The therapeutic latency of neuroleptic drugs and nonspecific postjunctional supersensitivity.
It is suggested that the antidopaminergic effects of neuroleptics are not directly responsible for the antipsychotic effect but, rather, that the antipsychotic effect is related to secondary changes in the efficacy of transmission at corticostriatal excitatory synapses. Arguments are presented in support of the following: (1) acute dopaminergic antagonism produces a relatively nonspecific sedation or deactivation, but most of the amelioration of psychosis develops slowly; (2) the development of dopaminergic supersensitivity is responsible for tolerance to the sedative effects of neuroleptics; and (3) excitatory synapses of the corticostriatal pathway, mediated by glutamic acid, are located on the same dendritic spines as the striatal dopaminergic synapses. Concomitant with the development of dopaminergic supersensitivity, these glutamate synapses become subsensitive. The glutamatergic subsensitivity is a result of the nonspecific nature of postsynaptic denervation supersensitivity. It is suggested that subsensitivity of striatal glutamate-mediated synapses is directly responsible for the antipsychotic effect of neuroleptic drugs. In support of this hypothesis, chronic neuroleptic administration was found to decrease the behavioral responsivity of mice to the glutamate agonist, quisqualic acid, and to the the antagonist, glutamic acid diethyl ester.
Freed
W J
WJ
Neuropsychiatry Branch, NIMH, Neuropsychiatric Research Hospital at Saint Elizabeths, Washington, DC 20032.
D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects*; D006801:Humans; D051379:Mice; D011954:Receptors, Dopamine / Q000187:drug effects*; D017470:Receptors, Glutamate; D017981:Receptors, Neurotransmitter / Q000187:drug effects; D012559:Schizophrenia / Q000188:drug therapy*; D012565:Schizophrenic Psychology
D014150:Antipsychotic Agents; D011954:Receptors, Dopamine; D017470:Receptors, Glutamate; D017981:Receptors, Neurotransmitter