[A new pharmacological strategy for schizophrenia: the partial agonists of D2 dopaminergic receptors. The principle characteristics of aripiprazole].
The D2 dopamine receptors play a pivotal role in the physiopathology of schizophrenia. Their over-stimulation in the limbic area, resulting from a hyperactivity of the mesolimbic dopaminergic neurones, is linked to positive expressions of the disease, whereas their lack of stimulation in cortical regions, depending on a hypoactivity of mesocortical dopaminergic neurones, underlies the negative expressions of the disease. Concerning the extrapyramidal side effects which emanate from treatments by neuroleptic drugs, they are triggered by the blockade of nigro-striatal dopaminergic transmissions. The ligands of D2 dopamine receptors can be characterized by their intrinsic activity (alpha). Dopamine, which is their physiological ligand, is a full agonist (alpha=1). On the contrary, neuroleptic drugs, by suppressing the constitutive activity of these receptors (spontaneous activity even without occupation by dopamine) are inverse agonists (alpha<0). Thus, they not only oppose the effects of dopamine but they also induce diametrically opposed effects. Between these extremes, are located the partial agonists, the so-called agonists-antagonists (1>alpha>0>-1), illustrated by OPC 14597=aripiprazole. This partial agonist, by stimulating D2 and D3 dopamine autoreceptors, moderates the functioning of hyperactive dopaminergic neurones. In addition, by taking the place of dopamine on D2 post-synaptic receptors, it changes their intense stimulation into a lesser one, which reduces positive expressions (delusions, hallucinations, agitation...). On the other hand, the occupation by aripiprazole of the D2 receptors that are not stimulated by dopamine (on account of an insufficient presynaptic dopaminergic activity) restores a certain amount of stimulation, which partly alleviates negative expressions of schizophrenia. Simultaneously to these actions, both on productive as well as on negative expressions of the disease, this agonist-antagonist is virtually devoid of several adverse effects developed by neuroleptic drugs (extrapyramidal side effects) and new antipsychotic drugs (hyperprolactinemia, sedation, late dyskinesia, modifications in thermoregulation, bulimia, overweight, depression...).
Costentin
J
J
Unité de neuropsychopharmacologie, CNRS, faculté de médecine et pharmacie, université de Rouen, 22, boulevard Gambetta, 76183 Rouen, France. jean.costentin@univ-rouen.fr
D014150:Antipsychotic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000068180:Aripiprazole; D001921:Brain / Q000187:drug effects; D006801:Humans; D009474:Neurons / Q000187:drug effects; D010879:Piperazines / Q000009:adverse effects / Q000627:therapeutic use*; D015363:Quinolones / Q000009:adverse effects / Q000627:therapeutic use*; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D012559:Schizophrenia / Q000188:drug therapy*; D009435:Synaptic Transmission / Q000187:drug effects
D014150:Antipsychotic Agents; D010879:Piperazines; D015363:Quinolones; D017448:Receptors, Dopamine D2; D000068180:Aripiprazole