title: Modulation of the antidepressant-like effects of sustained administration of carisbamate and lamotrigine on monoaminergic systems: electrophysiological studies in the rat brain.
abstract: Carisbamate and lamotrigine are anticonvulsants that act on neuronal voltage-gated sodium channels. Carisbamate has shown antidepressant-like effects in animal models of depression, and lamotrigine is a mood stabilizer with a therapeutic effect in depressive episodes of patients with bipolar disorder. This study examined the effects of carisbamate and lamotrigine on monoaminergic transmission in rodents, which could contribute to their antidepressant action. In vivo electrophysiological recordings were carried out in rats after 2 and 14 days administration of vehicle, carisbamate (60 mg/kg daily), or lamotrigine (25 mg/kg daily). Overall firing activity of the dorsal raphe nucleus (DRN) serotonin (5-HT), locus coeruleus norepinephrine, and ventral tegmental area dopamine (DA) neurons was decreased with carisbamate. Lamotrigine also decreased 5-HT neuronal firing, and this effect was abolished by lesion of the prefrontal cortex. Despite these decreases in firing activity after their prolonged administration, both anticonvulsants exhibited a significant increase in tonic activation of hippocampus 5-HT1A receptors, as shown by a disinhibition of the firing activity of pyramidal neurons in response to the selective antagonist WAY-100635 (N-{2-[4(2-methoxyphenyl)-1-piperazinyl] ethyl}-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride). This finding reveals an increase in the 5-HT level that may be attributed to a desensitization of the terminal 5-HT1B autoreceptors. This study demonstrates that sustained carisbamate and lamotrigine administration decreases 5-HT firing in the DRN but nevertheless enhances 5-HT transmission in the forebrain. This serotonergic effect may be associated with an antiglutamatergic action and may contribute to the antidepressant-like effect of carisbamate in the forced swim test and the antidepressant properties of lamotrigine.
authors.affiliation: University of Ottawa Institute of Mental Health Research (S.S., M.E.M., P.B.) and Department of Cellular and Molecular Medicine, University of Ottawa (S.S., P.B.), Ottawa, Ontario, Canada.
authors.forename: Stacey
authors.initials: S
authors.lastname: Shim
authors.forename: Mostafa
authors.initials: M
authors.lastname: El Mansari
authors.forename: Pierre
authors.initials: P
authors.lastname: Blier
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D015306:Biogenic Monoamines / Q000378:metabolism*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D056654:CA3 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism; D002219:Carbamates / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D000077213:Lamotrigine; D008125:Locus Coeruleus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011903:Raphe Nuclei / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D055366:Synaptic Potentials / Q000187:drug effects; D014227:Triazines / Q000008:administration & dosage / Q000494:pharmacology*; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D015306:Biogenic Monoamines; D002219:Carbamates; C518914:S-2-O-carbamoyl-1-o-chlorophenyl-ethanol; D014227:Triazines; D000077213:Lamotrigine