Philip Seeman

Dopamine receptor pharmacology

Although antipsychotic drugs originally helped to discover dopamine receptors, the five dopamine receptors presently identified and cloned are facilitating the search for and discovery of more selective antipsychotic and antiparkinson drugs. The D1-like dopamine receptors, D1 and D5, are sensitive to the same drugs as the D1 receptor in native tissues, but D5 is about 10 times more sensitive to dopamine than D1. The D2-like receptors, D2, D3, and D4, have approximately similar sensitivities to dopamine, but bromocriptine and raclopride are both about two orders of magnitude weaker at D4, whereas clozapine is one order more potent at D4, as compared with D2 and D3. The human dopamine D4 receptor has many variants. The sensitivities to clozapine of human variants D4.2, D4.4, and D4.7 are approximately similar, with dissociation constants between 5 and 24 nM, matching the spinal fluid concentration of clozapine under therapeutic conditions. Thus antipsychotic action may be effected through blockade of either dopamine D2 or D4 receptors.

Radioreceptor binding profile of the atypical antipsychotic olanzapine

The affinities of olanzapine, clozapine, haloperidol, and four potential antipsychotics were compared on binding to the neuronal receptors of a number of neurotransmitters. In both rat tissues and cell lines transfected with human receptors olanzapine had high affinity for dopamine D1, D2, D4, serotonin (5HT)2A, 5HT2C, 5HT3, α1-adrenergic, histamine H1, and five muscarinic receptor subtypes. Olanzapine had lower affinity for α2-adrenergic receptors and relatively low affinity for 5HT1 subtypes, GABAA, β-adrenergic receptors, and benzodiazepine binding sites. The receptor binding affinities for olanzapine was quite similar in tissues from rat and human brain. The binding profile of olanzapine was comparable to the atypical antipsychotic clozapine, while the binding profiles for haloperidol, resperidone, remoxipride, Org 5222, and seroquel were substantially different from that of clozapine. The receptor binding profile of olanzapine is consistent with the antidopaminergic, antiserotonergic, and antimuscarinic activity observed in animal models and predicts atypical antipsychotic activity in man.

Brain neurotransmitter receptors after long-term haloperidol: Dopamine, acetylcholine, serotonin, α-noradrenergic and naloxone receptors

Since long-term neuroleptic therapy is known to alter brain dopaminergic sensitivity, we tested the effects of chronic haloperidol administration (10 mg/kg/day for over 3 weeks) on the amount of the dopamine receptors (using 3H-apomorphine and 3H-haloperidol) in various regions of the rat brain. To test whether the changes in dopamine receptors were selectively produced, we also assayed acetylcholine receptors (with 3H-quinuclidinyl benzilate or 3H-QNB), alpha-noradrenergic receptors (with 3H-WB-4101), 3H-serotonin receptors and 3H-naloxone receptors. The specific binding of 3H-haloperidol increased significantly by 34% in the striatum and by 45% in the mesolimbic region after long-term haloperidol. The specific binding of 3H-apomorphine also increased significantly by 77% in the striatum and 55% in the mesolimbic area. Although there was a small significant increase of 20% in specific 3H-serotonin binding in the striatum, no such increment occurred in the hippocampus or the cerebral cortex. No significantly different binding occurred for the other 3H-ligands in these brain regions except for a 13% increase in alpha-noradrenergic binding in the cerebral cortex. These results indicate that long-term haloperidol treatment produces rather selective increases in dopamine/neuroleptic receptors, without much change in 4 other types of receptors. Such relatively selective increments in these receptors may be the basis of dopaminergic supersensitivity (e.g. tardive dyskinesia) after long-term haloperidol.

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 Alzheimers and Huntingtons diseases. The average D1 density in postmortem striata from Alzheimers 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 Parkinsons 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 Alzheimers 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 Alzheimers striata was 16.7 +/- 0.7 pmol/g, an elevation of 31%, the individual values of which had a normal distribution. In Parkinsons 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 Huntingtons 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 Alzheimers disease and 37% in Huntingtons 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.

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 or 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 Parkinsons Disease.Dopaminergic supersensivity persists for a period proportional to the length 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.

Dopamine receptors in brain and periphery

It is currently necessary to postulate only two receptors D(1) and D(2) to account for the majority of available data. This article reviews some of this information.

Anti-hyperactivity medication: methylphenidate and amphetamine

How do ‘stimulants’ reduce hyperactivity in children and adults? How can drugs which raise extracellular dopamine result in psychomotor slowing of hyperactive children when dopamine is known to enhance motor activity, such as in Parkinsons disease? These apparent paradoxes are the focus of this brief review on the mechanism of action of stimulant medications used in the treatment of children, and of an increasing number of adults who meet diagnostic criteria for attention deficit hyperactivity disorder.

Membrane Stabilization by Drugs: Tranquilizers, Steroids, and Anesthetics

Publisher Summary Anesthesia or stabilization of the nerve membrane is caused by alcohols, steroids, local anesthetics, phenothiazine tranquilizers, antihistamines, and various detergents. This chapter extends the idea of membrane stabilization to many types of cell membranes and subcellular membranes rather than confine the term just to the neurolemma. It also examines some of the physicochemical factors that may be important in determining the degree of membrane stabilization and presents a comparison of the many types of in vitro effects of membrane stabilizers along with a juxtaposition of the in vitro effects of local anesthetics and the phenothiazine tranquilizers on membrane-bound organelles. There is an extremely close analogy, both qualitative and quantitative, between neuron stabilization and erythrocyte stabilization against hypotonic hemolysis. A definite correlation exists between the anesthetic potency of steroids and the erythrocyte stabilization by a very diverse group of steroid compounds over a 100-fold range of concentrations. A second analogous action of stabilizers on nerve and nonneural membranes is to be found in their mode of toxicity at high concentrations. At high concentrations the majority if not all the neuron stabilizers cause a depolarization of the neurolemma; this is presumably related to the fact that practically all these compounds are surface-active and cause membrane emulsification at high drug concentration.

I. Erythrocyte membrane stabilization by tranquilizers and antihistamines

Abstract 1. Human erythrocytes are protected or stabilized against hypotonic and mechanical hemolysis in the presence of low concentrations of many phenothiazines, reserpine, and haloperidol. At high concentrations all these surfactants cause lysis. 2. The erythrocyte stabilization by these compounds is long-lasting and depends on the concentration of erythrocytes. 3. The stabilizing potency correlates aproximately with the clinical potency of the phenothiazine. 4. Adsorption studies indicate that at maximal stabilization there is about 65 A 2 of erythrocyte membrane associated with one molecule of promethazine, 100 A 2 for chlorpromazine HCl, 140 A 2 for trifluoperazine diHCl, and 180 A 2 for fluphenazine diHCl. Since the area of the phenothiazine ring is about 50 A 2 , these values represent 90 to 25 per cent involvement of the membrane, if no adsorption to hemoglobin occurs. 5. The membrane stabilization is rapidly reversible. Lowering the extracellular drug concentration or photo-oxidizing the adsorbed drug causes the membrane to return to its original condition of fragility. 6. The prevention of hemolysis is also associated with the prevention of K + release; this distinguishes membrane stabilization from pro-lysis wherein K + is released. 7. Replacing isotonic sucrose by isotonic NaCl potentiates the lytic effect of phenothiazines. 8. The decrease in osmotic fragility (which corresponds to between one third and one half an atmosphere of pressure) may be explained possibly by an expansion of the cell membrane.

Atypical neuroleptics have low affinity for dopamine D2 receptors or are selective for D4 receptors

This review examines the possible receptor basis of the atypical action of those atypical antipsychotic drugs that elicit low levels of Parkinsonism. Such an examination requires consistent and accurate dissociation constants for the antipsychotic drugs at the relevant dopamine and serotonin receptors. It has long been known, however, that the dissociation constant of a given antipsychotic drug at the dopamine D2 receptor varies between laboratories. Although such variation depends on several factors, it has recently been recognized that the radioligand used to measure the competition between the antipsychotic drug and the radioligand is an important variable. The present review summarizes information on this radioligand dependence. In general, a radioligand of low solubility in the membrane (i.e., low tissue:buffer partition) results in a low value for the antipsychotic dissociation constant when the drug competes with the radioligand. Hence, by first obtaining the antipsychotic dissociation constants using different radioligands of different solubility in the membrane, one can then extrapolate the data to low or “zero” ligand solubility. The extrapolated value represents the radioligand-independent dissociation constant of the antipsychotic. These values are here given for dopamine D2 and D4 receptors, as well as for serotonin 5-HT2A receptors. These values, moreover, agree with the dissociation constant directly obtained with the radioactive antipsychotic itself. For example, clozapine revealed a radioligand-independent value of 1.6 nM at the dopamine D4 receptor, agreeing with the value directly measured with [3H]-clozapine at D4. However, because clozapine competes with endogenous dopamine, the in vivo concentration of clozapine (to occupy dopamine D4 receptors) can be derived to be about 13 nM, agreeing with the value of 12 to 20 nM in the plasma water or spinal fluid observed in treated patients. The atypical neuroleptics remoxipride, clozapine, perlapine, seroquel, and melperone had low affinity for the dopamine D2 receptor (radioligand-independent dissociation constants of 30 to 90 nM). Such low affinity makes these latter five drugs readily displaceable by high levels of endogenous dopamine in the caudate or putamen. Most typical neuroleptics have radioligand-independent values of 0.3 to 5 nM at dopamine D2 receptors, making them more resistant to displacement by endogenous dopamine. Finally, a relation was found between the neuroleptic doses for rat catalepsy and the D2:D4 ratio of the radioligand-independent K values for these two receptors. Thus, the atypical neuroleptics appear to fall into two groups, those that have a low affinity for dopamine D2 receptors and those that are selective for dopamine D4 receptors.