Evaluation of antidepressant activity of 1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-YL)-cyclohexanol, a β-substituted phenylethylamine in mice

• Published in: European neuropsychopharmacology 2011-09, Vol.21 (9), p.705-714
• Main Authors: Dhir, Ashish, Malik, Sneh, Kessar, S.V, Singh, K.N, Kulkarni, S.K
• Format: Article
• Language: English
• Subjects: 1-(7-Methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-cyclohexanol; Animal models of depression; Animals; Antidepressive Agents - chemical synthesis; Antidepressive Agents - pharmacology; Antidepressive Agents - therapeutic use; Antidepressive Agents - toxicity; Antidepressive Agents, Second-Generation - administration & dosage; Antidepressive Agents, Second-Generation - toxicity; Antipsychotic Agents - administration & dosage; Antipsychotic Agents - toxicity; Behavior, Animal; Biogenic Amines - metabolism; Brain - physiology; Cyclohexanols - administration & dosage; Cyclohexanols - pharmacology; Cyclohexanols - therapeutic use; Cyclohexanols - toxicity; Depression - drug therapy; Disease Models, Animal; Hindlimb Suspension; Hypnotics and Sedatives - administration & dosage; Internal Medicine; Isoquinolines - pharmacology; Isoquinolines - therapeutic use; Isoquinolines - toxicity; Male; Mice; Motor Activity; Neurotransmitter Agents - pharmacology; Neurotransmitter Agents - therapeutic use; Neurotransmitter Agents - toxicity; Neurotransmitters; Pentobarbital - administration & dosage; Psychiatry; Reserpine - administration & dosage; Reserpine - toxicity; Sleep; Swimming; Trace amine receptors; Venlafaxine Hydrochloride
• ISSN: 0924-977X; 1873-7862
• DOI: 10.1016/j.euroneuro.2010.12.003

Abstract The β-phenylethylamines are known to act as ligands for the trace amine receptors, a novel family of G-protein-coupled receptors. The trace amines are stored and released along with various neurotransmitter agents such as norepinephrine, serotonin, and dopamine and thus work as neuromodulator or neurotransmitter agents. Trace amines are known to play an important role in the pathophysiology of major depression. In our earlier study, we have demonstrated the synthesis of various β-substituted phenylethylamine molecules hypothesized to be effective in various central nervous system disorders. The present study is an attempt to evaluate one of such molecules, 1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-cyclohexanol, in animal models of depression. Various behavioral paradigms of despair such as forced swim and tail-suspension tests were used to assess the antidepressant-like activity. Further, an alteration in the levels of various neurotransmitters (norepinephrine, serotonin, and dopamine) in the mouse brain following 1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-cyclohexanol administration was evaluated. The molecule (4–16 mg/kg., i.p.) dose-dependently inhibited the immobility period in mouse forced swim test, the effect comparable to venlafaxine. The ED50 values of 1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-cyclohexanol and venlafaxine in mouse forced swim test were found to be 5.27 [4.38–6.35] mg/kg., i.p and 4.66 [3.48–6.25] mg/kg., i.p., respectively. Further, 1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-cyclohexanol at 4–16 mg/kg., i.p. reversed the immobility period in mouse tail-suspension test. Additionally, the molecule at 8 mg/kg., i.p. reversed reserpine-induced behavioral despair in mouse forced swim test. When administered simultaneously, it (4 and 8 mg/kg., i.p) enhanced the antidepressant activity of sub-effective doses of imipramine (2 mg/kg., i.p.) or fluoxetine (2 mg/kg., i.p.) in the mouse forced swim test. Neurochemical analysis revealed that the molecule at 8 mg/kg., i.p. increased the levels of norepinephrine (21% increase) without affecting serotonin in the mouse brain. However, at higher dose (16 mg/kg., i.p.), it increased the levels of norepinephrine (13% increase), serotonin (37% increase), and dopamine (42% increase). The molecule enhanced the locomotor activity in mice only at higher doses. The molecule, unlike venlafaxine, which potentiated barbiturate-induced