Effects of mood stabilizers on the inhibition of adenylate cyclase via dopamine D(2)-like receptors.
OBJECTIVE
The mood stabilizing drugs lithium, carbamazepine and valproate modulate brain adenosine monophosphate (cAMP) levels, which are assumed to be elevated in bipolar disorder patients. The aim of this work was to investigate how these three mood stabilizing agents affect the regulation of cAMP levels by dopamine D(2)-like receptors in vitro in rat cortical neurons in culture and in vivo in the rat prefrontal cortex.


METHODS
The production of cAMP was measured in the cultured cortical neurons or in microdialysis samples collected from the prefrontal cortex of freely moving rats using the [8-(3)H] and [(125)I] radioimmunoassay kits.


RESULTS
In vitro and in vivo data showed that the treatment with the mood stabilizing drugs had no effect on basal cAMP levels in vitro, but had differential effects in vivo. Direct stimulation of adenylate cyclase (AC) with forskolin increased cAMP levels both in vitro and in vivo, and this effect was significantly inhibited by all three mood stabilizers. Activation of dopamine D(2)-like receptors with quinpirole partially inhibited forskolin-induced increase in cAMP in untreated cultures, but no effect was observed in cortical neuron cultures treated with the mood stabilizing drugs. Similar results were obtained by chronic treatment with lithium and valproate in the prefrontal cortex in vivo. However, surprisingly, in carbamazepine-treated rats the activation of dopamine D(2)-like receptors enhanced the responsiveness of AC to subsequent activation by forskolin, possibly as a consequence of chronic inhibition of the activity of the enzyme.


CONCLUSIONS
It was shown that each of these drugs affects basal- and forskolin-evoked cAMP levels in a distinct way, resulting in differential responses to dopamine D(2)-like receptors activation.
Montezinho
Liliana P
LP
Department of Biochemistry, NMR Centre, and Centre for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
Mørk
Arne
A
Duarte
Carlos B
CB
Penschuck
Silke
S
Geraldes
Carlos Fgc
CF
Castro
M Margarida Ca
MM
D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D002220:Carbamazepine / Q000008:administration & dosage / Q000494:pharmacology; D005576:Colforsin / Q000008:administration & dosage / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism; D016651:Lithium Carbonate / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D017551:Microdialysis; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D017397:Prefrontal Cortex / Q000166:cytology / Q000378:metabolism; D011619:Psychotropic Drugs / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011863:Radioimmunoassay; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000187:drug effects*; D014635:Valproic Acid / Q000008:administration & dosage / Q000494:pharmacology
D000067956:Adenylyl Cyclase Inhibitors; D011619:Psychotropic Drugs; D017448:Receptors, Dopamine D2; D005576:Colforsin; D016651:Lithium Carbonate; D002220:Carbamazepine; D014635:Valproic Acid; D000242:Cyclic AMP