Inhibition of both noradrenergic and serotonergic neurons in brain by the alpha-adrenergic agonist clonidine.

The catechol-O-methyltransferase polymorphism: relations to the tonic-phasic dopamine hypothesis and neuropsychiatric phenotypes.

Central α-adrenergic systems as targets for hypotensive drugs

Kinetics of pharmacologic response.

A large dose of intravenous methamphetamine hydrochloride reproduced the amphetamine psychosis in 12 of 14 patients dependent on amphetamine sulfate and failed to produce a psychosis in two patients who were eventually found to have not used amphetamine regularly above the therapeutic dose range. The psychosis was the facsimile of the disorder observed during drug abuse—a schizophrenic-like state of paranoia in a setting of clear consciousness accompanied by auditory or visual hallucinations, or both, but without thought disorder. Since in some cases the onset of the psychosis was sudden and occurred within one hour of commencing the intravenous injection, hypotheses about depletion of catecholamines and long term metabolites may need to be reconsidered.

The Experimental Reproduction of Amphetamine Psychosis

Pharmacokinetic studies of the amphetamine-like drugs have predominantly been made by using urinary excretion data (Beckett & others, 1968, 1969). The urinary excretion of amphetamine and related drugs depends largely on the lipid solubility of the undissociated form which amount is in turn governed by the degree of ionization of the drug at the urinary pH. From a search of the literature it appeared that only for some amphetamines have pK, values been determined, whereas information on lipid solubility was even more scarce. The pKa values of amphetamine, N-alkyl derivatives and related CNS stimulants were measured according to Leffler, Spencer & Burger (1954) using 0.1 mmol of the HC1 salt of the drug. The apparent partition coefficient (APC) in chloroform-water and heptane-water were measured in Teorell buffer of various pH values such that the concentration of drug in the organic and water layer was roughly the same. The concentrations of drug were measured by gas chromatography. The apparent partition coefficient at pH 7.4 and the true partition coefficient (TPC) being the partition coefficient of the The latter is measured by the pKa value.

Some physico-chemical properties of amphetamine and related drugs.

Intracerebral injection of 1 Μl volumes of solutions containing noradrenaline, clonidine, oxymetazoline and phentolamine were performed in the antero-lateral hypothalamus of the Wistar rat at the level of the pars infracommissuralis of the Stria terminalis. Intrahypothalamic clonidine in a dose as low as 1 Μg strongly increased food intake in satiated rats. Clonidine (4 Μg) was more potent than noradrenaline (12 Μg) but as potent as oxymetazoline (1.5 Μg). The clonidine induced eating response was completely blocked by the α-sympatholytic drug phentolamine. The results emphasize the role of clonidine as an activator of noradrenaline receptors in the central nervous system.

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Clonidine induced intrahypothalamic stimulation of eating in rats.

Bizarre social behaviour in rats induced by a combination of a peripheral decarboxylase inhibitor and DOPA.

A method is described with which it is possible to measure locomotor activity and food intake simultaneously in the same rat or other small animal. From a study of a number of psychomotorstimulant drugs and anorectic agents it may be concluded that locomotorstimulation and appetite-suppression are two different effects that may or may not characterize the same drug. Methamphetamine and phenmetrazine are stimulants in doses that do not inhibit food intake. Amphepramon reduced food intake in low doses but acts as a stimulant in higher doses. Chlorphemternine and phenfluramine are anorectic agents that are not stimulants, even in high doses.

Locomotor activity and anorexogenic action

Clonidine, a closely related analogue of the sympathomimetic imidazolines reduces heart rate and lowers blood pressure in animals as well as in patients with hypertension (Hoefke & Kobinger, 1966; Michel, Zimmerman & others, 1966). There is evidence that clonidine acts in the central nervous system (Sherman, Greca & others, 1968; Shaw, Hunyor & Korner, 1971) by activation of noradrenaline receptors (Schmitt & Schmitt, 1969, 1970; Kobinger & Walland, 1971). Although the findings indicate a central site of action in bulbar or diencephalic structures (Schmitt & Schmitt, 1969; Shaw & others, 1971), clonidine has not been studied after intracerebral application. We have injected clonidine via stereotaxically implanted cannulas directly into various areas of the hypothalamus in anaesthesized rats while blood pressure and heart rate were recorded simultaneously on a Grass polygraph. Most of the injections were made 2.5-3.5 mm anterior and 2.42.8 mm below the interaural line and 0.5-0.7 mm lateral acording to the atlas of Konig & Klippel (1963). Details of the experimental procedure will be published elsewhere.

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J. M. van Rossum

Papers

Some physico-chemical properties of amphetamine and related drugs.

Clonidine induced intrahypothalamic stimulation of eating in rats.

Bizarre social behaviour in rats induced by a combination of a peripheral decarboxylase inhibitor and DOPA.

Locomotor activity and anorexogenic action

Clonidine-induced cardiovascular effects after stereotaxic application in the hypothalamus of rats