Antipsychotic drugs classified by their effects on the release of dopamine and noradrenaline in the prefrontal cortex and striatum.
Dose-effect curves were established for the effects of the antipsychotic drugs haloperidol, clozapine, olanzapine, risperidone and ziprasidone on extracellular levels of dopamine and noradrenaline in the medial prefrontal cortex, and of dopamine in the striatum. Haloperidol was more effective in stimulating the release of dopamine in the striatum, whereas clozapine was much more effective in the medial prefrontal cortex. The efficacy of risperidone, olanzapine and ziprasidone did not differ for the two brain areas. The benzamides sulpiride and raclopride increased dopamine release in the striatum but did not affect the release of dopamine and noradrenaline in the medial prefrontal cortex. In the presence of dopamine/noradrenaline reuptake inhibitors, the benzamides strongly increased the release of dopamine-but not of noradrenaline-in the medial prefrontal cortex. The 5-HT(2) receptor antagonist R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (MDL100,907) (800 nmol/kg) and the dopamine D(2) receptor antagonist raclopride (2 micromol/kg) displayed a clear synergism in increasing the release of dopamine in the medial prefrontal cortex. No such synergism was seen in the case of noradrenaline. Co-administration of the 5-HT(2) receptor agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine HCl (DOI) (850 nmol/kg) with clozapine (10 micromol/kg) or haloperidol (800 nmol/kg) blocked the increase in dopamine as well as noradrenaline in the medial prefrontal cortex. It is concluded that typical and non-benzamide atypical antipsychotics increase extracellular dopamine in the medial prefrontal cortex via a synergistic interaction by blocking 5-HT(2) as well as dopamine D(2) receptors. The increase in extracellular noradrenaline in the medial prefrontal cortex that was observed after administration of antipsychotics is explained by inhibition of 5-HT(2) receptors and not dopamine D(2) receptors. Finally, the significance of the classification of antipsychotic drugs based on their selective action on the release of dopamine and noradrenaline in the medial prefrontal cortex is discussed. In particular, the position of the benzamides is discussed.
Westerink
B H
BH
Department of Medicinal Chemistry, University Center for Pharmacy, Deusinglaan 1, 9713AV, Groningen, Netherlands. westerink@farm.rug.nl
Kawahara
Y
Y
De Boer
P
P
Geels
C
C
De Vries
J B
JB
Wikström
H V
HV
Van Kalkeren
A
A
Van Vliet
B
B
Kruse
C G
CG
Long
S K
SK
D000818:Animals; D014150:Antipsychotic Agents / Q000145:classification / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D009638:Norepinephrine / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D020891:Raclopride / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism; D013469:Sulpiride / Q000494:pharmacology
D014150:Antipsychotic Agents; D011985:Receptors, Serotonin; D020891:Raclopride; D013469:Sulpiride; D006220:Haloperidol; D004298:Dopamine; D009638:Norepinephrine