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The correlation between the clinical activity of antipsychotic agents and their affinity for the D2 dopamine receptor has been the mainstay of the hypothesis that schizophrenia is due to excessive dopaminergic function. More recently, the unique clinical profile of the atypical antipsychotic clozapine has been proposed to involve actions on additional receptor systems. In particular, the high affinity of clozapine for the 5HT2A receptor subtype has been suggested to contribute to its reduced side-effect liability, greater efficacy and its activity in therapy-resistant schizophrenia. We have used the highly selective 5-HT2A antagonist MDL 100,907 to explore the contribution of 5-HT2A receptor blockade to antipsychotic activity. Biochemical, electrophysiological and behavioral studies reveal that selective 5HT2A receptor antagonists have the preclinical profile of an atypical antipsychotic. The limited clinical evidence available also suggests that compounds producing 5-HT2A receptor blockade are effective, in particular, against the negative symptoms of schizophrenia.

A method is described for the simultaneous analysis of S-adenosylmethionine (SAM) and its metabolites, S-adenosylhomocysteine (SAH) and decarboxylated S-adenosylmethionine along with the natural polyamines, putrescine, spermidine and spermine. The separation is obtained by a reversed-phase ion-pair liquid chromatographic procedure with gradient elution followed by dual detection. The UV absorbance at 254 nm is used for the analysis of SAM and of the SAM metabolites, whereas the polyamines and some major amino acids, e.g., methionine, tyrosine and tryptophan, are analyzed by fluorescence detection after UV-cell derivatization with o-phthalaldehyde. A separate ion-pair reversed-phase high-performance liquid chromatographic (HPLC) procedure using isocratic elution and electrochemical detection is employed to analyse in the same tissue extracts the catechols and 5-hydroxyindoles, 3,4-dihydroxyphenylalanine (DOPA), dopamine, norepinephrine, 3,4-dihydroxyphenylacetic acid, homovanillic acid, 4-hydroxy-3- methoxyphenylalanine , tryptophan, 5-hydroxytryptophan, serotonin and 5- hydroxyindolacetic acid. The sample preparation for the two HPLC procedures requires only homogenization of the tissues in perchloric acid and centrifugation before injection onto the column. The two chromatographic procedures have been applied to study the interrelationship, in various tissues of rats, between the SAM and SAH levels and the biogenic catechols after different treatments with L-DOPA alone or in combination with alpha- monofluoromethyl -DOPA, a potent enzyme-activated irreversible inhibitor of aromatic L-amino acid decarboxylase.

We hypothesised that it would be possible to prevent the development of post-synaptic dopamine receptor supersensitivity to 6-hydroxydopamine lesions of the nigro-striatal tract in rats if they were constantly infused with the dopamine agonist apomorphine. Using osmotic minipumps to infuse apomorphine for 15 days in unilaterally lesioned rats, it was possible to delay the development of supersensitivity of the lesioned side for 9 days but not to prevent its eventual appearance. At the same time, evidence for the development of subsensitivity of presynaptic dopamine receptors of the intact side following chronic infusion of apomorphine was inferred from the production of rotations directed towards the lesioned side.

Gamma-vinyl GABA, an inhibitor of GABA-transaminase, produced a dose-related reduction of food intake in rats, after both single, (125-1000 mg/kg IP or 500 mg/kg PO) and repeated (250 mg/kg/day IP) administration. No tolerance was observed to the effect of repeated injections. Catecholamine and indoleamine systems in the CNS do not appear to be implicated in this anorexic effect. Combination of gamma-vinyl GABA with amphetamine (2.5 mg/kg) enhanced the anorexic effects of the latter compound whilst attenuating its stimulant effects. The data suggest an important role for GABA in the control of food intake.