Acute administration of haloperidol enhances dopaminergic transmission.
It has been demonstrated that haloperidol, by blocking presynaptic D2 receptors, enhances dopamine release. However, it is generally assumed that augmentation of dopaminergic transmission is precluded by haloperidol's postsynaptic actions. This assumption was assessed in the present experiment by testing the effects of acute haloperidol administration on the activity of the striatum. Somatosensory stimulation was used to evoke striatal field potentials in rats anesthetized with either urethane or sodium pentobarbital. Haloperidol suppressed striatal responses in a dose-dependent fashion. Enhanced dopaminergic activity, caused by i.v. cocaine or substantia nigra stimulation, similarly suppressed striatal responses. Rather than blocking the effects of cocaine in the striatum, coadministration of haloperidol was additive, causing increased suppression. Substantia nigra lesions that depleted striatal dopamine blocked the suppressive effects of haloperidol. Administration of R-(+)-8-chloro-2,3,4,5-tetrahydro-3- methyl-5-phenyl-1H-3-benzazepine-7-ol to prevent postsynaptic actions of dopamine mediated by D1 receptors did not attenuate haloperidol-induced suppression. The present data suggest that acute administration of haloperidol actually augments dopaminergic activity due to relatively strong presynaptic actions and relatively weak postsynaptic blocking effects. It is plausible that this initial increase in dopaminergic transmission may participate in producing the neural changes evoked by chronic haloperidol administration that allow this drug to have antipsychotic potency.
Lidsky
T I
TI
Department of Psychobiology, New York State Institute For Basic Research in Developmental Disabilities, Staten Island.
Banerjee
S P
SP
D000818:Animals; D004298:Dopamine / Q000378:metabolism*; D065127:Dopamine D2 Receptor Antagonists; D005071:Evoked Potentials; D006220:Haloperidol / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013003:Somatosensory Cortex / Q000502:physiology; D013378:Substantia Nigra / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D065127:Dopamine D2 Receptor Antagonists; D005680:gamma-Aminobutyric Acid; D006220:Haloperidol; D004298:Dopamine