title: Antidepressant-like effect of 1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-YL)-cyclohexanol, a putative trace amine receptor ligand involves l-arginine-nitric oxide-cyclic guanosine monophosphate pathway.
abstract: 1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-YL)-cyclohexanol is a novel putative trace amine receptor modulator hypothesized to be useful for treatment-resistant depression. In our previous study, we have demonstrated the antidepressant-like effect of this molecule in mouse forced swim and tail suspension tests and shown to act via modulating the levels of norepinephrine, serotonin and dopamine. The present study attempts to explore the involvement of l-arginine-nitric oxide-cyclic guanosine monophosphate pathway in the antidepressant-like effect of 1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-YL)-cyclohexanol in the mouse forced swim test. The antidepressant-like action of 1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-YL)-cyclohexanol (8 mg/kg, i.p) was reversed by pretreatment with L-arginine (750 mg/kg, i.p.), a nitric oxide precursor. In contrast, pretreatment with methylene blue (a soluble guanlyate cyclase inhibitor and nitric oxide synthase (NOS) inhibitor) or 7-nitroindazole (a specific neuronal NOS inhibitor) potentiated the antidepressant-like effect of sub-effective dose of 1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-YL)-cyclohexanol (2mg/kg, i.p.) in this test model. Furthermore, the antidepressant-like effect of this molecule (8 mg/kg, i.p.) was reversed by sildenafil (5mg/kg, i.p.), a phosphodiesterase inhibitor. In conclusion, the antidepressant-like action of 1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-YL)-cyclohexanol involved L-arginine-nitric oxide-cyclic guanosine monophospate signaling pathway.
authors.affiliation: Department of Neurology, University of California Davis Medical Center, Sacramento, CA 95816, USA.
authors.forename: Ashish
authors.initials: A
authors.lastname: Dhir
authors.forename: S K
authors.initials: SK
authors.lastname: Kulkarni
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001120:Arginine / Q000494:pharmacology / Q000502:physiology*; D001679:Biogenic Amines / Q000502:physiology*; D001923:Brain Chemistry / Q000187:drug effects; D006152:Cyclic GMP / Q000502:physiology*; D003511:Cyclohexanols / Q000494:pharmacology*; D003863:Depression / Q000188:drug therapy / Q000523:psychology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D007191:Indazoles / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D008751:Methylene Blue / Q000494:pharmacology; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D018377:Neurotransmitter Agents / Q000378:metabolism; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology; D013550:Swimming / Q000523:psychology
chemical_list: C569238:1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)cyclohexanol; D000928:Antidepressive Agents; D001679:Biogenic Amines; D003511:Cyclohexanols; D007191:Indazoles; D007546:Isoquinolines; D018377:Neurotransmitter Agents; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D009569:Nitric Oxide; D001120:Arginine; D000068677:Sildenafil Citrate; D019001:Nitric Oxide Synthase; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D008751:Methylene Blue; C080122:7-nitroindazole