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Biomedical subjects

P Seeman

Publications and source records attributed to P Seeman.

At least 145 records · Page 8Linked to original sources
PubMed1987

Dopamine receptors and the dopamine hypothesis of schizophrenia.

The discovery of neuroleptic drugs in 1952 provided a new strategy for seeking a biological basis of schizophrenia. This entailed a search for a primary site of neuroleptic action. The Parkinsonian effects caused by neuroleptics suggested that dopamine transmission may be disrupted by these drugs. In 1963 it was proposed that neuroleptics blocked "monoamine receptors" or impeded the release of monoamine metabolites. The neuroleptic concentration in plasma water or cerebrospinal fluid was of the order of 2 nM for haloperidol in clinical therapy. A systematic research was made between 1963 and 1974 for a primary site of neuroleptic action which would be sensitive to 2 nM haloperidol and stereoselective for (+)-butaclamol. Direct evidence that neuroleptics selectively blocked dopamine receptors occurred in 1974 with the finding that nanomolar concentrations of these drugs stereoselectively inhibited the binding of [3H]-dopamine or [3H]-haloperidol. These binding sites, now termed D2 dopamine receptors (which inhibit adenylate cyclase), are blocked by neuroleptics in direct relation to the antipsychotic potencies of the neuroleptics. No such correlation exists for D1 receptors (which stimulate adenylate cyclase). Based on the fact that dopamine-mimetic drugs elicited hallucinations, and that neuroleptics caused rigidity, Van Rossum in 1966 had suggested a hypothesis that dopamine pathways may be overactive in schizophrenia. The D2-selective blockade by all neuroleptics (except the monoamine-depleting reserpine) provided strong support for the dopamine hypothesis. Further support now comes from postmortem data and in vivo positron tomographic data, both of which indicate that the density of D2 receptors are elevated in the schizophrenic brain. The postmortem data indicate a bimodal pattern with half the schizophrenics having striatal D2 densities of 14 pmol/g (control is 13 pmol/g) and the other half having 26 pmol/g. Current positron tomographic data indicate D2 densities of 14 pmol/g in control subjects, but values of 34 pmol/g in drug-naive schizophrenics. Future tests of the dopamine hypothesis of schizophrenia may entail an examination of the amino acid composition and genes for D2 receptors in schizophrenic tissue, an examination of the ability of the D2 receptor to become phosphorylated and to desensitize into the low-affinity state, and an examination of the interaction of D2 receptors with D1 receptors or other neurotransmitters.

Antipsychotic Agents↗
PubMed1987

Human brain dopamine receptors in children and aging adults.

Since spontaneous oral dyskinesias are more prevalent in the elderly, and since these movements may be controlled by the balance of brain dopamine D1 and D2 dopamine receptors, we measured the densities of these receptors in 247 postmortem brain striata. In childhood, the densities of D1 and D2 dopamine receptors in the brain striatum rise and fall together. After age 20 years, D1 receptors disappear at 3.2% per decade while D2 receptors disappear at about 2.2% per decade. Overall, therefore, the D1/D2 ratio falls with age. Since perioral motion in rats is dominated by a high D1/D2 ratio, the observed decline in the human D1/D2 ratio with age suggests that the perioral control mechanisms for humans and rats may be different.

Aged↗
PubMed1987

The absolute density of neurotransmitter receptors in the brain. Example for dopamine receptors.

Since the absolute density of dopamine receptors can vary in disease, it is essential to establish the normal values for the absolute densities of D1 and D2 receptors in the brain. Absolute densities are most conveniently reported in units of picomoles per gram of original tissue, readily permitting their comparison to data obtained by positron emission tomography in patients. The density of D1 receptors is approximately 120 pmol/g in the rat striatum and 19 pmol/g in the human striatum. The density of D2 receptors is about 32 pmol/g in the rat striatum and 14 pmol/g in the human striatum, these values being determined by Teflon-glass homogenization and the centrifugation method. The customary Polytron-homogenization procedure results in a loss of about 9% of the D2 receptors in rat tissue and about 28% in human tissues; filtration results in a further loss of about 12%. There is general agreement between the in vitro and in vivo densities, but only if the receptors are measured by the amount of radioisotope specifically displaced.

Animals↗
PubMed1987

Human brain D1 and D2 dopamine receptors in schizophrenia, Alzheimer's, Parkinson's, and Huntington's diseases.

Because dopamine D2 receptors are known to be elevated in schizophrenic brain striata, this study examined whether a similar dopamine receptor elevation occurred in other diseases including neuroleptic-treated Alzheimer's and Huntington's diseases. The average D1 density in postmortem striata from Alzheimer's patients was 17.6 +/- 0.1 pmol/g, similar to an age-matched control density of 16.6 +/- 0.4 pmol/g. The average D1 density in schizophrenia patients was 19.0 +/- 0.6 pmol/g, similar to the age-matched control density of 17.9 +/- 0.6 pmol/g. In Parkinson's disease patients, however, the D1 receptor density was elevated, with values of 22.8 +/- 1.2 pmol/g (in patients not receiving L-DOPA) and 19.6 +/- 1.5 pmol/g (in patients receiving L-DOPA) compared to the age-matched control density of 16.0 +/- 0.4 pmol/g. The D2 receptors in Alzheimer's striata averaged 13.4 +/- 0.6 pmol/g (in patients who had not received neuroleptics), almost identical to the control density of 12.7 +/- 0.3 pmol/g. The average D2 density in neuroleptic-treated Alzheimer's striata was 16.7 +/- 0.7 pmol/g, an elevation of 31%, the individual values of which had a normal distribution. In Parkinson's disease patients, the D2 densities were elevated in tissues from patients not receiving L-DOPA (19.9 +/- 1.5 pmol/g in putamen and 14.8 +/- 1.2 pmol/g in striatum) compared to the age-matched control values of 13.0 +/- 0.4 pmol/g and 12.6 +/- 0.3 pmol/g, respectively. In Huntington's disease patients, the D2 density averaged 7.5 +/- 0.4 pmol/g in patients who had not received neuroleptics, but was 10.3 +/- 0.6 pmol/g in those who had. Although all of the D1 and D2 densities in each of the above diseases and subgroups revealed a normal distribution pattern, the D2 densities in schizophrenia displayed a bimodal distribution pattern, with 48 striata having a mode at 14 pmol/g, and the other 44 striata having a mode at 26 pmol/g. Thus, compared to the neuroleptic-induced and unimodal elevations in D2 of 31% in Alzheimer's disease and 37% in Huntington's disease, the schizophrenic striata with a mode of 26 pmol/g (105% above control) appear to contain more D2 receptors than can be accounted for by the neuroleptic administration alone.

Adult↗
PubMed1987

Dopamine D1 and D2 receptors are sensitive to the cationic form of apomorphine.

The protonated form of apomorphine was found to be active at the high affinity state of dopamine D1 and D2 receptors in canine striatum, since pH reduction from 7.4 to 6.4 enhanced the apomorphine potency 3-fold at both these sites without affecting the potency of the permanently charged apomorphine methiodide. It was estimated that the protonated form of apomorphine was approximately 20-fold more potent than the uncharged form of apomorphine at both the D1 and the D2 receptors.

Animals↗
PubMed1987

Response of tardive and L-dopa-induced dyskinesias to antidepressants.

We report two patients with dyskinesia responding to antidepressants. The first is a 70-year-old man with depression, Parkinsonism and neuroleptic-induced tardive dyskinesia who presented with hysterical mutism. After recovery from the mutism, he was started on desipramine for depression. One week later the dyskinesia improved markedly. The second patient is a 61-year-old man with Parkinson's disease, dementia, depression and L-dopa-induced oro-lingual-facial dyskinesias. He was taking levodopa, trihexyphenydil and bromocriptine. The depression was treated first with desipramine and later with trazodone. The dyskinesia improved significantly on both drugs. The response of the dyskinesias to antidepressant medication may be due to the fact that antidepressants decrease beta-adrenoreceptor sensitivity and density which in turn may result in a diminished release of dopamine since beta-adrenoceptors mediate the noradrenaline-stimulated release of dopamine.

Aged↗
PubMed1986

Photoaffinity labelling of dopamine D2 receptors by [3H]azidomethylspiperone.

We have characterized the dopamine D2 receptor photoaffinity probe, [3H]azido-N-methylspiperone ([3H]AMS). In the absence of light, [3H]AMS bound reversibly and with high affinity (Kd 70 pM) to sites in canine striatal membranes and was competitively inhibited by dopaminergic agonists and antagonists with an appropriate D2 receptor specificity. Upon photolysis, [3H]AMS covalently incorporated into a peptide of Mr 92,000 as assessed by fluorography following SDS-polyacrylamide gel electrophoresis. Labelling of this peptide was specifically and stereoselectively blocked by D2 antagonists and agonists. Minor specifically labelled peptides of Mr 70,000-55,000 were observed under some conditions and were the result of proteolytic degradation of the peptide at Mr 92,000.

Affinity Labels↗
PubMed1986

Age-related changes of beta-adrenoceptors in spleen lymphocytes and cerebral cortex of NZB/BIN mice.

The density (Bmax) of beta-adrenoceptors in splenic lymphocytes of NZB/BIN mice decreased up to an age of about 40 weeks and then levelled out. The Bmax in cerebral cortex, on the other hand, increased in the first half of life and then changed relatively little. The dissociation constant of the ligand (Kd) was larger in the cortex than the spleen and showed relatively little age-dependent change.

Aging↗
PubMed1986

Dopamine D1 receptors characterized with [3H]SCH 23390. Solubilization of a guanine nucleotide-sensitive form of the receptor.

Dopamine D1 receptors were solubilized from canine and bovine striatal membranes with the detergent digitonin. The receptors retained the pharmacological characteristics of membrane-bound D1 receptors, as assessed by the binding of the selective antagonist [3H]SCH 23390. The binding of [3H]SCH 23390 to solubilized receptor preparations was specific, saturable, and reversible, with a dissociation constant of 5 nM. Dopaminergic antagonists and agonists inhibited [3H]SCH 23390 binding in a stereoselective and concentration-dependent manner with an appropriate rank order of potency for D1 receptors. Moreover, agonist high affinity binding to D1 receptors and its sensitivity to guanine nucleotides was preserved following solubilization, with agonist dissociation constants virtually identical to those observed with membrane-bound receptors. To ascertain the molecular basis for the existence of an agonist-high affinity receptor complex, D1 receptors labeled with [3H] dopamine (agonist) or [3H]SCH 23390 (antagonist) prior to, or following, solubilization were subjected to high pressure liquid steric-exclusion chromatography. All agonist- and antagonist-labeled receptor species elute as the same apparent molecular size. Treatment of brain membranes with the guanine nucleotide guanyl-5'-yl imidodiphosphate prior to solubilization prevented the retention of [3H]dopamine but not [3H]SCH 23390-labeled soluble receptors. This suggests that the same guanine nucleotide-dopamine D1 receptor complex formed in membranes is stable to solubilization and confers agonist high affinity binding in soluble preparations. These results contrast with those reported on the digitonin-solubilized dopamine D2 receptor, and the molecular mechanism responsible for this difference remains to be elucidated.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1986

Dopamine D2 receptor density remains constant in treated Parkinson's disease.

D2 dopamine receptor densities were measured in postmortem samples of the caudate nucleus and putamen from 36 parkinsonian patients. The relationship between the age of the patient, duration of the disease, and duration of L-dopa therapy versus density of brain D2 dopamine receptors was examined using [3H]spiperone. Receptor density in parkinsonian tissues was constant over the age range of 56 to 90 years, as was the case for control tissues. Density did not change with duration of disease up to 24 years. Treatment with L-dopa did not cause progressive reduction in receptor density. The diminished clinical response in the final stages of Parkinson's disease is not due to receptor dropout, and must depend on other factors.

Age Factors↗
PubMed1986

[3H]-domperidone labels only a single population of receptors which convert from high to low affinity for dopamine in rat brain.

Dopamine recognized and competed for a single population of [3H]-domperidone-binding sites in rat striatum and olfactory tubercle when tested in the presence of sodium ions and guanine nucleotide [Gpp(NH)p]. In the absence of Na+ and Gpp(NH)p, however, dopamine recognized two components of [3H]-domperidone binding. Thus, [3H]-domperidone labelled only a single population of dopamine receptors (type D2) which fully converted from high to low affinity for dopamine. These results agree with those found previously using [3H]-spiperone and [3H]-YM-09151-2.

Animals↗
PubMed1986

Age-related changes in beta-adrenoceptors of lymphocytes.

The density of adrenoceptors (Bmax) is greater on B than on T splenocytes. It decreases more or less rapidly on membranes of both populations, as animals age. The exception, we have observed in this respect, is an increase in Bmax on B cells of SJL mice, between the 6th and 25th week of life.

Aging↗
PubMed1986

Age-related changes of beta-adrenoceptors in aging inbred mice.

The density (Bmax) and antagonist dissociation constant (KD) of beta-adrenoceptors were determined on spleen and brain of three different inbred strains of mice--BALB/cJ, C3H/HeJ, and C57BL/6J. Receptor densities (Bmax) differed with strain and declined in both spleen and cortical receptor populations as mice became older. Age-related changes in KD were found on spleen cells of BALB/cJ and in the cortex of C3H/HeJ and C57BL/6J. Bmax and KD in different organs of the same strain changed at different rates. changed at different rates.

Aging↗