[Dopaminergic modifications caused by neuroleptics. Functional and therapeutic hypotheses on tardive dyskinesias].
While neuroleptic action cannot be reduced to a single effect, the fact that their clinical consequences may be linked to dopaminergic receptor binding (DA) has now gained widespread acceptance. There are at least two types of DA receptors (D1 and D2), each of which is a different molecular entity. D1 receptors activate adenylate cyclase via the intermediary of a Gs protein whereas D2 receptors may either inhibit adenylate cyclase when bound to Gi or Go proteins or play a role in opening the ion channel or in the phosphatidylinositol cycle via the intermediary of a G translating protein, the existence of which has recently been demonstrated. In the short run, DA receptor blockade induces depolarization of DA neurons together with an increase in DA synthesis and release followed, in the case of nigro-striatal neurons, by "hyper-depolarization" inducing a drop in DA synthesis and release. This phenomenon, mistakenly called "tolerance", also exists in meso-limbic neurons but not in meso-cortical neurons. In the longer run, chronic blockade of DA receptors by neuroleptics induces hypersensitivity linked to an increase in the number of receptor sites. This hypersensitivity, detected by behavioural, electrophysiological and biochemical methods, is evident for sub-cortical structures but has not yet been firmly established for the cortex. The nature of this hypersensitivity could be identical to that observed in denervation experiments. Nonetheless, in certain already controversial studies, the mechanism involved in denervation hypersensitivity and that induced by repeated dosing with neuroleptics are distinct, a cumulation of effects having been observed.(ABSTRACT TRUNCATED AT 250 WORDS)
Tassin
J P
JP
Collège de France, Chaire de Neuropharmacologie, INSERM U.114, Paris.
D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000494:pharmacology*; D004409:Dyskinesia, Drug-Induced / Q000209:etiology / Q000503:physiopathology* / Q000628:therapy; D006801:Humans; D051381:Rats; D011954:Receptors, Dopamine / Q000187:drug effects* / Q000502:physiology
D014150:Antipsychotic Agents; D011954:Receptors, Dopamine
Modifications dopaminergiques sous l'action des neuroleptiques. Hypothèses fonctionnelles et thérapeutiques sur les dyskinésies tardives.