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The effect of various antipsychotic drugs on the blockade of dopaminergic receptors in striatum and limbic forebrain was examined by establishing dose-response curves for the increase in HVA and for the antagonism of d-amphetamine-induced rotation in rats with unilateral lesions of the substantia nigra. A good quantitative correlation was found between dopaminergic blockade in the striatum as reflected by the ED100 for striatal HVA increase and the ED50 for rotational antagonism and the occurrence of extrapyramidal side effects in man. The ED100 for the increase in HVA in the limbic forebrain showed the same rank order of potency as those in the striatum: Haloperidol greater than primozide greater than chlorpromazine greater than thioridazine greater than clozapine. The results thus demonstrate a very good correlation between the degree of dopaminergic blockade and the increase of extrapyramidal side effects in man, but suggest the possibility of a dissociation between dopaminergic blockade and antipsychotic activity.

The glucuronide of 7-hydroxychlorpromazine (CPOH), formed by incubation with hepatic microsomes and UDP-[U-14C]glucuronic acid, was isolated by extraction into 1-butanol at pH 1 and assayed by liquid scintillation counting. Although concentrations of CPOH greater than 3 X 10(-4) M stimulated its conjugation, the apparent KM of the transferase in microsomes from guinea pig liver for CPOH was 9.5 X 10(-5) M. The apparent activation of glucuronyltransferase by high concentrations of CPOH was prevented when preparations were maximmally stimulated by Triton X-100. The rate of conjugation of CPOH by preparations of guinea pig liver was almost twice that measured with those of rat liver. However, the maximal stimulation of the conjugation of CPOH by Triton with preparations of rat liver was almost twice that observed with microsomes from guinea pig liver. The conjugation of CPOH by microsomes from rat and guinea pig liver was inhibited about 25% by SKF 525-A (1 X 10(-4) M). The inhibitory action of SKF 525-A decreased at concentrations greater than 5 X 10(-4) M and no inhibition was observed at 1 X 10(-3) M.

The response of the noNEpinephrine (NE) sensitive cyclic AMP generating system in slices of the rat limbic forebrain after both the acute and chronic administration of the tricyclic antidepressants desipramine (DMI) and iprindole as well as electro-convulsive treatment (ECT) was investigated. Neither the basal level of cyclic AMP nor the hormonal response to NE were altered after administration of a single dose of short term treatment with DMI and iprindole. However, the administration of the antidepressants on a clinically more relevant time basis markedly reduced the sensitivity of the cyclic AMP generating system to NE. This change in sensitivity was not related to the levels of the drugs in brain. The response of cyclic AMP to NE was also reduced by ECT, but the onset of this action was shorter than that observed with the antidepressants. ECT also antagonized the enhanced response of cyclic AMP to NE following destruction of central adrenergic nerve terminals with 6-hydroxydopamine. It thus appears that the therapeutic action of tricyclic antidepressants could be related to postsynaptic adaptive changes in the sensitivity of the noradrenergic adenylate cyclase receptor system rather than to acute presynaptic events.

The methylated metabolites of diethylstilbestrol (DES) were formed by incubation with S-adenosyl-(3H-methyl)-L-methionine (SAM) and preparations of rat liver. Formation of the O-methyl-catechol metabolite required the 10,000 g supernatant fraction, NADPH and SAM. The nonionic detergent Triton X-100 (0.025%, v/v) did not affect the activity of the methyltransferase but stimulated glucuronyltransferase and inactivated the mixed function oxidases. Thus, incubation with Triton abolished methylation of DES by the 10,000 g supernatant fraction, but methylation and glucuronidation of DES was observed when incubated with microsomes and NADPH and reincubated with Triton, soluble fraction, UDP-glucuronic acid and SAM. Since DES itself was not methylated by the soluble fraction, the results suggest that DES is oxidized by mixed function oxidases to a catechol which is methylated and then glucuronidated. Results of reincubation studies support this sequence. Methylation does not impair glucuronidation of the catechol but glucuronidation prevents its methylation.

The major classes of lipoprotein, very low density, low density, and high density, as well as the lipoprotein-free protein were isolated from plasma by rate-zonal centrifugation. Fractionation of plasma after the addition of delta9-tetrahydrocannabinol (THC) showed that over 60% of the drug is associated with the lipoprotein; the remainder of the drug appears to be bound by albumin. In human plasma the low density lipoprotein is the major lipoprotein; in rat plasma the very low density and high density lipoproteins predominate. The distribution of THC in the lipoprotein reflected this species difference. In both species the distribution of THC among the lipoproteins appears to be related to their content of neutral lipid or total lipid rather than that of phospholipid or protein. Fractionation of plasma after the addition of estradiol, imipramine, prostaglandin E2, digitoxin, or dicumarol demonstrated that the lipoproteins contribute little to their binding. Thus, even among lipid-soluble compounds, the binding of THC in plasma is unusual.