dopamine D3 receptors in vivo.

[125I]Iodosulpride binding was studied in frontal rat brain sections by quantitative autoradiography. Using preincubated (= washed) sections, selective labelling and identification of dopamine D3 receptors was obtained using 0.2 nM [125I]iodosulpride in the presence of 100 nM domperidone for the occlusion of the D2 receptors. A high density of D3 receptors was noticed in the islands of Calleja. When preincubation of the sections was omitted, no D3 receptor labelling could be achieved, indicating tight binding to the receptor of an endogenous inhibitor. Such a tight receptor occupancy was not observed for the D2 receptor and various other neurotransmitter receptors. The occlusion of the D3 receptor could be prevented by tetrabenazine-induced monoamine depletion of the rats. It can be concluded, therefore, that D3 receptors are massively occupied by a monoamine, likely to be dopamine. This observation prompts the question to what extent dopamine D3 receptors can become occupied in vivo by systematically applied exogenous compounds.

Posterior jaw bone resorption in osseointegrated implant-supported overdentures.

For several years, osseointegrated implant-supported overdentures have been used in the rehabilitation of full edentulism with excellent results, at least in the lower jaw. This study involved 3 groups of patients with different prosthetic reconstructions: (1) mandibular overdentures supported by 2 implants connected by a bar (30 patients), (2) mandibular fixed prostheses supported by 4-6 implants (25 patients) and (3) mandibular complete dentures without implant support as controls (85 patients). The primary aim of this study was to examine on orthopantomograms (by means of the area index to minimize distortion and magnification errors), posterior mandibular ridge resorption in the 3 treatment groups. The present data demonstrated a minimal posterior mandibular ridge resorption in patients with fixed implant-supported prostheses. A more considerable posterior ridge resorption was observed in the complete denture group and especially in the overdenture wearers. For the latter, the annual posterior jaw bone resorption after the post-extraction remodeling period of 6 months, was 2- to 3-fold that of full denture wearers. When patients were edentulous for more than 10 years, the difference between the 2 latter groups disappeared. It is suggested that although the overdenture design on 2 implants offers advantages from a financial and failure rate point of view, its indications in younger patients should cautiously be evaluated in a long-term perspective concerning posterior mandibular bone resorption.

The reliability of pocket probing around screw-type implants.

This study involved 108 patients (age 38-82 years) rehabilitated with overdentures in the lower jaw supported by 2 endosseous screw-shaped implants. At each follow-up visit, the clinical attachment level (PAL) around the implants was assessed with a Merrit-B probe or a constant force electronic probe, Peri-probe, and biannually parallel long-cone radiographs were taken to locate the marginal bone level. These data were used to examine the relationship between bone and attachment level estimations around implants. As a mean, bone level and PAL, for mesial and distal sites, was 0.67 and 0.61 for the Merrit-B probe, and 0.76 and 0.65, respectively for the Peri-probe. The highest correlations were obtained for sites with a healthy gingiva or in absence of intra-bony craters. Duplicate PAL registrations showed a standard deviation for the intra-examiner variability of 2.37 (Peri-probe) or 0.40 mm (Merrit-B probe) with more than 90% of the variation within 0.5 mm. The mean difference in PAL between Merrit-B probe or Peri-probe was 0.05 mm. It was concluded that the clinical attachment level determination is a reliable indicator for bone level around implants with a moderate healthy gingiva.