Dopamine-D1 and -D2 receptors differentially regulate synapsin II expression in the rat brain.
We previously demonstrated that chronic treatment with the dopamine-D2 receptor antagonist, haloperidol, increases mRNA and protein content of the phosphoprotein, synapsin II, in the rat striatum. Since dopamine-D2 receptor antagonism and dopamine-D1 receptor blockade can have opposing effects on gene expression, the present investigation compared the effects of haloperidol with those of the dopamine-D1 receptor antagonist, R-[+]-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH23390), on the expression of synapsin II protein. Haloperidol and SCH23390 respectively elevated and reduced concentrations of the molecule in mouse primary midbrain cell cultures. Additional experiments revealed that the dopamine-D1 receptor agonist, R-[+]-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzapezine-7,8-diol (SKF38393), upregulated the phosphoprotein in these cells. Furthermore, in vivo rat studies demonstrated that chronic haloperidol treatment increases synapsin II protein expression in the medial prefrontal cortex and nucleus accumbens, as was observed in the striatum. In contrast, chronic SCH23390 administration reduced concentrations of this protein in all of these regions, although the reductions seen in the medial prefrontal cortex were insignificant. Neither haloperidol nor the dopamine-D1 receptor antagonist affected synapsin I protein expression in any of the studied brain areas. Based on these findings, we propose dopamine receptors may specifically regulate synapsin II expression through a cyclic AMP-dependent pathway. Since synapsin II is involved in neurotransmitter release and synaptogenesis, and changes in synaptic efficacy and structure are suggested in schizophrenia as well as in haloperidol treatment, our findings offer insight into the mechanistic actions of the antipsychotic agent at the synaptic level.
Chong
V Z
VZ
Department of Psychiatry and Behavioural Neurosciences, McMaster University, 1200 Main Street West, Hamilton, HSC 4N78 Ontario, Canada L8N 3Z5.
Skoblenick
K
K
Morin
F
F
Xu
Y
Y
Mishra
R K
RK
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000502:physiology*; D002478:Cells, Cultured; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006220:Haloperidol / Q000494:pharmacology; D007150:Immunohistochemistry; D007700:Kinetics; D008636:Mesencephalon / Q000166:cytology / Q000196:embryology / Q000502:physiology; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000502:physiology; D051381:Rats; D017447:Receptors, Dopamine D1 / Q000502:physiology*; D017448:Receptors, Dopamine D2 / Q000502:physiology*; D016704:Synapsins / Q000378:metabolism*
D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D016704:Synapsins; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D006220:Haloperidol