Haloperidol and clozapine increase intraneuronal dopamine metabolism, but not gamma-butyrolactone-resistant dopamine release.
In a previous study, two coexisting mechanisms of dopamine release were identified in dopamine neuron terminals. One can be blocked with gamma-butyrolactone, suggesting it is impulse flow-dependent, while the other one cannot and is apparently impulse flow-independent. The goal of this study was to further characterize the gamma-butyrolactone-resistant mechanism and its relation to dopamine metabolism. Following acute and chronic haloperidol or clozapine treatment, gamma-butyrolactone was given to block dopamine neuronal impulse flow. In all groups, 3-methoxytyramine levels after monoamine oxidase inhibition with pargyline (an index of dopamine release) were measured in the frontal cortex, nucleus accumbens and striatum. Regional steady-state levels of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were also measured in the rats treated acutely with neuroleptics. In all three regions, gamma-butyrolactone reduced the 3-methoxytyramine levels by over 50% after chronic neuroleptic treatment. This indicates that dopamine release from the terminals is primarily impulse flow-dependent during chronic neuroleptic treatment, both in the dopamine neurons which do undergo depolarization block, and in those that do not. No neuroleptic effect on the gamma-butyrolactone-resistant dopamine release was observed, while DOPAC and HVA were markedly elevated by the acute treatment, suggesting a predominant production of these metabolites from unreleased dopamine.
Chrapusta
S J
SJ
Neuropsychiatry Branch, NIMH Neuroscience Center at Saint Elizabeths, Washington, D.C. 20032.
Karoum
F
F
Egan
M F
MF
Wyatt
R J
RJ
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D015107:4-Butyrolactone / Q000494:pharmacology*; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003024:Clozapine / Q000494:pharmacology*; D004298:Dopamine / Q000031:analogs & derivatives / Q000378:metabolism*; D018492:Dopamine Antagonists; D006220:Haloperidol / Q000494:pharmacology*; D006719:Homovanillic Acid / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000187:drug effects
D018492:Dopamine Antagonists; D011954:Receptors, Dopamine; D015102:3,4-Dihydroxyphenylacetic Acid; D003024:Clozapine; D006220:Haloperidol; C001746:3-methoxytyramine; D015107:4-Butyrolactone; D004298:Dopamine; D006719:Homovanillic Acid