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Biomedical subjects

P Seeman

Publications and source records attributed to P Seeman.

At least 253 records · Page 14Linked to original sources
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↗
PubMed1978

Dopamine receptors in the central nervous system.

Dopamine receptors in the central nervous system can be studied by measuring the specific binding of [3H]dopamine, [3H]haloperidol, d-[3H]LSD, [3H]dihydroergocryptine or [3H]apomorphine. The receptors are stereoselectively blocked by +)-butaclamol, a neuroleptic. All neuroleptics inhibit the specific binding of [3H]haloperidol in relation to their clinical potencies. The radioligand that desorbs most slowly from the receptor is [3H]apomorphine, thus making it a reliable ligand for dopamine receptors. Dopamine agonists that compete for [3H]apomorphine binding do so at concentrations that correlate with their potency in stimulating striatal adenylate cyclase. Structure-activity analysis, using [3H]apomorphine, confirms that the active dopamine-mimetic conformation is the beta rotamer of dopamine. Prolonged exposure in vitro of caudate homogenate to high concentrations of dopamine leads to increased binding of [3H]apomorphine or [3H]haloperidol, suggesting receptor "sensitization." Chronic haloperidol treatment of rats leads to an increased number of dopamine/neuroleptic receptors in the striatum, but a decrease in the pituitary.

Adenylyl Cyclases↗
PubMed1977

Alcohol tolerance in a cholinergic nerve terminal: relation to the membrane expansion-fluidization theory of ethanol action.

Phrenic nerve terminals from rats subjected to long-term ethanol treatment were more resistant to ethanol (in vitro) than terminals from sucrose-fed rats, as measured by the effect of ethanol on the frequency of miniature end plate potentials. Long-term ethanol exposure may thus induce the synthesis of more rigid membrane lipids, reducing membrane "fluidizability". This may provide a neurocellular basis for ethanol tolerance and cross-tolerance with anesthetics and barbiturates.

Animals↗
PubMed1977

Tolerance of haloperidol catalepsy.

Haloperidol (0.75 and 1.5 mg/kg p.o.) was administered daily for 16 days to male Wistar rats. The animals received an acute injection of haloperidol (0.5-2.0 mg/kg i.p. or 1.0-4.0 mg/kg p.o.) and catalepsy was measured. After 16 days on haloperidol, all animals became tolerant to the drug, exhibiting decreased cataleptic response to haloperidol; the intensity of catalepsy returned to normal after an additional 16 days abstinence from the drug. In addition, a group of animals treated and tested daily for catalepsy demonstrated that the time course of tolerance development to haloperidol was biphasic, with a rapid phase (T1/2 = 2.5 days) and a slower phase (T1/2 = 5.5 days).

Administration, Oral↗
PubMed1977

New detection of brain dopamine receptors with (3H)dihydroergocryptine.

Because dihydroergocryptine (DHE) and closely related ergots are dopamine-mimetic agonists, we tested [3H]DHE as a possible ligand for [3H]dopamine receptors in the calf caudate. In order to avoid [3H]DHE from tagging alpha-adrenergic receptors, an excess of 500 nM phentolamine was used to block these sites, permitting the dopamine receptors to be measured separately. Specific binding of [3H]DHE was defined as total binding minus that occurring in the presence of 1 muM (+)-butaclamol. Excess phentolamine reduced the specific binding of [3H]DHE from 328 down to 138 fmol/mg, the difference presumably representing alpha-receptors. The KD for [3H]DHE was 0.55 nM (with or without phentolamine), and this high affinity site was blocked (in the presence of phentolamine) by 250nM apomorphine, 650 nM dopamine, and 1200 mM (minus)-norepinephrine, indicating that[3H]DHE was binding to dopamine receptors. All neuroleptics blocked specific [3H]DHE binding in direct relation to the clinical potency of the neuroleptic. The displacement of specific [3H]DHE binding by dopamine or by norepinephrine (in the presence of phentolamine) revealed two subsets of dopamine receptors.

Animals↗
PubMed1977

Conduction-blocking concentrations of anesthetics increase with nerve axon diameter: studies with alcohol, lidocaine and tetrodotoxin on single myelinated fibers.

The equilibrium blocking concentrations of benzyl alcohol, lidocaine and tetrodotoxin just sufficient to block nerve impulse conduction were determined on myelinated single fibers of the bullfrog. For all three anesthetics it was found that the fastest conducting fibers (45 m/sec; about 18 micron diameter) required about 4 times higher blocking concentrations than the slowest fibers (8 m/sec; about 3 micron diameter). The drugs did not affect the frog sciatic nerve length constant (2 mm), using tetrodotoxin to block the action potential. In agreement with Uehara's single fiber study using urethane (Uehara, Y.:Jap. J. Physiol. 10: 267-274, 1960), it is concluded that smaller myelinated fibers are more sensitive to anesthetic blockade.

Action Potentials↗