James V. Dingell

A possible common mechanism of action of antidepressant treatments

SummaryThe response of the norepinephrine (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 electroconvulsive treatment (ECT) was investigated. Neither the basal level of cyclic AMP nor the hormonal response to NE were altered after the administration of a single dose or 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 metabolism and excretion of Δ9-tetrahydrocannabinol in the rat☆☆☆

Abstract THE AVAILABILITY of synthetic Δ9-tetrahydrocannabinol (THC), a psychotomimetic component of marihuana has stimulated the investigation of its behavioral effects and pharmacological actions. Recent reports have described the excretion of THC (1,2), the formation of the 11-hydroxy metabolite of THC by liver microsomes (3,4) and its excretion in urine (5). The present studies were undertaken to further investigate the fundamental aspects of the fate of THC in rats. These studies have confirmed the findings of Agurell et al , that in rats THC is excreted almost completely in feces as more polar metabolites. Moreover, evidence is presented which shows that THC disappears from the tissues of rats in a biphasic fashion. That is, immediately after its administration the levels of THC in rats decline very rapidly; after several hours, however, the compound disappears with a long half-life which resembles the rate of excretion of metabolites in urine and feces. Moreover, it appears that neither the hepatic metabolism nor excretion in bile are limiting factors in the excretion of metabolites of THC in feces. The rate of excretion of these compounds is probably determined by their rate of movement down the intestine possibly combined with an enterohepatic circulation.

The relative role of storage and synthesis of brain norepinephrine in the psychomotor stimulation evoked by amphetamine or by desipramine and tetrabenazine

SummaryThe relative role of storage and synthesis of brain norepinephrine in the psychomotor stimulation evoked by amphetamine or by desipramine and tetrabenazine has been investigated. The blockade of norepinephrine synthesis by the tyrosine hydroxylase inhibitor α-MT abolishes the central stimulatory action of amphetamine but not that evoked by tetrabenazine in DMI pretreated rats. In contrast, depletion of norepinephrine by α-MMT prevents the central stimulation evoked by the DMI-tetrabenazine combination but not that elicited by amphetamine. The α-methylated tyrosine derivatives do not interfere with either the metabolism of amphetamine and DMI or their entry into the brain. The results of the present studies, thus, are consistent with the views that the central action of amphetamine requires an uninterrupted synthesis of brain norepinphrine whereas a rapid release of norepinephrine from its storage sites is essential for the behavioral stimulation elicited by tetrabenazine in DMI pretreated rats.

On the significance of the increase in homovanillic acid (HVA) caused by antipsychotic drugs in corpus striatum and limbic forebrain.

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 > pimozide > chlorpromazine > thioridazine > 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 effects of aliphatic halogenated hydrocarbons on hepatic drug metabolism

Abstract Pretreatment of rats with CCl 4 prolonged the sleeping times evoked by hexobarbital. The metabolism of hexobarbital by the isolated perfused rat liver was reduced after intoxication with CCl 4 and may have been responsible, in part, for the enhanced action of the barbiturate. Poisoning with CCl 4 impaired the oxidation of hexobarbital and aminopyrine as well as the reduction of p -nitrobenzoic acid by liver microsomes. The activity of the drug-metabolizing enzymes declined to about 10 per cent of normal within 8 hr and remained at low levels 24 hr after the administration of CCl 4 . The return of enzyme activity to normal levels started coincident with the disappearance of CCl 4 from the liver and required about 8 days for completion. In contrast to the striking toxicity of carbon tetrachloride, drug metabolism was not reduced after the administration of methylene chloride, and chloroform evoked only a moderate impairment of aminopyrine demethylation.

The intracellular localization of Δ9-tetrahydrocannabinol in liver and its effects on drug metabolism in vitro

Abstract In the hepatic cell Δ 9 -tetrahydrocannabinol (THC) is localized in nuclei and microsomes. The intracellular binding of THC affects hepatic drug metabolism: nuclei markedly reduce the metabolism of THC by hepatic microsomes; THC inhibits the microsomal oxidation of aminopyrine and hexobarbital, the conjugation of estradiol and p -nitrophenol and enhances the reduction of p -nitrobenzoic acid. The metabolism of THC, in vitro , is strikingly inhibited by SKF-525A but not by desipramine, nortriptyline and iprindole which are potent inhibitors of the oxidation of other drugs.

On the mechanism of amphetamine potentiation by iprindole

Iprindol verstärkt und verlängert die psychomotorische Aktivität vond-Amphetamin in der Ratte, eine Potenzierung, die mit erhöhter Konzentration und verlängerter Halbwertszeit vond-Amphetamin in Gehirn und Körper einhergeht. Iprindol scheint ähnlich wie die Antidepressiva der Imipramin-Klasse den Stoffwechsel von Amphetamin in vivo zu hemmen.

Impairment of hepatic drug metabolism in calcium deficiency

Abstract The duration of action of hexobarbital but not that of barbital, a nonmetabolized barbiturate, is prolonged in calcium-deficient rats. This finding led to the investigation of the effects of calcium deprivation on drug metabolism in vitro . Calcium deficiency lowers the rate of metabolism of drugs by both oxidative and reductive pathways in liver microsomes. This impairment of hepatic drug metabolism appears to result from a decrease in the specific activity of the enzymes in the liver microsomes.

Methylation of desmethylimipramine by rabbit lung in vitro

Abstract Studies of the methylation of analogs of imipramine by N-methyltransferase are described. Desmethylimipramine and nortriptyline, both secondary amines, are rapidly methylated by an enzyme in the soluble fraction of rabbit lung. Desdimethylimipramine, a primary amine, is slowly methylated by this enzyme. Imipramine, although not a substrate for the transferase, enhances the methylation of an endogenous substrate.

Effect of triton X-100 on the conjugation of tetrahydrocortisone, in vitro.

Abstract The detergent, Triton X-100, increased the conjugation of estrone, estradiol and tetrahydrocortisone (THE) by uridine diphosphate glucuronyl transferase (UDPGT) in rat liver microsomes; the maximal increase of the conjugation of these substrates was measured when the concentration of Triton in the incubation mixtures was 0.05 per cent. However, the magnitude of the increase and the effect seen with varying Triton concentration were substrate dependent, which is consistent with the hypothesis that multiple forms of UDPGT may be present in hepatic microsomes. The effects of various compounds which had previously been shown to either increase or decrease the conjugation of THE in non-activated enzyme preparations were re-examined in Triton-activated preparations. Compounds such as β-diethylaminoethyldiphenylpropylacetate (SKF-525A) and 7-hydroxychlorpromazine which inhibited conjugation in non-activated preparations also inhibited conjugation in Triton-activated preparations. Alternatively, the demethylated metabolites of chlorpromazine, which increased activity in non-treated preparations, decreased activity slightly in preparations maximally stimulated by Triton. Bisubstrate kinetic analysis of the THE conjugation of UDPGT also revealed differences between the properties of the non-treated and Triton-activated enzyme preparations. Triton activation caused an increase in the V max of the reaction in the forward direction while having an insignificant effect on the dissociation constant for THE.