Anxiolytic- and antidepressant-like effects of the methadone metabolite 2-ethyl-5-methyl-3,3-diphenyl-1-pyrroline (EMDP)

NEUROPHARMACOLOGY

卷:101

Article

Forcelli, Patrick A.¹  Turner, Jill R.²  Lee, Bridgin G.²  Olson, Thao T.¹  Xie, Teresa¹  Xiao, Yingxian¹  Blendy, Julie A.²  Kellar, Kenneth J.¹ 

[1] Georgetown Univ, Dept Physiol & Pharmacol, Washington, DC 20057 USA

[2] Univ Penn, Dept Pharmacol, Perelman Sch Med, Philadelphia, PA 19104 USA

关键词: Anxiety;    Depression;    Nicotinic acetylcholine receptor;    Behavior;    Rodent;    Opiate;   

DOI  :  10.1016/j.neuropharm.2015.09.012

来源: Elsevier

【 摘 要 】

The enhancement of GABAergic and monoaminergic neurotransmission has been the mainstay of pharmacotherapy and the focus of drug-discovery for anxiety and depressive disorders for several decades. However, the significant limitations of drugs used for these disorders underscores the need for novel therapeutic targets. Neuronal nicotinic acetylcholine receptors (nAChRs) may represent one such target. For example, mecamylamine, a non-competitive antagonist of nAChRs, displays positive effects in preclinical tests for anxiolytic and antidepressant activity in rodents. In addition, nicotine elicits similar effects in rodent models, possibly by receptor desensitization. Previous studies (Xiao et al., 2001) have identified two metabolites of methadone, EMDP (2-ethyl-5-methyl-3,3-diphenyl-1-pyrroline) and EDDP (2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine), which are considered to be inactive at opiate receptors, as relatively potent noncompetitive channel blockers of rat alpha 3 beta 4 nAChRs. Here, we show that these compounds are likewise highly effective blockers of human (alpha 3 beta 4 and alpha 4 beta 2 nAChRs. Moreover, we show that they display relatively low affinity for opiate binding sites labeled by [H-3]-naloxone. We then evaluated these compounds in rats and mice in preclinical behavioral models predictive of potential anxiolytic and antidepressant efficacy. We found that EMDP, but not EDDP, displayed robust effects predictive of anxiolytic and antidepressant efficacy without significant effects on locomotor activity. Moreover, EMDP at behaviorally active doses, unlike mecamylamine, did not produce eyelid ptosis, suggesting it may produce fewer autonomic side effects than mecamylamine. Thus, the methadone metabolite EMDP may represent a novel therapeutic avenue for the treatment of some affective disorders. (C) 2015 Elsevier Ltd. All rights reserved.

【 授权许可】

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