title: Lu AA21004, a novel multimodal antidepressant, produces regionally selective increases of multiple neurotransmitters--a rat microdialysis and electrophysiology study.
abstract: The monoaminergic network, including serotonin (5-HT), norepinephrine (NE), and dopamine (DA) pathways, is highly interconnected and has a well-established role in mood disorders. Preclinical research suggests that 5-HT receptor subtypes, including 5-HT1A, 5-HT1B, 5-HT3, and 5-HT7 receptors as well as the 5-HT transporter (SERT), may have important roles in treating depression. This study evaluated the neuropharmacological profile of Lu AA21004, a novel multimodal antidepressant combining 5-HT3 and 5-HT7 receptor antagonism, 5-HT1B receptor partial agonism, 5-HT1A receptor agonism, and SERT inhibition in recombinant cell lines. Extracellular 5-HT, NE and DA levels were evaluated in the ventral hippocampus (vHC), medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) after acute and subchronic treatment with Lu AA21004 or escitalopram. The acute effects of LuAA21004 on NE and DA neuronal firing were also evaluated in the locus coeruleus (LC) and ventral tegmental area (VTA), respectively. Acute Lu AA21004 dose-dependently increased 5-HT in the vHC, mPFC and NAc. Maximal 5-HT levels in the vHC were higher than those in the mPFC. Furthermore, mPFC 5-HT levels were increased at low SERT occupancy levels. In the vHC and mPFC, but not the NAc, high Lu AA21004 doses increased NE and DA levels. Lu AA21004 slightly decreased LC NE neuronal firing and had no effect on VTA DA firing. Results are discussed in context of occupancy at 5-HT3, 5-HT1B and 5-HT1A receptors and SERT. In conclusion, Lu AA21004, acting via two pharmacological modalities, 5-HT receptor modulation and SERT inhibition, results in a brain region-dependent increase of multiple neurotransmitter concentrations.
authors.affiliation: Lundbeck Research USA, 215 College Rd, Paramus, NJ 07652, USA.
authors.forename: Alan L
authors.initials: AL
authors.lastname: Pehrson
authors.forename: Thomas
authors.initials: T
authors.lastname: Cremers
authors.forename: Cecile
authors.initials: C
authors.lastname: Bétry
authors.forename: Marieke G C
authors.initials: MG
authors.lastname: van der Hart
authors.forename: Laerke
authors.initials: L
authors.lastname: Jørgensen
authors.forename: Mathias
authors.initials: M
authors.lastname: Madsen
authors.forename: Nasser
authors.initials: N
authors.lastname: Haddjeri
authors.forename: Bjarke
authors.initials: B
authors.lastname: Ebert
authors.forename: Connie
authors.initials: C
authors.lastname: Sanchez
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D015306:Biogenic Monoamines / Q000378:metabolism; D015283:Citalopram / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008125:Locus Coeruleus / Q000187:drug effects / Q000502:physiology; D008297:Male; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D044302:Receptor, Serotonin, 5-HT1B / Q000378:metabolism; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013440:Sulfides / Q000494:pharmacology*; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000502:physiology; D000078784:Vortioxetine
chemical_list: D000928:Antidepressive Agents; D015306:Biogenic Monoamines; D015283:Citalopram; D018377:Neurotransmitter Agents; D010879:Piperazines; D044282:Receptor, Serotonin, 5-HT1A; D044302:Receptor, Serotonin, 5-HT1B; D044406:Receptors, Serotonin, 5-HT3; D017367:Selective Serotonin Reuptake Inhibitors; D013440:Sulfides; D000078784:Vortioxetine