Lamotrigine induced selective changes in 5-HT(1A) receptor mediated response in rat brain.
A new anticonvulsant drug lamotrigine (LTG) has recently been reported to be effective in treating patients with bipolar affective disorder, depression and schizoaffective disorder, suggesting that it is a mood stabilizer. However, the mechanism of action underlying its efficacy in mood disorders is not understood. This study examined the in vivo effect of LTG on 5-HT(1A) receptor-mediated adenylyl cyclase (AC) response in regions of rat brain, as this pathway has been implicated in the therapeutic action of various classes of mood stabilizers. The density of 5-HT(1A) receptors was measured by radioligand binding assay using [(3)H]8-OH-DPAT (0.05-0.8nM) in frontal cortex and hippocampus of rats treated orally with LTG (5mg/kg) for 7 days. AC activity was assayed using [(3)H]ATP. The oral administration of LTG significantly decreased the density of cortical (50%, P<0.001) but not hippocampal 5-HT(1A) receptors, without significant change in the affinity of [(3)H]8-OH-DPAT to 5-HT(1A) receptor in these regions. There was no significant alteration in basal or forskolin-stimulated AC activity in either of regions. However, a significant decrease (P<0.01) in the inhibition of forskolin-stimulated AC activity by 8-OH-DPAT was observed only in cortical membranes of LTG treated rats when compared to control. These results suggest that one mode of action of LTG may be by the downregulation of cortical 5-HT(1A) receptor-mediated AC response.
Vinod
K Y
KY
Department of Neurochemistry, National Institute of Mental Health and Neurosciences, P.B. No. 2900, Bangalore-560029, India.
Subhash
M N
MN
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D000928:Antidepressive Agents / Q000494:pharmacology*; D018692:Antimanic Agents / Q000494:pharmacology*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D015536:Down-Regulation / Q000187:drug effects*; D005625:Frontal Lobe / Q000187:drug effects* / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D000077213:Lamotrigine; D008297:Male; D009419:Nerve Tissue Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D009928:Organ Specificity; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics; D044263:Receptors, Serotonin, 5-HT1; D015290:Second Messenger Systems / Q000187:drug effects*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D014227:Triazines / Q000494:pharmacology*
D000067956:Adenylyl Cyclase Inhibitors; D000927:Anticonvulsants; D000928:Antidepressive Agents; D018692:Antimanic Agents; D009419:Nerve Tissue Proteins; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists; D014227:Triazines; D005576:Colforsin; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D000077213:Lamotrigine