Effect of lamotrigine and carbamazepine on corticotropin-releasing factor-associated serotonergic transmission in rat do
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ORIGINAL INVESTIGATION
Effect of lamotrigine and carbamazepine on corticotropin-releasing factor-associated serotonergic transmission in rat dorsal raphe nucleus Shunske Tanahashi & Satoshi Yamamura & Masanori Nakagawa & Eishi Motomura & Motohiro Okada
Received: 20 April 2011 / Accepted: 13 September 2011 / Published online: 27 September 2011 # Springer-Verlag 2011
Abstract Corticotropin-releasing factor (CRF) and serotonin are important transmitters of the pathophysiology of mood disorder. To clarify the mechanisms of action of lamotrigine (LTG) and carbamazepine (CBZ), we determined their effects on serotonin release associated with CRF in rat dorsal raphe nucleus (DRN) and median prefrontal cortex (mPFC) using dual-probe microdialysis. Neither perfusion with CRF1 nor CRF2 antagonists into DRN-affected serotonin release in DRN and mPFC. Perfusion of 10 μM CRF into DRN increased serotonin release in both regions, whereas 0.1 μM CRF decreased and had no effect on serotonin release in DRN and mPFC, respectively. Pre-perfusion with CRF1 antagonist into DRN inhibited 0.1 μM CRF-induced serotonin reduction, whereas pre-perfusion with CRF2 antagonist in DRN inhibited 10 μM CRF-induced serotonin elevation, without affecting 0.1 μM CRF-induced serotonin reduction. LTG perfusion concentration dependently decreased serotonin releases in DRN and mPFC. Therapeutic and supratherapeutic concentrations of CBZ increased and decreased serotonin releases in both regions, respectively. Pre-perfusion with subtherapeutic concentration LTG inhibited CRF1-induced serotonin reduction without affecting CRF2-induced serotonin release, whereas pre-perfusion with therapeutic concentration of LTG inhibited both CRF1- and CRF2-actions. In contrast, both therapeutic and supratherapeutic concentrations of CBZ inhibited CRF2-induced serotonin release without affecting S. Tanahashi : S. Yamamura : M. Nakagawa : E. Motomura : M. Okada (*) Department of Psychiatry, Division of Neuroscience, Graduate School of Medicine, Brain Science and Animal Model Research Center (BSAM), Mie University, 2-174 Edobashi, Tsu, Mie 514-8507, Japan e-mail: [email protected]
CRF1-induced serotonin reduction. Neither LTG nor CBZ affected the CRF-induced cAMP production in cells overexpressing CRF1 and CRF2 receptors. This study demonstrated that inhibition of CRF2-receptor-mediated serotonergic transmission is a mechanism shared by LTG and CBZ, two clinically related compounds, whereas LTG but not CBZ inhibits CRF1-receptor-mediated serotonergic transmission. Therefore, these mechanisms may contribute to the clinical actions of these agents. Keywords CRF . Dorsal raphe nucleus . Lamotrigine . Carbamazepine . Medial prefrontal cortex . Microdialysis . Serotonin
Introduction The drugs carbamazepine (CBZ) and lamotrigine (LTG) have wide-ranging antiepileptic (Marson et al. 2007a, b; Mattson 2002) and mood-stabilizing activities (Yatham et al. 2009). Inhibition of voltage-gated sodium channels is the major mechanism underlying the antiepileptic actions of CB
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