Faculty Bibliography

Low doses of the dopamine agonist ET-495 were administered to nonpsychotic volunteer subjects by slow intravenous infusion, followed by a bolus of 1.5--2.5 mg haloperidol. ET-495 caused progressive dysphoria and sedation (in some cases, light sleep), effects believed to be mediated by dopaminergic inhibition. However, ET-495 also elevated growth hormone and suppressed prolactin, typical responses to dopamine agonist activity. Haloperidol reversed both the sedation and prolactin suppression induced by ET-495. These findings suggest: (1) that the sedation and hormonal responses were produced by stimulation of dopamine receptors; (2) that neurotransmitter systems mediating behavioral and neuroendocrine regulation may have differential neuropharmacological characteristics

The effects of the antipsychotic/antidepressant drug CI-686 on apomorphine- and amphetamine-induced stereotypies, dopamine metabolism, neuroleptic binding, and serum prolactin levels were determined. CI-686 displayed profiles of activity in each of these systems that differs markedly from those of other antipsychotics. CI-686's unique preclinical profile suggests a mechanism of action other than dopamine antagonism which could have implications regarding current thinking on the pathophysiology of schizophrenia

Direct administration of met-enkephalin into brain elicits behavioral effects which are short-lived, suggesting that, like other putative neurotransmitters, it is rapidly degraded. We now report on the purification and partial characterization of an enzyme (tentatively designated ML-enkephalinase) from human corpora striata that has a marked preference for met-enkephalin as substrate, inactivating it by cleaving the tyr-gly bond. The data presented strongly support the contention that metenkephalin can be rapidly degraded by enzymes in human brain. The enzyme we have purified appears to be a soluble, freeze-sensitive, metalloenzyme, with a M.W. = 61,500 daltons. The enzyme shows a high degree of specificity; met-enkephalin is preferred over other substrates tested; and cleavage at the tyr-gly bond appears to be the major (or only) reaction catalyzed. Studies with inhibitors differentiate this enzyme from previously characterized peptidase as well as from several enzymes in other species reported to degrade met-enkephalin. Our data suggest that this enzyme may play a key role in physiologic enkephalin homeostasis in man

A one-to-one relationship between clinical antipsychotic potency and pharmacologic dopaminergic antagonism is implicit in the dopamine hypothesis of neuroleptic action. Thiethylperazine maleate, a classical antiemetic phenothiazine, displays dopaminergic antagonism in behavioral, neurochemical, and neuroendocrine systems, but is paradoxical insofar as it is thought not to possess clinical neuroleptic activity. In three tests of dopaminergic antagonism--elevation of levels of CSF homovanillic acid in monkeys, striatal dihydroxyphenylacetic acid in rats, and prolactin in man--as well as in a clinical trial of neuroleptic efficacy in schizophrenics, thiethylperazine was fully active and approximately three times as potent as chlorpromazine. Differences in efficacy between this and earlier clinical studies can be accounted for on the basis of dosage

Prolactin levels were determined in plasma samples obtained before and after administration of apomorphine or L-dopa to otherwise unmedicated chronic schizophrenic patients or control subjects. Basal prolactin levels did not differ in these two groups. Suppression of prolactin levels after each dopamine agonist was highly significant. Suppression in schizophrenics was slightly less than in controls following apomorphine and slightly greater following L-dopa. The authors discuss the implications of these findings as well as the limitations of the prolactin regulatory system as an index of dopamine agonist sensitivity