Commentary on Dinan's Hypothesis

1987 ◽  
Vol 151 (4) ◽  
pp. 459-460 ◽  
Author(s):  
Leslie L. Iversen
Keyword(s):  
Dopamine Receptors ◽  
Drug Action ◽  
Common Mechanism ◽  
Neuroleptic Drug ◽  
Pharmacological Properties ◽  
Neuroleptic Drugs ◽  
Dopamine Hypothesis ◽  
Potent Antagonist ◽  
D2 Antagonists ◽  
Rich Spectrum

Dinan's paper seeks to question the validity of the now widely accepted hypothesis that neuroleptic drugs of various different chemical categories all act by a common mechanism, namely by blockade of dopamine receptors of the D2 type in brain (for review see Creese et al, 1978, 1983; Iversen, 1985). While it is always refreshing to re-examine existing scientific dogma, his criticisms did not appear to me to be very substantial. Having quite fairly reviewed the evidence in favour of the “dopamine hypothesis” for neuroleptic drug action, Dinan summarises his reasons for questioning it. He points out that many neuroleptic drugs have potent actions on a number of other targets, apart from the dopamine receptors in brain. This is indeed so, and the archetypal compound, chlorpromazine, has a particularly rich spectrum of pharmacological activity, being a potent antagonist of serotonin (5-HT2) receptors, ?-adrenoceptors, and histamine (HI) receptors in brain and other tissues. Other neuroleptics also have potent actions on a number of other systems. Indeed, if one were to have studied only chlorpromazine, it is doubtful whether the “dopamine hypothesis” could ever have been developed. The strength of this hypothesis lies in the fact that of all the diverse pharmacological actions which different neuroleptic drugs exhibit, this is the only action that is common to all neuroleptic compounds. Furthermore, in a large group of neuroleptics, which differ widely in potency (doses in man ranging from 1 mg/day to almost 1000 mg/day), the potencies of these drugs as dopamine (D2) antagonists correlate significantly with their clinical potencies. Attempts to make such correlations with any other known pharmacological properties of these drugs fail to show significance (Creese et al, 1978, 1983).

Beyond the Dopamine Hypothesis

1989 ◽  
Vol 155 (3) ◽  
pp. 305-316 ◽  
Author(s):  
G. P. Reynolds
Keyword(s):  
Amino Acid ◽  
Drug Treatment ◽  
Dopamine Neurons ◽  
Postmortem Brain ◽  
Neuroleptic Drug ◽  
Neuroleptic Drugs ◽  
Imaging Studies ◽  
Postmortem Brain Tissue ◽  
Dopamine Hypothesis

The dopamine hypothesis still provides a valuable approach to the study of schizophrenia and its treatment by drugs. Although the neuroleptic drugs appear to act via an inhibition of dopamine receptors, measurements of dopamine metabolites in vivo, or of the transmitter and its receptors in postmortem brain tissue, do not provide unequivocal evidence of a hyperactivity of dopaminergic neurotransmission in the disease. Nevertheless, increased dopamine function might be a consequence of a primary neuronal abnormality in another system. Recent imaging studies and neuropathological reports suggest that, in some patients, there may be a deficit and/or disturbance of neurons in certain temporal limbic regions, and this is supported by some neurochemical investigations, particularly of neuropeptide and amino-acid transmitter systems. A loss of such neurons could conceivably lead to a disinhibition of limbic dopamine neurons, providing the means whereby neuroleptic drug treatment might ameliorate the effects of a neuronal deficit in schizophrenia.

Pre-clinical Pharmacology of Atypical Antipsychotic Drugs: A Selective Review

1996 ◽  
Vol 168 (S29) ◽  
pp. 23-31 ◽  
Author(s):  
Herbert Y. Meltzer
Keyword(s):  
Atypical Antipsychotic ◽  
Antipsychotic Drugs ◽  
Chronic Administration ◽  
Receptor Occupancy ◽  
Dopamine Neurons ◽  
Neuroleptic Drug ◽  
Neuroleptic Drugs ◽  
Subsequent Decrease ◽  
Dopamine Hypothesis ◽  
Ventral Tegmental

The primary basis for the action of neuroleptic drugs has been suggested to be a blockade of D2 receptors in the mesolimbic system, with subsequent decrease in the firing rate of ventral tegmental (A10) dopamine neurons by the process of depolarisation inactivation (Matthyssee, 1974; Bunney et al, 1991). The main evidence for this hypothesis is that: the affinities for the D2 receptor of all effective antipsychotic drugs are positively correlated with their average clinical dose (Seeman & Lee, 1975; Creese et al, 1976); and chronic administration of antipsychotic drugs produces nearly complete inhibition of the firing of ventral tegmental (A10) dopamine neurons that project to the limbic forebrain (Chiodo & Bunney, 1983). Clozapine, the prototypical atypical antipsychotic drug, also satisfies both criteria (Seeman & Lee, 1975; Chiodo & Bunney, 1985). However, the demonstration that clozapine is more effective than other neuroleptics for the treatment of both schizophrenic patients who are responsive to typical neuroleptics (Meltzer, 1992) as well as those who are resistant (Kane et al, 1988) suggests that this simple dopamine hypothesis of neuroleptic drug action is insufficient. Indeed, there is evidence that clozapine at clinically effective doses produces less D2 receptor occupancy and, hence, less antagonism of D2 receptors in the striatum, and probably also in the limbic system, than typical neuroleptic drugs (Farde et al, 1992); this further challenges the adequacy of the dopamine hypothesis to explain the greater efficacy of clozapine. This leaves the need to consider what else besides a D2 receptor blockade may explain the action of clozapine and, indeed, whether limited blockade is superior to a more complete one.

Dopamine and its agonists reduce a light-sensitive poor of cyclic AMP in mouse photoreceptors

1990 ◽  
Vol 4 (1) ◽  
pp. 43-52 ◽  
Author(s):  
Adolph I. Cohen ◽  
Christine Blazynski
Keyword(s):  
Cyclic Amp ◽  
Bright Light ◽  
Light Response ◽  
D2 Receptors ◽  
Retinal Neurons ◽  
Apparent Loss ◽  
Substituted Benzamides ◽  
Major Loss ◽  
Potent Antagonist ◽  
D2 Antagonists

AbstractThe exposure to bright light of dark-adapted (DKA) mouse retinas incubated in the dark (DI) in IBMX-containing medium causes a marked loss of cyclic AMP. This light response also occurs if the medium contains 10 mM aspartate or cobaltous ion, agents believed to confine the effects of light to photoreceptors. Thus, the action of light in the presence of either of these agents defines a light-sensitive pool of cyclic AMP in photoreceptors. This pool could also be reduced or eliminated in DKA-DI retinas by nanomolar to micromolar levels of dopamine (if the medium contained SCH23390, a potent antagonist of Dl receptors), thus indicating an agonistic action of dopamine at D2 receptors. The D2 agonists LY171555 (EC50 10 nM) or (+)-3-PPP also reduced the cyclic AMP level in the dark. Of the D2 antagonists tested, the butyrophenone spiperone (in the presence of the 5HT-2 blocker ketanserin) countered the action of the D2 agonists but substituted benzamides were ineffective. Consistently, the D2 agonists had no effect on cyclic AMP levels of mutant retinas lacking photoreceptors (rd'rd), but reduced cyclic AMP in DKA-Dl glutamate-modified retinas which exhibit a major loss of inner retinal neurons without apparent loss of photoreceptors. The Dl antagonist SCH23390 only reduced cyclic AMP levels of DKA-DI retinas when cyclic AMP levels had been elevated by adding dopamine to the incubation medium.

Finger Tremor and Extrapyramidal Side Effects of Neuroleptic Drugs

1979 ◽  
Vol 134 (5) ◽  
pp. 488-493 ◽  
Author(s):  
Paul Collins ◽  
Ian Lee ◽  
Peter Tyrer
Keyword(s):  
Side Effects ◽  
Negative Relationship ◽  
Peak Frequency ◽  
Neuroleptic Drug ◽  
Neuroleptic Drugs ◽  
Extrapyramidal Side Effects ◽  
Significant Negative Relationship ◽  
Tremor Frequency ◽  
Finger Tremor ◽  
The Relationship

SummaryFinger tremor and extrapyramidal side-effects (EPSEs) were measured in seven patients before and during neuroleptic drug treatment to assess the relationship between the onset of EPSEs and changes in finger tremor spectra. Tremor and EPSEs were also measured in twelve patients stabilized on neuroleptic drugs to determine whether tremor could provide a reliable index of the presence and severity of extrapyramidal system disturbance. A downward shift in peak tremor frequency was noted within 48 hours of starting neuroleptic drug therapy, usually before the onset of EPSEs, and a significant negative relationship between the severity of EPSEs and tremor frequency (but not tremor amplitude). The peak frequency of finger tremor is thus a sensitive index of extrapyramidal disturbance and might be of value in predicting which patients taking neuroleptic drugs need anti-parkinsonian therapy.

scholarly journals Dopamine receptor sites in the anterior pituitary.

1979 ◽  
Vol 27 (8) ◽  
pp. 1205-1207 ◽  
Author(s):  
P C Goldsmith ◽  
M J Cronin ◽  
R I Weiner
Keyword(s):  
Dopamine Receptors ◽  
Dopamine Receptor ◽  
Anterior Pituitary ◽  
Receptor Site ◽  
Cell Types ◽  
Pituitary Cells ◽  
Vesicle Membrane ◽  
Receptor Sites ◽  
Immunocytochemical Method ◽  
Potent Antagonist

An immunocytochemical method was developed to visualize dopamine receptor sites on dispersed anterior pituitary cells of the rat. Dopamine receptors were labeled with the antagonist haloperidol. Some cells were incubated with haloperidol and a 100-fold excess of the potent antagonist D-butaclamol to determine nonspecific binding. The labeled sites were stained with an antibody against haloperidol and the peroxidase anti-peroxidase (PAP) technique. PAP complexes which served as markers for dopamine binding sites appeared on the outer plasmalemmal surface of the vast majority of mammotrophs. PAP complexes attached to the inner surface of endocytotic vesicle membrane suggested internalization of receptor-rich portions of the plasmalemma. Some gonadotrophs and somatotrophs were specifically stained to a lesser extent. However, high receptor site density and internalization of PAP complexes were never observed on cell types other than mammotrophs. The presence of dopamine receptors on the plasmalemma of mammotrophs provides strong additional evidence that dopamine acts upon these cells as a prolactin inhibitory hormone.

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