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Biomedical subjects

P Seeman

Publications and source records attributed to P Seeman.

At least 37 records · Page 2Linked to original sources
PubMed1978

Dopaminergic supersensitivity after neuroleptics: time-course and specificity.

It is known that a single dose of a neuroleptic can elicit dopaminergic supersensitivity in animals. On the other hand, the clinical syndrome of tardive dyskinesia takes many months of years to develop. To resolve this apparent discrepancy, it is possible that subclinical or latent tardive dyskinesia is fully compensated in most patients taking neuroleptics. In others, where the tardive dyskinesia is full-blown and grossly apparent, the dopaminergic supersensitivity may be decompensated. Such compensatory and decompensatory phases have been proposed earlier by Hornykiewicz (1974), in the case of Parkinson's Disease. Dopaminergic supersensitivity persists for a period proportional to the lenght of the neuroleptic treatment. It is not yet clear whether the relation between the length of treatment and the persistence of supersensitivity holds for very long treatments, but in principle the relationship might account for the persistence of tardive dyskinesia after years of neuroleptic pretreatment.

Animals↗
PubMed1978

Antiparkinsonian drug doses and neuroleptic receptors.

The clinical potency of 3 drugs, apomorphine, N-propylnorapomorphine, and bromocryptine, have been found to be closely correlated to their potencies in competing for 3H-haloperidol and 3H-spiroperidol both of which label the dopamine receptor. This correlation indicates that the direct binding assay may be used to predict clinical potencies of anti-parkinsonian drugs, and indicates that agonists as well as antagonists compete potently for 3H-neuroleptic binding.

Animals↗
PubMed1978

High-affinity 3H-serotonin binding to caudate: inhibition by hallucinogens and serotoninergic drugs.

The specific binding of 3H-serotonin to calf caudate homogenate was studied. The dissociation constant was 2nM and the number of specific sites was 14fmoles/mg protein. Of many drugs tested, inhibition of specific 3H-serotonin binding occurred almost exclusively with serotonin agonists and antagonists. The concentrations for 50% inhibition of 3H-serotonin binding by serotonergic agonists follow: bufotenin, 6nM; 5-methoxytryptamine, 12 nM; psilocin, 35nM; dimethyltryptamine, 220 nM; and tryptamine, 270 nM. The concentrations for the antagonists were: LSD 9.5 nM; methysergide 16nM and metergoline 25nM.

Animals↗
PubMed1978

The L-dopa on-off effect in Parkinson disease: treatment by transient drug withdrawal and dopamine receptor resensitization.

It has been suggested that patients with Parkinson disease partially compensate for neuron loss by developing denervation supersensitivity, and, if so, that prolonged levodopa (L-dopa) therapy might lead to desensitization. As a preliminary test of this hypothesis, and in order to study whether it was possible to "resensitize" a patient who had already presumably been desensitized by previous L-dopa therapy, a patient who had become unpredictably responsive to L-dopa was investigated. The patient had been taking L-dopa for eight years and had exhibited severe dyskinesia-akinesia oscillation ("on-off" phenomenon) before the study. There was no consistent response to his hourly doses of Prolopa (L-dopa and benserazide in a 4:1 ratio). He was first lowered, over 33 days, to 20% of his original Prolopa dose. The dosage was then increased until a consistent response was observed. The three main results achieved were, first, overall reduction by 64% of the daily requirement for L-dopa; second, conversion from a previously unpredictable to a predictable response to each dose of L-dopa; and, third, change in his movement fluctuations to a pattern more typical of "end-of-dose" akinesia than the "on-off" phenomenon. The results support the idea of dopamine receptor resensitization upon reduction of the L-dopa dosage.

Humans↗
PubMed1978

Selective labeling of serotonin receptors by d-[3H]lysergic acid diethylamide in calf caudate.

Since it was known that d-lysergic acid diethylamide (LSD) affected catecholaminergic as well as serotoninergic neurons, the objective in this study was to enhance the selectivity of [3H]LSD binding to serotonin receptors in vitro by using crude homogenates of calf caudate. In the presence of a combination of 50 nM each of phentolamine (added to preclude the binding of [3H]LSD to alpha-adrenoceptors), apomorphine, and spiperone (added to preclude the binding of [3H]LSD to dopamine receptors), it was found by Scatchard analysis that the total number of [3H]LSD sites went down to 300 fmol/mg, compared to 1100 fmol/mg in the absence of the catecholamine-blocking drugs. The IC50 values (concentrations to inhibit binding by 50%) for various drugs were tested on the binding of [3H]LSD in the presence of 50 nM each of apomorphine (A), phentolamine (P) and spiperone (S). With this combination, the IC50 for serotonin was 35 nM (compared to 1000 nM without it), indicating that [3H]LSD had become considerably more selectively displaceable by serotonin under these conditions whereas the effects of norepinephrine and dopamine on [3H]LSD binding were eliminated. Various ergots had approximately equal IC50 values against [3H]serotonin and [3H]LSD but tryptamines were much more selective against [3H]serotonin; the data may indicate the existence of the two types of serotonin receptors.

Animals↗
PubMed1978

Multiple receptors for brain dopamine.

This study was done to obtain direct in vitro evidence for the possible existence of more than one type of dopaminergic binding site in homogenates of the caudate nucleus from calf brain. Five radioligands for dopaminergic sites were tested. The inhibitions of two agonist radioligands ([3H]dopamine, [3H]apomorphine) by haloperidol, chlorpromazine, or piflutixol were biphasic. The inhibitions of [3H]haloperidol, [3H]spiroperidol, and [3H]dihydroergocryptine binding by dopamine and (-)-norepinephrine were also biphasic. Thus, both 3H-labeled agonists and 3H-labeled antagonists were possibly binding to two high-affinity sites.

Animals↗
PubMed1978

Selective labeling of alpha-adrenergic receptors in caudate nucleus by [3H] dihydroergocryptine in the presence of spiperone-blocked dopamine receptors.

Because it was known that [(3)H]dihydroergocryptine can label alpha-adrenergic receptors as well as dopamine receptors, this study was done to establish the conditions under which [(3)H]dihydroergocryptine would be a reliable ligand for selective labeling of alpha-adrenergic receptors. The calf caudate was chosen because it contains both dopamine and adrenergic receptors, and 5 nM spiperone (spiroperidol) was used to block the neuroleptic/dopamine receptors. Thus, in the presence of spiperone, [(3)H]dihydroergocryptine exhibited saturable binding with a K(d) of 0.73 nM and a total number of sites of 150 fmol/mg of protein. The catechol neurotransmitters competed for [(3)H]dihydroergocryptine binding in the potencies order epinephrine > (-)-norepinephrine > dopamine, indicating that [(3)H]dihydroergocryptine (in the presence of 5 nM spiperone) was revealing alpha receptors. The alpha-adrenergic antagonists also competed for binding in the appropriate order: phentolamine > phenoxybenzamine > dibenamine. Finally, chlorpromazine was more potent than haloperidol in competing for [(3)H]dihydroergocryptine, also in accord with the properties of alpha receptors. These results with [(3)H]dihydroergocryptine as an alpha-adrenergic receptor ligand correlate well with those published by others for [(3)H]WB-4101.

Adrenergic alpha-Antagonists↗
PubMed1978

Effect of haloperidol and apomorphine treatment on dopamine receptors in pituitary and striatum.

Prompted by an interest in the similarity of brain and tuberoinfundibular systems, the authors studied butaclamol-specific neuroleptic and apomorphine binding in pituitary and striatum after chronic haloperidol and acute apomorphine treatment. Striatal binding increases but pituitary binding decreases in haloperidol-treated rats. Pituitary binding changes rapidly in response to apomorphine exposure and striatal binding does not. These findings suggest that factors influencing binding differ in these two tissues.

Animals↗