Selective D2 receptor PET in manganese-exposed workers.

OBJECTIVE: To investigate the associations between manganese (Mn) exposure, D2 dopamine receptors (D2Rs), and parkinsonism using [11C](N-methyl)benperidol (NMB) PET. METHODS: We used NMB PET to evaluate 50 workers with a range of Mn exposure: 22 Mn-exposed welders, 15 Mn-exposed workers, and 13 nonexposed workers. Cumulative Mn exposure was estimated from work histories, and movement disorder specialists examined all workers. We calculated NMB D2R nondisplaceable binding potential (BPND) for the striatum, globus pallidus, thalamus, and substantia nigra (SN). Multivariate analysis of covariance with post hoc descriptive discriminate analysis identified regional differences by exposure group. We used linear regression to examine the association among Mn exposure, Unified Parkinson's Disease Rating Scale motor subsection 3 (UPDRS3) score, and regional D2R BPND. RESULTS: D2R BPND in the SN had the greatest discriminant power among exposure groups (p < 0.01). Age-adjusted SN D2R BPND was 0.073 (95% confidence interval [CI] 0.022-0.124) greater in Mn-exposed welders and 0.068 (95% CI 0.013-0.124) greater in Mn-exposed workers compared to nonexposed workers. After adjustment for age, SN D2R BPND was 0.0021 (95% CI 0.0005-0.0042) higher for each year of Mn exposure. Each 0.10 increase in SN D2R BPND was associated with a 2.65 (95% CI 0.56-4.75) increase in UPDRS3 score. CONCLUSIONS AND RELEVANCE: Nigral D2R BPND increased with Mn exposure and clinical parkinsonism, indicating dose-dependent dopaminergic dysfunction of the SN in Mn neurotoxicity.

Analysis of pharmacology data and the prediction of adverse drug reactions and off-target effects from chemical structure.

Preclinical Safety Pharmacology (PSP) attempts to anticipate adverse drug reactions (ADRs) during early phases of drug discovery by testing compounds in simple, in vitro binding assays (that is, preclinical profiling). The selection of PSP targets is based largely on circumstantial evidence of their contribution to known clinical ADRs, inferred from findings in clinical trials, animal experiments, and molecular studies going back more than forty years. In this work we explore PSP chemical space and its relevance for the prediction of adverse drug reactions. Firstly, in silico (computational) Bayesian models for 70 PSP-related targets were built, which are able to detect 93% of the ligands binding at IC(50) < or = 10 microM at an overall correct classification rate of about 94%. Secondly, employing the World Drug Index (WDI), a model for adverse drug reactions was built directly based on normalized side-effect annotations in the WDI, which does not require any underlying functional knowledge. This is, to our knowledge, the first attempt to predict adverse drug reactions across hundreds of categories from chemical structure alone. On average 90% of the adverse drug reactions observed with known, clinically used compounds were detected, an overall correct classification rate of 92%. Drugs withdrawn from the market (Rapacuronium, Suprofen) were tested in the model and their predicted ADRs align well with known ADRs. The analysis was repeated for acetylsalicylic acid and Benperidol which are still on the market. Importantly, features of the models are interpretable and back-projectable to chemical structure, raising the possibility of rationally engineering out adverse effects. By combining PSP and ADR models new hypotheses linking targets and adverse effects can be proposed and examples for the opioid mu and the muscarinic M2 receptors, as well as for cyclooxygenase-1 are presented. It is hoped that the generation of predictive models for adverse drug reactions is able to help support early SAR to accelerate drug discovery and decrease late stage attrition in drug discovery projects. In addition, models such as the ones presented here can be used for compound profiling in all development stages.

[D2-dopamine receptor upregulation and treatment response under neuroleptic therapy]. / D2-Dopaminrezeptorhochregulation und Behandlungserfolg unter neuroleptischer Therapie. Eine Verlaufsuntersuchung erstbehandelter Patienten mit schizophrenen Psychosen.

Animal and post mortem studies indicate that neuroleptic therapy may induce D2-dopamine receptor upregulation in the basal ganglia. To address this phenomenon in a clinical study, we investigated the D2-dopamine receptor binding in 15 DSM-III-R schizophrenics in the drug-naive state and three days after completion of a standardized neuroleptic therapy (benperidol 12-16 mg/d for 25 days) using single photon emission computed tomography (SPECT). SPECT scans were obtained 2 h after intravenous injection of 185 MBq 123I-IBZM. For analysis, basal ganglia to frontal cortex (BG/FC) ratios were calculated and the patient sample was subgrouped into patients with a favourable versus a poor treatment response. Neuroleptic treatment led to decreased BG/FC ratios in patients with a favourable response, but increased ratios in the poor responders (df = 1, F = 4.1, p = 0.06). Changes of BG/FC ratios were significantly correlated with extrapyramidal side effects, but not with neurological soft signs (NSS). Our findings indicate that neuroleptic therapy induces D2-dopamine receptor upregulation in a subgroup of patients characterized by poor treatment response and pronounced extrapyramidal side effects.

Behavioural interactions between 5-hydroxytryptophan, neuroleptic agents and 5-HT receptor antagonists in modifying rodent responding to aversive situations.

1. The ability of 5-hydroxytryptophan, 5-HT2 receptor antagonists and typical and atypical neuroleptic agents to modify behavioural responding to aversive situations was investigated in the mouse light/dark test and rat social interaction. 2. The administration of 5-hydroxytryptophan inhibited rat social interaction and the exploratory behaviour of mice in the light/dark test. 3. The 5-HT2 receptor antagonists, ketanserin, ritanserin, MDL11939, methysergide and RP62203, the neuroleptic agents, spiperone, haloperidol and benperidol, and the atypical neuroleptic agent, clozapine, when administered alone failed to modify mouse or rat behaviour. In contrast, when administered alone, sulpiride in rats and mice and thioridazine in rats disinhibited behaviour. 4. Methysergide, RP62203, ketanserin, ritanserin and MDL11939 antagonized the inhibitory effects of 5-hydroxytryptophan or reversed the inhibitory effects to one of disinhibition. 5. Low doses of spiperone (but not haloperidol or benperidol) also antagonized the inhibitory effects of 5-hydroxytryptophan in the rat but not the mouse. Higher doses of the three neuroleptic agents caused locomotor depression in both rats and mice which obscured any specific changes in behavioural responding to the aversive situations. 6. The disinhibitory profile of sulpiride in both mice and rats and thioridazine in rats was evident during their interaction with 5-hydroxytryptophan. Thioridazine in the mouse and clozapine in rats and mice also reversed the inhibitory effects of 5-hydroxytryptophan to one of disinhibition. 7. In summary, we present evidence that the atypical neuroleptic agents, thioridazine and clozapine, with their known affinity for the 5-HT2 receptors, can mimic the actions of reference 5-HT2 receptor antagonists to antagonize the inhibitory effects of 5-hydroxytryptophan in rodent models of anxiety. The results are intepreted in terms of drug action on different 5-HT2 and other 5-HT receptor subtypes. In addition, thioridazine and sulpiride have disinhibitory effects in their own right which remain to be explained.

Sleep induced by low doses of apomorphine in rats.

The effect of apomorphine on the EEG of freely moving rats was studied. Apomorphine at the dose of 1 mg/kg caused stereotypy and a marked reduction of total sleep. On the contrary, acute subcutaneous administration of apomorphine at the dose of 100 microgram/kg, or less, markedly increased the amount of total sleep (corresponding mostly to synchronized sleep). Moreover, the infusion of apomorphine (80 microgram/kg/h) for 4 h doubled the duration of slow and REM sleep. The hypnotic effect of apomorphine was prevented by neuroleptics, such as pimozide, benzperidol and L-sulpiride, at doses which, per se, did not modify the EEG of the animals. These results suggest the existence in the CNS of DA receptors mediating sleep.

Facilitatory effect of naloxone and involvement of specific ligand-opiate receptor system in the antinociceptive effects of non-opioid drugs.

The facilitatory effects exerted by naloxone on a nociceptive reaction (jumping) in the hot plate test was not modified by three phosphodiesterase inhibitors, theophylline, Ro-20-1724 and I.C.I. 63197 which had on themselves different effects on the latency of jumping. The facilitatory effects of naloxone were not diminished by neuroleptics, cholinergic agonists or miscellaneous drugs (baclofen, indomethacin, ketoprofen, n-dipropylacetate, diazepam and potassium chlorazepate). Naloxone antagonized the antinocieceptive effects of neuroleptics in different patterns. No competitive component could be observed with haloperidol, whereas such a phenomenon was apparent with benperidol. Pimozide was an intermediary case. The antinociceptive effects of two cholinergic agonists, arecoline and eserine were antagonized by naloxone and stereospecifically by the (-) isomer, Mr 2266. The (+) isomer, Mr 2267 was inactive. The antagonism by the opioid antagonists of the antinociceptive effects of cholinergic agonists appeared to be of a competitive type. Thus the facilitatory effects of naloxone did not apparently involve activation of adenyl cyclase or the mediation of dopaminergic or cholinergic (neural) structures. The antinociceptive effects of benperidol and pimozide but not of haloperidol might result from the triggering of specific opiate receptors and those of cholinergic agonists from such a triggering and/or from release of endogenous ligands.

Self-inhibitory dopamine-receptors and central effects of apomorphine.

Apomorphine, a central dopamine-receptor agonist, is well known to produce excitatory effects in animals. However, low doses exert depressant effects as hypomotility, sedation and sleep. The mechanism of these effects are discussed in terms of a stimulation by apomorphine of DA-receptors, different from the post-synaptic ones, provided of an inhibitory effect on DA-synthesis and on the firing of dopaminergic neurons.

Butyrophenone influences on the opiate receptor.

Interaction of neuroleptic drugs with the opiate receptors was investigated by inhibition of the stereospecific binding of 3H-naloxone. Benperidol and pimozide, with IC50's of 0.3-0.5 muM, were more potent than the classical opiates meperidine and propoxyphene. A systematic structure-activity relationship was evident with the basic opiate structure of a benzene and a piperidine ring preserved in active compounds. No correlation between neuroleptic activity and binding to the opiate receptor was demonstrated.

Endocrine changes in male sexual deviants after treatment with anti-androgens, oestrogens or tranquillizers.

The endocrine effects of drugs on two groups of 12 male sexual offenders in a special hospital were studied. In the first study benperidol, chlorpromazine and placebo were compared and in the second ethynyl oestradiol and cyproterone acetate were compared with no treatment. In the first study there was no difference between the three drugs in their effects on plasma testosterone or luteinizing hormone (LH). In the second study cyproterone acetate produced a reduction in plasma testosterone, LH and follicle-stimulating hormone (FSH). Ethynyl oestradiol produced a rise in plasma testosterone and LH, and no change in FSH. Neither drug changed total plasma oestrogen levels. The unexpected effects of ethynyl oestradiol were attributed to an increase in sex hormone-binding globulin (SHBG) leading to a rise in bound, inactive testosterone. Direct measurement showed a two- to threefold increase in SHBG with ethynyl oestradiol treatment and no change in SHBG with cyproterone acetate treatment. In spite of these contrasting endocrine effects, ethynyl oestradiol, cyproterone acetate and benperidol produced similar behavioural changes.