The Pharmacological Basis of Therapeutics A Textbook of Pharmacology, Toxicology and Therapeutics for Physicians and Medical Students. By Prof. Louis Goodman and Prof. Alfred Gilman. Pp. xiii + 1383. (New York: The Macmillan Company, 1941.) 50s. net.

The Pharmacological Basis of Therapeutics

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 for the treatment of positive symptoms. A contribution of the new dopamine receptor subtypes D3 and in particular D4 receptors has been proposed.

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

Dopamine receptors: Molecular biology, biochemistry and behavioural aspects

Objective: To determine whether clomipramine hydrochloride, a serotonin reuptake blocker with unique antiobsessional properties, is differentially effective for obsessivecompulsive and stereotyped motor behaviors in autistic disorder compared with placebo and with the noradrenergic tricyclic antidepressant agent, desipramine hydrochloride. Design: Following a 2-week, single-blind placebo washout phase, 12 autistic subjects completed a 10week, double-blind, crossover comparison of clomipramine and placebo, and 12 different subjects completed a similar comparison of clomipramine and desipramine. Setting: Outpatient clinic. Patients: A referral sample of 30 male and female autistic patients were enrolled, and 24 completed the study. Measures: Key outcome measures were the Autism Relevant Subscale of the Children's Psychiatric Rating Scale, the Modified Comprehensive Psychopathological Rating Scale—Obsessive-Copulsive Disorder Subscale, and the Clinical Global Impressions Scale. Results: Clomipramine was superior to both placebo and desipramine on ratings of autistic symptoms (including stereotypies), anger, and compulsive, ritualized behaviors (P Conclusion: Biological links between compulsions and stereotyped, repetitive behaviors in autistic disorder should be explored.

A Double-blind Comparison of Clomipramine, Desipramine, and Placebo in the Treatment of Autistic Disorder

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.

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

Pretreatment with quipazine, a serotonin agonist, and clomipramine, a selective serotonin neuronal uptake blocker, was found to potentiate the cataleptic effect of haloperidol in a dose-dependent manner in rats. Pretreatment with methysergide, a serotonin antagonist, reduced the cataleptic effect of haloperidol. The results indicate that the cataleptic effect of neuroleptics depends on the balance between the dopaminergic and serotonergic systems, and that the serotonergic system exerts an inhibitory influence on the dopaminergic system.

Effect of drugs influencing central serotonergic mechanisms on haloperidol-induced catalepsy.

Intraperitoneally administered morphine induced catalepsy in mice. Morphine pretreatment however, failed to antagonize apomorphine-induced cage climbing behaviour thereby ruling out the possibility of its possessing DA receptor blocking activity. Pretreatment with L-histidine, a precursor of histamine, and atropine, potentiated the cataleptic effect of morphine whilst pretreatment with chlorcyclizine, an H1 receptor blocker, and naloxone, a morphine antagonist, antagonized morphine-catalepsy. Pretreatment with metiamide, an H2 receptor blocker, and methysergide, a 5-HT antagonist, did not significantly alter the cataleptic effect of morphine. The results with L-histidine and chlorcyclizine suggest an involvement of central histaminergic mechanisms in the cataleptogenic effect of morphine in mice. Further, as the cataleptic effect of morphine was also antagonized by naloxone it appears that the interaction of morphine with the central histaminergic mechanisms is mediated through specific opiate receptors.

Involvement of histaminergic mechanisms in the cataleptogenic effect of morphine in mice

Pretreatment with l-tryptophan, a precursor of serotonin, was found to decrease the intensity of stereotyped behavior induced by methamphetamine, while methysergide, a serotonin antagonist, was found to increase the intensity of methamphetamine-induced stereotyped behavior. These results suggest that the intensity of methamphetamine-induced stereotypy depends on the balance between central dopaminergic and serotonergic systems and that the central serotonergic system may have an opposing, tonic effect upon central dopaminergic systems involved in the mediation of stereotypy. In contrast to l-tryptophan, however, pretreatment with quipazine, a serotonin agonist, and clomipramine, a selective, serotonin neuronal uptake blocker, was found to potentiate the stereotyped behavior induced by methamphetamine. The probable mechanisms by which quipazine and clomipramine might have potentiated the methamphetamine-induced stereotypy are discussed.

Effect of drugs influencing central serotonergic mechanisms on methamphetamine-induced stereotyped behavior in the rat.

Effect of L-histidine and chlorcyclizine on apomorphine-induced climbing behaviour and methamphetamine stereotypy in mice.

Rationale
5-Hydroxytryptamine, via stimulation of 5-HT2C receptors, exerts a tonic inhibitory influence on dopaminergic neurotransmission, whereas activation of 5-HT2A receptors enhances stimulated DAergic neurotransmission. The antidepressant trazodone is a 5-HT2A/2C receptor antagonist.

J. H. Jadhav

Papers

Effect of drugs influencing central serotonergic mechanisms on haloperidol-induced catalepsy.

Involvement of histaminergic mechanisms in the cataleptogenic effect of morphine in mice

Effect of drugs influencing central serotonergic mechanisms on methamphetamine-induced stereotyped behavior in the rat.

Effect of L-histidine and chlorcyclizine on apomorphine-induced climbing behaviour and methamphetamine stereotypy in mice.

Effects of the antidepressant trazodone, a 5-HT 2A/2C receptor antagonist, on dopamine-dependent behaviors in rats.