Myoclonic disorders .2. Antimyoclonic drug sites and mechanisms of action

Drugs that alter GABA, glutamate, 5-HT and glycine neurotransmission are among the most effective antimyoclonic or myoclonus-evoking drugs. Potentiation of the effect of GABA by allosteric modulation at the GABA(A) receptor complex is a clinically important mechanism of action of several classes of anticonvulsants such as 1,4-benzodiazepine agonists and barbiturates. Because glutamate plays a role in some acquired and genetic neurological disorders, antiglutamate drugs may reverse or prevent underlying brain injury besides providing symptomatic therapy. Antiglutamate actions, such as inhibition of release, may explain the antimyoclonic effects of phenytoin-like anticonvulsants, but glutamate receptor subunits are potentially morepromising sites of action of newer antimyoclonic drugs. Because evidence suggests that serotonin neurotransmission is altered in some myoclonic disorders, the discovery of: multiple 5-HT receptor subtypes, most not yet studied in myoclonus, offers many exciting possibilities for drug development. The potential role of glycine in myoclonus has been expanded by the discovery of a glycine receptor linked to glutamate receptors, stimulating new interest in the therapeutic modulation of glycinergic neurotransmission. Other neurotransmitters, neuropeptides or cotransmitters have been identified as potentially important in experimental myoclonus or uncontrolled clinical trials. The Pale of serendipity in the discovery of antimyoclonic drugs should not be underestimated, as exemplified by the nootropic piracetam, a drug in search of a mechanism of action.