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.