The dopamine D4 receptor in schizophrenia: an update

Kerwin, Robert; Collier, David

doi:10.1017/s0033291700034619

Cited by 10 publications

(2 citation statements)

References 49 publications

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“…However, several lines of evidence seem to contradict this proposal. First, the elevation in D 4 receptors claimed originally has not been reliably replicated (20). Second, other antipsychotics, including typical agents, also have a high affinity for the D 4 receptor (e.g.…”

Section: High Affinity For Dopamine D 4 Receptorsmentioning

confidence: 99%

Atypical Antipsychotics: New Directions and New Challenges in the Treatment of Schizophrenia

2001

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"Atypical" antipsychotics represent a new generation of antipsychotics with a significantly lower incidence of extrapyramidal side effects (EPS), as well as little or no effect on prolactin elevation. These advantages constitute a major improvement in the treatment of patients with schizophrenia. The exact mechanisms that make these drugs atypical is not clear. However, a preferential action on serotonin 5-HT2 or D4 receptors, or a more rapid dissociation from the dopamine D2 receptor, may account for atypicality. Although the atypical antipsychotics have overcome EPS, other side effects such as weight gain and impaired glucose tolerance/lipid abnormalities have come to the fore. Thus, the challenges are far from over. The current atypicals are much more effective against the psychosis of schizophrenia than against the other, more enduring aspects of this disorder, e.g. negative symptoms and cognitive dysfunction. At present, the atypicals use a "pharmacological shotgun" strategy to treat aspects of the disease in all patients. A more sophisticated and perhaps effective approach to schizophrenia may lie in independently targeting the pathophysiological mechanisms of each clinical dimension (i.e. positive, negative, cognitive, and affective) with more selective drugs that can be combined and individually titrated to the needs of each patient.

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Section: High Affinity For Dopamine D 4 Receptorsmentioning

confidence: 99%

Atypical Antipsychotics: New Directions and New Challenges in the Treatment of Schizophrenia

2001

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“…Although Reynolds and Mason (1995) did not detect elevated 0 4 -like sites in schizophrenia tissues, they assumed that the specific activity of [1 25 1]-epidepride fell with time; however, as outlined elsewhere , the specific activity of [ 125 1]-epidepride remains constant because the molecule self-destructs upon decay. Further discussion of the 0 4 -like binding sites in schizophrenia is given by Kerwin and Collier (1996).…”

Section: Selective Block Of Dopamine D 4 Receptorsmentioning

confidence: 99%

Atypical Neuroleptics Have Low Affinity for Dopamine D2 Receptors or Are Selective for D4 Receptors

Seeman

Corbett²,

Tol

1997

Neuropsychopharmacology

210

116

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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.

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