Behavioural effects of trishomocubanes in rats with unilateral 6-hydroxydopamine lesions.
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.
van Dijk
Addy
A
Department of Pharmacology, Institute for Biomedical Research, School of Medical Sciences, Bosch Building, University of Sydney, NSW 2006, Australia.
Johnston
Christopher
C
Allbutt
Haydn
H
Kassiou
Michael
M
Henderson
Jasmine
J
D000661:Amphetamine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001952:Bridged-Ring Compounds / Q000737:chemistry / Q000627:therapeutic use*; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D007839:Functional Laterality / Q000187:drug effects; D018782:Maze Learning / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced* / Q000188:drug therapy*; D011187:Posture; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000378:metabolism; D014738:Vibrissae / Q000187:drug effects
D001952:Bridged-Ring Compounds; D015259:Dopamine Agents; D018696:Neuroprotective Agents; D017480:Receptors, sigma; D016627:Oxidopamine; D000661:Amphetamine