Desipramine treatment in normal subjects. Effects on neuroendocrine responses to tryptophan and on platelet serotonin (5-HT)-related receptors.

Normal subjects took the tricyclic antidepressant, desipramine hydrochloride, for 16 days. Following treatment there was an increase in the number of specific binding sites on the platelet for both tritiated imipramine and tritiated LSD, the latter site probably representing a platelet serotonin (5-HT) receptor. During desipramine treatment the prolactin response to tryptophan (L-tryptophan) was enhanced, and this enhancement correlated with the increase in platelet LSD binding. The results confirm previous observations that desipramine administration increases certain 5-HT-mediated neuroendocrine responses. Our findings further indicate that desipramine may alter both 5-HT uptake and 5-HT receptor sensitivity, and suggest that the platelet LSD receptor may in certain conditions provide a useful model of 5-HT receptors in the brain.

Antipsychotic drug effects in a model of schizophrenic attentional disorder: a randomized controlled trial of the effects of haloperidol on latent inhibition in healthy people.

We studied the effects of haloperidol (0.5 mg, intravenously) on latent inhibition in an auditory paradigm and two visual paradigms in healthy subjects. Haloperidol increased latent inhibition in one visual paradigm and tended to increase latent inhibition in an auditory task, compared to saline-injected controls. These results indicate that haloperidol can enhance the selectivity of attention. In contrast, previous studies have reported that acute schizophrenics show reduced latent inhibition.

Haloperidol enhances latent inhibition in visual tasks in healthy people.

We have previously shown that 0.5 mg haloperidol (i.v.) increased latent inhibition in one of two visual tasks. The present study analysed the effects of a higher dose of haloperidol (1.0 mg, i.v.) on latent inhibition in these two visual tasks in healthy volunteers in a randomised controlled trial. In the task where 0.5 mg haloperidol had enhanced latent inhibition, 1.0 mg had the same effect, thus replicating the previous result. In the task where 0.5 mg haloperidol had been ineffective, 1.0 mg haloperidol enhanced latent inhibition in high schizotypal subjects only. This indicates that subjects with higher schizotypy scores are more sensitive to dopamine blockade. A comparison of the results from the studies at the two different doses suggests a dose dependence of haloperidol's effects on latent inhibition that parallels results from animal work.

Characterisation of [3H]lysergic acid diethylamide binding to a 5-hydroxytryptamine receptor on human platelet membranes.

Specific binding of [3H]lysergic acid diethylamide (LSD) to human platelet membranes, as defined by 300 nM spiperone, was saturable over the concentration range of 0.25-2.5 nM [3H]LSD. At 0.5 nM [3H]LSD the half-time for association at 37 degrees C was 56 min, half-time for dissociation was 173 min, and the kinetically derived affinity was 0.24 nM. In 19 control subjects equilibrium binding studies gave an affinity of 0.53 +/- 0.02 nM (mean +/- S.E.M.) and capacity of 57.1 +/- 5.6 fmol/mg protein (mean +/- S.E.M.). The inhibition profile was consistent with that of a 5-hydroxytryptamine (5-HT) receptor. There was a significant correlation between the inhibition of [3H]LSD binding and the inhibition of 5-HT-induced shape change, but not inhibition of active platelet uptake of 5-HT. There was also a significant correlation between the inhibition of [3H]LSD binding to human platelet membranes and human frontal cortex. Platelet [3H]LSD binding may therefore be a useful model for study of peripheral and central 5-HT receptors in man.

Intravenous administration of haloperidol to healthy volunteers: lack of subjective effects but clear objective effects.

Healthy volunteers who received i.v. injections of either saline or haloperidol (0.5 or 1.0 mg) made visual analogue scale ratings of subjective mood, tension, shakiness and the global feeling of having received an active drug. The subjective ratings of volunteers who received haloperidol did not differ, overall, from those who received saline. In contrast, the drug caused clear objective changes in several psychological tests. I.v. administration of low doses of haloperidol may permit double-blind testing of the psychological actions of haloperidol in healthy volunteers.

Indomethacin-responsive episodic cluster headache.

The case of a man with a 34 year history of episodic cluster headaches is described. At the peak of a cluster the headaches occurred up to twenty times a day. The headaches were unresponsive to conventional therapy but were dramatically abolished by indomethacin. This effect of indomethacin was confirmed in a double-blind placebo-controlled trial.

Basal cell naevus syndrome and intracranial meningioma.

Two cases of the basal cell naevus syndrome in association with an intracranial meningioma are described and the relationship discussed.

Effect of central cholinergic stimulation on regional cerebral blood flow in Alzheimer disease.

Patients with Alzheimer disease (AD) had reduced regional cerebral blood flow (rCBF) in the posterior parietotemporal region compared with controls, as determined with technetium-99m hexamethyl propyleneamine oxime and single photon emission tomography. Central cholinergic stimulation with physostigmine produced a focal increase in rCBF in the posterior parietotemporal region in the patients with AD but not in controls.

Human platelet 5-hydroxytryptamine receptors: binding of [3H]-lysergic acid diethylamide (LSD). Effects of chronic neuroleptic and antidepressant drug administration.

Chronic treatment with phenothiazines and thioxanthenes has been found to enhance 5-HT-induced aggregation of human platelets. A method has been developed to study 5-HT2 receptor binding sites on platelets utilising [3H]-LSD and more recently 125I/LSD. Results are presented which suggest that the LSD binding site is indeed the 5-HT2 binding site and that the LSD binding characterises the specific receptor responsible for 5-HT-induced shape change and aggregation. In a group of patients receiving phenothiazines or thioxanthenes, the Bmax of LSD binding was increased. The mean binding affinity was decreased possibly due to a persistence of neuroleptic in the platelet membrane preparation. Analysis showed that this was not the reason why the mean binding capacity was increased. The results show that chronic phenothiazine and thioxanthene delta treatment 'up-regulates' platelet 5-HT2 binding sites and that this may be accompanied by increased sensitivity to platelet aggregation by 5-HT. In normal subjects desipramine treatment increased the Bmax of platelet LSD binding and this was accompanied by an increased prolactin response to tryptophan which is thought to be mediated by central 5-HT function.

Pharmacokinetic investigation of the interaction of azapropazone with phenytoin.

We have investigated the interaction of azapropazone with phenytoin in five healthy volunteers. From steady-state plasma phenytoin concentrations of about 17 mumol/l there was at least a two-fold increase following the introduction of azapropazone. The main mechanism of the interaction was a decrease in phenytoin clearance, attributable to competitive inhibition by azapropazone of phenytoin p-hydroxylation. Protein-binding of phenytoin in the plasma (as assessed by salivary phenytoin concentrations) was significantly reduced from 92 to 90% by azapropazone and similar changes occurred in in vitro studies of [3H]-phenytoin protein binding.

Increased platelet membrane [3H]-LSD binding in patients on chronic neuroleptic treatment.

Using a [3H]-lysergic acid diethylamide [( 3H]-LSD) binding technique, platelet 5-hydroxytryptamine (5-HT) receptor number and affinity were compared in schizophrenics treated with depot thioxanthenes and phenothiazines and controls. There was an approximately 30% increase in platelet receptor number (Bmax) in the patient group. There was a decrease in affinity (increase in Kd) of about 30% in the patient group. This was probably due to the persistence of the neuroleptic in the platelet membrane preparation. There was a weak positive correlation between receptor number and total neuroleptic dosage. The increased number of 5-HT receptors is consistent with the previously reported enhancement of 5-HT-induced platelet aggregation in patients treated with long-term phenothiazines and thioxanthenes. Our findings are compatible with 5-HT up-regulation in human platelets produced by depot neuroleptic therapy. It is not known whether parallel changes may be occurring in brain 5-HT receptors.

Reduced latent inhibition in people with schizophrenia: an effect of psychosis or of its treatment.

BACKGROUND: People with schizophrenia show impaired attention. This could result from reduced latent inhibition (a measure of ability to filter out irrelevant stimuli). Previous studies have found reduced auditory latent inhibition in people with acute schizophrenia: we tested whether this results from psychosis or from drug treatment. METHOD: We measured auditory latent inhibition in two studies. One compared antipsychotic-naive people with acute schizophrenia with patients within two weeks of starting antipsychotic treatment. The second compared healthy volunteers given either saline or 1.0 mg haloperidol, intravenously. RESULTS: Latent inhibition was absent in treated patients, but was clearly present in patients who were naive to antipsychotics. Latent inhibition was absent in volunteers given haloperidol, but was clearly present in those given saline. CONCLUSIONS: The reduced auditory latent inhibition seen in acute schizophrenia is more plausibly due to antipsychotic treatment than to the disorder. Unless neuropsychological models of schizophrenia incorporate evidence from drug-free patients and drug-treated healthy controls, they may be invalid.

Decreased platelet 3H-imipramine binding sites in classical migraine.

Patients with classical migraine investigated between attacks had significantly fewer platelet 3H-imipramine binding sites than control subjects and this finding was more marked in males than in females. There was no abnormality of binding characteristics of platelet 5-hydroxytryptamine receptors or of platelet alpha 2-adrenoceptors. Because the reduced 3H-imipramine binding capacity was found in classical migraineurs who were investigated between attacks, it may reflect a predisposition to migraine rather than being a consequence of attacks.