Antipsychotic drugs have been widely used to treat psychoses and neuropsychiatric disorders like schizophrenia. A debilitating side-effect of these drugs called parkinsonism - which includes involuntary movements, tremors and other severe physical conditions - limits their efficacy.
University of California, Irvine scientists led by Emiliana Borrelli and colleagues have discovered the key cellular mechanism that underlies the antipsychotic-induced parkinsonism. These studies present evidence that will stimulate a targeted approach for the design of novel antipsychotics without side-effects.
In the journal Neuron, the researchers report that antipsychotics side-effects are due to blockade of the dopamine D2 receptor in a specialized type of neurons in the striatum, called interneurons. Blockade of D2 receptor in these neurons increases neurotransmitter signaling (acetylcholine) above threshold on neighbor neurons leading to motor abnormalities in rodents (catalepsy) and in humans (parkinsonism). Catalepsy is marked by severe muscular rigidity and fixity of posture regardless of external stimuli. Indeed, in mouse studies, the Borrelli team discovered that removing D2 receptors in nerve cells (cholinergic interneurons) did not result in catalepsy in the mice upon antipsychotic treatment.