Behavioural effects of trishomocubanes in rats with unilateral 6-hydroxydopamine lesions

被引:14
|
作者
van Dijk, Addy [1 ]
Johnston, Christopher [1 ]
Allbutt, Haydn [1 ]
Kassiou, Michael [2 ,3 ,4 ]
Henderson, Jasmine [1 ]
机构
[1] Univ Sydney, Dept Pharmacol, Inst Biomed Res, Sch Med Sci, Sydney, NSW 2006, Australia
[2] Univ Sydney, Discipline Med Radiat Sci, Sydney, NSW 2006, Australia
[3] Univ Sydney, Sch Chem, Sydney, NSW 2006, Australia
[4] Univ Sydney, Brain & Mind Res Inst, ZA-2050 Johannesburg, South Africa
关键词
rat; medial forebrain bundle; sigma receptors; locomotor behaviour; tyrosine hydroxylase; anxiety; sedation;
D O I
10.1016/j.bbr.2008.02.034
中图分类号
B84 [心理学]; C [社会科学总论]; Q98 [人类学];
学科分类号
03 ; 0303 ; 030303 ; 04 ; 0402 ;
摘要
Whilst dopamine replacement improves cardinal features of Parkinson's disease, chronic levodopa administration is associated with dose-related side effects and not all symptoms are ameliorated, necessitating the development of new treatments. Studies of trishomocubanes, a novel group of sigma ligands, have shown enhanced amphetamine-stimulated striatal release of dopamine and a potentially neuroprotective action in vitro and reversal of reserpine-induced catalepsy in vivo. Such effects warrant investigation in animal models of parkinsonism. Our study therefore examines two novel trishomocubane compounds, N-(3'-fluorophenyl)methyl-4-azahexacyclo[5.4.1.0(2.6).0(3.10).0(5.9).0(8.11)]dodecan-3-ol (1) and, N(3'-fluorophenyl)ethyl-4-azahexacyclo[5.4.1.0(2.6).0(3.10).0(5.9).0(8.11)]dodecan-3-ol (2) in the 6-hydroxydopamine (6-OHDA) rat model of Parkinson's disease. A variety of motor behaviours were studied in rats given 6-OHDA lesions. Groups of lesioned rats were given either (1) or (2) or vehicle solution i.p. Acute administration of 3 mg/kg (1) resulted in a decrease in locomotor activity. Twenty-five milligrams per kilogram (2) caused a decrease in locomotor activity at t = 10 and t = 20 min of the locomotor test but this was not found when (2) was co-administered with either apomorphine or amphetamine. The decreased locomotor activity indicates that (1) and (2) may have sedative/anxiolytic effect(s). However, elevated plus maze data failed to demonstrate anxiolysis with (2). Quantification of dopaminergic neurons did not demonstrate any significant difference in the magnitude of cell loss between drug-treated vs. vehicle treated rats so no neuroprotective effect was demonstrated in this model at the doses utilised. (c) 2008 Elsevier B.V. All rights reserved.
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页码:14 / 21
页数:8
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