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

Abstract

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.