YM-09151-2 but not l-sulpiride induces transient dopamine release in rat striatum via a tetrodotoxin-insensitive mechanism.
The effects of the selective dopamine D2 receptor antagonists YM-09151-2 and l-sulpiride on the in vivo release of dopamine (DA), L-3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) in rat striatum were investigated. The drugs were injected into the striatum through a microinjection needle attached to a dialysis probe. YM-09151-2 (0.1 or 1.0 microgram/0.5 microliter) injected into the striatum produced a dramatic rapid-onset transient increase in striatal DA release in a dose-dependent manner. However, the DA increase induced by l-sulpiride (15 or 75 ng/0.5 microliter) was small and of slower onset. An increase of DOPAC levels by YM-09151-2 was biphasic: The first peak occurred at 40 min, followed by a delayed-onset gradual increase. Slower-onset gradual increases were also found in DOPAC levels after l-sulpiride injection and in HVA levels after injections of both YM-09151-2 and l-sulpiride. The infusion of tetrodotoxin (TTX; 2 microM) revealed two different types of DA release mechanisms: The rapid-onset transient DA release induced by YM-09151-2 was TTX insensitive, whereas the slower-onset DA release induced by l-sulpiride was TTX sensitive. Moreover, the rapid-onset transient DA release was Ca2+ independent and was not affected by pretreatment with l-sulpiride or nomifensine. Therefore, it is concluded that YM-09151-2 injected into the striatum produced a transient striatal DA release that is independent of D2 receptors and the action potential.
Tomiyama
K
K
Department of Pharmacology, Nihon University School of Dentistry, Tokyo, Japan.
Noguchi
M
M
Koshikawa
N
N
Kobayashi
M
M
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D002118:Calcium / Q000494:pharmacology; D002555:Cerebrospinal Fluid; D003342:Corpus Striatum / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D065127:Dopamine D2 Receptor Antagonists; D006719:Homovanillic Acid / Q000378:metabolism; D007267:Injections; D007552:Isotonic Solutions / Q000494:pharmacology; D008297:Male; D009627:Nomifensine / Q000494:pharmacology; D051381:Rats; D000077331:Ringer's Solution; D013469:Sulpiride / Q000494:pharmacology*; D013779:Tetrodotoxin / Q000494:pharmacology*
D001549:Benzamides; D065127:Dopamine D2 Receptor Antagonists; D007552:Isotonic Solutions; D015102:3,4-Dihydroxyphenylacetic Acid; D009627:Nomifensine; D013779:Tetrodotoxin; D013469:Sulpiride; D000077331:Ringer's Solution; C030265:nemonapride; D002118:Calcium; D004298:Dopamine; D006719:Homovanillic Acid