Activation of post-synaptic dopamine D₁ receptors promotes the release of tissue plasminogen activator in the nucleus accumbens via PKA signaling.
We have previously demonstrated that tissue plasminogen activator (tPA) plays an important role through the conversion of plasminogen to plasmin in the release of dopamine in the nucleus accumbens (NAc) evoked by depolarization or the systemic administration of drugs of abuse such as morphine and nicotine. In the present study, we examined the mechanisms by which drugs of abuse increase extracellular tPA activity in the NAc in vivo using in situ zymography. The dopamine D(1) receptor (D(1) R) agonist SKF38393, but not D(2) receptor agonist quinpirole, significantly increased extracellular tPA activity in the NAc. The effect of SKF38393 was blocked by pre-treatment with the dopamine D(1) R antagonist SCH23390. Microinjection of Rp-cAMPs, a protein kinase A inhibitor, into the NAc completely blocked the effect of SKF38393. Systemic administration of morphine and methamphetamine increased extracellular tPA activity in the NAc, and these effects were completely blocked by pre-treatment with SCH23390 and raclopride. The results suggest that activation of post-synaptic dopamine D(1) Rs in the NAc leads to an increase in extracellular tPA activity via protein kinase A signaling. Furthermore, dopamine D(2) receptors are also involved in the release of tPA induced by morphine and methamphetamine.
Ito
Mina
M
Laboratory of Neuropsychopharmacology, Division of Life Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa, Japan.
Nagai
Taku
T
Mizoguchi
Hiroyuki
H
Sato
Kosuke
K
Hayase
Minoru
M
Otsuka
Noboru
N
Fukakusa
Ayumi
A
Kumagai
Nozomi
N
Kim
Hyoung-Chun
HC
Nabeshima
Toshitaka
T
Takuma
Kazuhiro
K
Yamada
Kiyofumi
K
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D001923:Brain Chemistry / Q000187:drug effects; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D007150:Immunohistochemistry; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D009020:Morphine / Q000494:pharmacology; D009714:Nucleus Accumbens / Q000378:metabolism*; D016627:Oxidopamine / Q000633:toxicity; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020891:Raclopride / Q000494:pharmacology; D017447:Receptors, Dopamine D1 / Q000819:agonists*; D015398:Signal Transduction / Q000187:drug effects; D013565:Sympatholytics / Q000633:toxicity; D013569:Synapses / Q000502:physiology*; D010959:Tissue Plasminogen Activator / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D000701:Analgesics, Opioid; D001552:Benzazepines; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D047428:Protein Kinase Inhibitors; D017447:Receptors, Dopamine D1; C534628:SCH 23390; D013565:Sympatholytics; D020891:Raclopride; D008694:Methamphetamine; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D009020:Morphine; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D017868:Cyclic AMP-Dependent Protein Kinases; D010959:Tissue Plasminogen Activator