An hypothesis regarding the antipsychotic effect of neuroleptic drugs

The antipsychotic effect of neuroleptic drugs appears gradually over the course of several weeks of chronic drug administration. Neuroleptic drugs are thought to act by blocking dopamine receptors; however, the dopamine-blocking effect of neuroleptics appears rapidly. One effect of dopamine antagonists which develops slowly is dopaminergic supersensitivity. It is suggested that this dopaminergic supersensitivity is related to the development of tolerance to some of the acute sedative properties of neuroleptics, but not to the antipsychotic effect. A population of glutamate receptors which are postsynaptic to the cortico-striatal afferents is located on the same neurons as striatal dopamine receptors. These glutamate synapses are located on the heads of dendritic spines of striato-nigral projection neurons, while the dopaminergic synapses are predominantly located on the necks of these same dendritic spines. Similar relationships could exist for mesolimbic and mesocortical dopamine systems. In peripheral systems, postjunctional denervation supersensitivity is known to be nonspecific; in other words, denervation of a single innervation of an excitable cell can alter the response to a range of stimuli. The antipsychotic effect of neuroleptics is therefore suggested to be due to nonspecific postjunctional subsensitivity at glutamate synapses, which develops concomitant with supersensitivity at dopaminergic synapses.